Atherosclerosis

Definition

Arteriosclerosis versus atherosclerosis

• Arteriosclerosis: General term for thickening and loss of elasticity of arteries.
• Atherosclerosis: A specific form of arteriosclerosis involving intimal plaques with lipid accumulation.
• Other forms include:
  • Arteriolosclerosis
  • Medial calcific sclerosis of Mönckeberg

Common sites

1. Abdominal aorta
2. Coronary arteries
3. Popliteal arteries
4. Internal carotid arteries
5. Circle of Willis
6. Renal arteries

Risk factors

A. Non-modifiable risk factors

1. Increasing age
   Lesions develop gradually over decades and commonly become clinically apparent in middle or old age.
2. Male sex
   Men are affected earlier than women. Premenopausal women have relative protection; risk rises after menopause.
3. Family history and genetic factors
   Includes familial hypercholesterolemia and inherited predisposition to hypertension, diabetes, or dyslipidaemia.

B. Major modifiable risk factors

1. Hyperlipidaemia, particularly increased LDL cholesterol
2. Hypertension
3. Cigarette smoking
4. Diabetes mellitus
5. Inflammation, including chronic inflammatory diseases

C. Additional or emerging factors

• Obesity and sedentary lifestyle
• Diet rich in saturated fat and trans-fat
• Low HDL cholesterol
• Hypertriglyceridaemia
• Elevated lipoprotein(a)
• Metabolic syndrome
• Hyperhomocysteinaemia
• Chronic kidney disease
• Psychological stress

Pathogenesis: response-to-injury hypothesis

Sequence of events

1. Endothelial dysfunction or injury

• Hyperlipidaemia
• Hypertension
• Smoking
• Diabetes
• Turbulent blood flow
• Inflammatory mediators

• Increased permeability to lipoproteins
• Increased leukocyte and platelet adhesion
• Reduced nitric oxide production
• Pro-inflammatory and pro-thrombotic activity

2. Accumulation and modification of LDL in intima

• Is toxic to endothelial cells and smooth muscle cells
• Attracts monocytes
• Promotes inflammation
• Is readily ingested by macrophages

3. Monocyte adhesion and foam-cell formation

• Monocytes adhere to endothelial cells via adhesion molecules.
• They migrate into the intima and become macrophages.
• Macrophages engulf oxidized LDL through scavenger receptors.
• Lipid-laden macrophages are called foam cells.

4. Platelet activation and cytokine release

• PDGF
• FGF
• TGF-β
• IL-1
• TNF

5. Smooth-muscle-cell migration and proliferation

• Collagen
• Elastin
• Proteoglycans

6. Formation of fibrofatty plaque

• Central lipid-rich necrotic core
• Fibrous cap overlying the core
• Inflammatory cells, especially macrophages and T cells
• Calcification in advanced lesions
• Neovascularization from the vasa vasorum

Morphology

1. Fatty streak

• Earliest lesion of atherosclerosis
• Appears as flat, yellow streaks in the intima
• Composed mainly of foam cells
• Begins in childhood and may progress or regress
• Does not significantly obstruct blood flow

2. Atheromatous or fibrofatty plaque

3. Complicated plaque

• Calcification
• Ulceration or erosion
• Rupture of fibrous cap
• Intraplaque hemorrhage
• Superimposed thrombosis
• Atheroembolism
• Aneurysm formation due to weakening of the arterial media

Stable and vulnerable plaques

Clinical consequences and complications

1. Progressive luminal narrowing

• Coronary artery narrowing → stable angina, chronic ischemic heart disease
• Carotid artery narrowing → transient ischemic attacks
• Peripheral arterial narrowing → intermittent claudication
• Renal artery narrowing → renovascular hypertension
• Mesenteric artery narrowing → intestinal angina

2. Acute plaque rupture, erosion, or ulceration

• Acute myocardial infarction
• Unstable angina
• Sudden cardiac death
• Ischaemic stroke
• Acute limb ischemia

3. Thrombosis

4. Atheroembolism

5. Aneurysm formation

• Aortic aneurysm
• Mural thrombosis
• Rupture
• Embolization

Prevention and management principles

1. Stop smoking.
2. Maintain healthy body weight and regular physical activity.
3. Consume a diet low in saturated fat and trans-fat, with fruits, vegetables, whole grains, and unsaturated fats.
4. Control hypertension.
5. Control diabetes mellitus.
6. Reduce LDL cholesterol with lifestyle measures and lipid-lowering therapy, especially statins when indicated.
7. Use antiplatelet therapy only when clinically indicated, particularly in established atherosclerotic cardiovascular disease.
8. Screen and manage high-risk individuals, including those with diabetes, familial hypercholesterolaemia, or established cardiovascular disease.

Conclusion

Atherosclerosis: Long Essay

Definition

Arteriosclerosis is a general term for thickened and stiff arteries.
Atherosclerosis is the specific form in which lipid-rich plaques form in the arterial intima.

Sites commonly affected

1. Abdominal aorta
2. Coronary arteries
3. Popliteal arteries
4. Internal carotid arteries
5. Circle of Willis and cerebral arteries
6. Renal arteries
7. Mesenteric arteries

Causes and Etiology

Important causal mechanisms

• Endothelial dysfunction or injury
• Accumulation of LDL cholesterol in arterial intima
• Oxidation and modification of LDL
• Inflammatory-cell recruitment
• Macrophage foam-cell formation
• Smooth-muscle-cell migration and collagen deposition
• Plaque growth, rupture, thrombosis, and embolization

Risk Factors

A. Non-modifiable risk factors

B. Major modifiable risk factors

1. Hyperlipidaemia, especially raised LDL cholesterol
2. Hypertension
3. Cigarette smoking and tobacco exposure
4. Diabetes mellitus
5. Chronic inflammation

C. Additional factors

• Obesity and central adiposity
• Physical inactivity
• Diet high in saturated fats, trans fats, refined carbohydrate, and salt
• Low HDL cholesterol
• Raised triglycerides
• Elevated lipoprotein(a)
• Metabolic syndrome
• Chronic kidney disease
• Excess alcohol intake
• Psychosocial stress
• Sleep disorders, including obstructive sleep apnoea

Pathogenesis

Response-to-injury hypothesis

Flow diagram of atherogenesis

Risk factors
  ↓
Hyperlipidaemia, hypertension, diabetes, smoking, turbulent blood flow
  ↓
Endothelial dysfunction / injury
  ↓
↑ Permeability to LDL + ↑ leukocyte adhesion + ↓ nitric oxide
  ↓
LDL enters arterial intima
  ↓
LDL oxidation / modification
  ↓
Monocyte adhesion → migration into intima → macrophage formation
  ↓
Macrophages engulf oxidized LDL
  ↓
Foam cells form
  ↓
Fatty streak
  ↓
Smooth-muscle-cell migration and proliferation
  ↓
Collagen and extracellular-matrix deposition
  ↓
Fibrofatty atherosclerotic plaque
  ↓
Stable plaque                 Vulnerable plaque
(chronic stenosis)            (rupture/erosion)
   ↓                                ↓
Chronic ischaemia             Thrombosis / embolism

Steps in detail

1. Endothelial dysfunction

• Increased endothelial permeability to lipoproteins
• Increased expression of leukocyte adhesion molecules
• Reduced nitric oxide production
• Increased vasoconstriction
• Pro-inflammatory and pro-thrombotic state

2. LDL accumulation and oxidation

• Is toxic to endothelial cells
• Attracts monocytes
• Promotes cytokine release
• Is easily ingested by macrophages
• Promotes foam-cell formation

3. Monocyte migration and foam-cell formation

4. Inflammation

5. Smooth-muscle-cell migration and extracellular matrix formation

• Collagen
• Elastin
• Proteoglycans
• Other extracellular-matrix components

6. Mature plaque and its complications

              Arterial lumen
                   ↓
       ┌──────────────────────┐
       │ Fibrous cap          │
       │ Collagen + smooth    │
       │ muscle cells         │
       ├──────────────────────┤
       │ Macrophages /        │
       │ inflammatory cells   │
       ├──────────────────────┤
       │ Lipid-rich necrotic  │
       │ core: cholesterol,   │
       │ foam cells, debris   │
       └──────────────────────┘
              Arterial media

Morphology

1. Fatty streak

• Earliest lesion
• Flat, yellow streaks in intima
• Mainly composed of macrophage foam cells
• Begins in childhood or adolescence
• Usually does not obstruct blood flow

2. Fibrofatty or atheromatous plaque

• Raised intimal lesion
• Yellow-white in appearance
• Has a fibrous cap and lipid-rich necrotic core
• Progressively narrows arterial lumen
• May calcify

3. Complicated plaque

• Calcification
• Plaque ulceration
• Plaque erosion
• Rupture of fibrous cap
• Intraplaque haemorrhage
• Superimposed thrombosis
• Cholesterol embolization
• Aneurysm formation

Stable and Vulnerable Plaques

Clinical Features and Complications

Major mechanisms of complications

Atherosclerotic plaque
       ↓
1. Progressive stenosis → chronic ischaemia
2. Plaque rupture/erosion → thrombosis → acute occlusion
3. Plaque debris → cholesterol emboli
4. Medial weakening → aneurysm and rupture

Investigations

1. Clinical evaluation

History

• Exertional chest pain, dyspnoea, palpitations
• Transient weakness, facial deviation, speech difficulty, visual loss
• Calf pain on walking, rest pain, cold feet, non-healing ulcers
• Postprandial abdominal pain and weight loss
• Smoking, dietary habits, physical activity
• Diabetes, hypertension, kidney disease
• Family history of premature cardiovascular disease

Examination

• Blood pressure in both arms
• Body mass index and waist circumference
• Carotid, abdominal, and femoral bruits
• Peripheral pulse status
• Cool limbs, trophic skin changes, ulcers, gangrene
• Cardiac signs of ischaemic heart disease or heart failure

2. Laboratory investigations

3. Non-invasive vascular tests

4. Invasive tests

Conventional catheter angiography

• Defines arterial anatomy and stenosis
• Often performed when intervention is likely
• Allows angioplasty and stent placement in the same setting
• Has risks including bleeding, contrast nephropathy, embolization, and vascular injury

Intravascular ultrasound and optical coherence tomography

Diagnosis

Risk-factor assessment
        +
Symptoms and physical signs
        +
Evidence of plaque, stenosis, ischaemia, or infarction on imaging/tests
        =
Clinical diagnosis of atherosclerotic cardiovascular disease

Diagnostic examples

Prevention

Primordial prevention

• Healthy food habits from childhood
• Regular physical activity
• Avoiding tobacco and vaping
• Maintaining normal weight
• Limiting alcohol
• Adequate sleep and stress control

Primary prevention

1. Assess cardiovascular risk.
2. Control blood pressure.
3. Detect and treat diabetes.
4. Treat dyslipidaemia according to overall cardiovascular risk.
5. Encourage a heart-healthy diet.
6. Advise physical activity.
7. Stop smoking.
8. Use statins when overall risk and LDL level justify treatment.

Secondary prevention

• High-intensity statin or maximally tolerated statin
• Strict blood-pressure control
• Diabetes management
• Smoking cessation
• Antiplatelet therapy where clinically indicated
• Cardiac rehabilitation or supervised exercise where appropriate
• Regular follow-up and medication adherence

Treatment

A. Lifestyle management

Diet

• Vegetables, fruits, whole grains, legumes, nuts
• Fish and unsaturated fats
• Reduced saturated fat and trans-fat
• Reduced processed meat, added sugar, and refined carbohydrates
• Salt restriction, especially in hypertension
• Appropriate calorie intake for weight reduction if overweight

Physical activity

• Regular aerobic activity plus resistance training
• Individualize exercise for age, symptoms, and cardiac status
• Supervised exercise therapy is useful in symptomatic peripheral arterial disease

Tobacco cessation

• Strongly advise complete cessation
• Use counselling, nicotine replacement, varenicline, or bupropion where appropriate
• Avoid second-hand smoke

B. Control of associated risk factors

C. Lipid-lowering treatment

1. Statins

• Lower LDL cholesterol
• Improve endothelial function
• Reduce vascular inflammation
• Stabilize plaques
• Reduce myocardial infarction, stroke, and cardiovascular death

• Atorvastatin 40-80 mg/day
• Rosuvastatin 20-40 mg/day

2. Add-on treatment

• Ezetimibe
• PCSK9 inhibitors
• Other specialist-directed lipid-lowering treatments

D. Antiplatelet treatment

• Low-dose aspirin is commonly used for secondary prevention if not contraindicated.
• Clopidogrel is an alternative when aspirin cannot be used.
• Dual antiplatelet therapy is used for a defined period after acute coronary syndrome or coronary stenting under specialist guidance.

Antiplatelet drugs should not be self-started for everyone with risk factors because bleeding risk must be considered.

E. Symptom-directed treatment

Coronary artery disease

• Beta-blockers
• Calcium-channel blockers
• Nitrates
• Other antianginal medicines as appropriate
• Revascularization for selected patients

Peripheral arterial disease

• Supervised exercise programme
• Antiplatelet therapy where indicated
• Statin treatment
• Wound and foot care in diabetes
• Revascularization for severe claudication not responding to medical therapy or for critical limb ischaemia

F. Revascularization

• Percutaneous coronary intervention with balloon angioplasty and stent
• Coronary artery bypass grafting
• Carotid endarterectomy
• Carotid stenting in selected cases
• Peripheral angioplasty/stenting
• Surgical bypass grafting

Ayurvedic Perspective

Important note

• Dhamani Pratichaya
• Medoroga / Medovriddhi
• Srotorodha
• Kaphaja Hridroga
• In advanced disease, possible involvement of Vata due to obstruction, often discussed as Avarana of Vata

1. Dhamani Pratichaya

2. Samprapti: Ayurvedic pathogenesis

Nidana: causative factors

• Excessive guru, snigdha, madhura, and abhishyandi ahara
• Excess intake of fried food, heavy food, excess dairy, sweets, and processed foods
• Sedentary lifestyle, day sleep, and lack of exercise
• Overeating and frequent eating before digestion of the previous meal
• Mental stress, anger, worry, and disturbed sleep
• Hereditary predisposition
• Ageing and impaired metabolic capacity

Samprapti diagram

Kapha-Meda aggravating ahara and vihara
   + sedentary lifestyle + day sleep + stress
                     ↓
                 Agnimandya
           (impaired metabolism)
                     ↓
       Ama formation + Meda dushti / Medovriddhi
                     ↓
     Abaddha Medas and altered lipid metabolism
                     ↓
   Srotorodha / Dhamani Pratichaya
   (obstruction and thickening of channels)
                     ↓
    Vata avarana and impaired circulation
                     ↓
 Hridroga / dhamani-related manifestations
      comparable to atherosclerotic disease

3. Dosha and dushya involvement

4. Ayurvedic preventive principles

Ahara

• Avoid excess fried, oily, heavy, sweet, and processed foods.
• Avoid overeating and irregular food timing.
• Prefer vegetables, legumes, whole grains, fruit, and fibre-rich meals.
• Limit excess salt, sugar, alcohol, and tobacco.
• Use an individualized dietary plan based on comorbidities, body constitution, and modern nutrition advice.

Vihara

• Daily physical activity appropriate to capacity
• Avoid day sleep, especially after heavy meals
• Maintain proper sleep routine
• Weight management
• Stress reduction through breathing practices, yoga, mindfulness, or meditation
• Avoid tobacco in all forms

Dinacharya and Ritucharya

5. Ayurvedic management concepts

• Nidana parivarjana: removal of causative diet and lifestyle factors
• Langhana: lightening measures where appropriate
• Deepana and Pachana: measures aimed at improving digestive/metabolic function
• Lekhana: conceptual approach to reduction of excessive Meda/Kapha
• Medohara ahara-vihara
• Shodhana, including selected Panchakarma approaches, only after individual assessment

Herbs and formulations

• Guggulu preparations
• Arjuna
• Garlic
• Turmeric/curcumin
• Triphala
• Pushkarmoola-based formulations

Integrative Conclusion

Evidence-based cardiovascular diagnosis and treatment
                  +
Diet, exercise, weight control, tobacco cessation
                  +
Stress management and safe individualized Ayurvedic lifestyle measures
                  =
Better long-term prevention and adherence

Dyslipidemia: Long Essay

Definition

• Raised total cholesterol
• Raised low-density lipoprotein cholesterol, LDL-C
• Raised triglycerides
• Reduced high-density lipoprotein cholesterol, HDL-C
• Raised non-HDL cholesterol, apolipoprotein B, or lipoprotein(a)

Normal Lipoprotein Transport

Diagram: Lipoprotein pathway

Dietary fat
    ↓
Intestine
    ↓
Chylomicrons ──→ triglycerides delivered to muscle and adipose tissue
    ↓ remnants
Liver
    ↓
VLDL ──→ IDL ──→ LDL
                    ↓
       LDL enters arterial wall
                    ↓
      Oxidation + inflammation
                    ↓
        Atherosclerotic plaque

HDL ──→ removes cholesterol from tissues/artery wall
          ↓
        Liver → bile excretion

Classification

1. Primary dyslipidemia

• Familial hypercholesterolaemia
• Familial combined hyperlipidaemia
• Familial hypertriglyceridaemia
• Familial chylomicronaemia syndrome
• Elevated inherited lipoprotein(a)

2. Secondary dyslipidemia

Causes

A. Dietary and lifestyle causes

• Diet high in saturated fats, trans fats, refined carbohydrates, and excess calories
• Obesity, particularly central obesity
• Sedentary lifestyle
• Excess alcohol, especially with high triglycerides
• Smoking
• Poorly controlled diabetes
• Metabolic syndrome

B. Endocrine and metabolic conditions

• Diabetes mellitus and insulin resistance
• Hypothyroidism
• Cushing syndrome
• Polycystic ovarian syndrome
• Obesity
• Pregnancy

C. Renal and hepatic disorders

• Chronic kidney disease
• Nephrotic syndrome
• Cholestatic liver disease
• Non-alcoholic fatty liver disease

D. Drugs causing dyslipidemia

• Thiazide diuretics
• Some beta-blockers
• Corticosteroids
• Oral oestrogens
• Retinoids
• Protease inhibitors
• Cyclosporine and tacrolimus
• Certain antipsychotics
• Immunosuppressive drugs

E. Genetic causes

• Familial hypercholesterolaemia
• Familial combined hyperlipidaemia
• ApoB defects
• LDL receptor defects
• Lipoprotein lipase deficiency
• ApoC-II deficiency

Pathogenesis

Pathogenesis of raised LDL cholesterol

Genetic tendency / unhealthy diet / diabetes / hypothyroidism
                         ↓
       ↑ LDL production or ↓ LDL receptor clearance
                         ↓
             Increased circulating LDL-C
                         ↓
       LDL enters and is retained in arterial intima
                         ↓
            LDL oxidation and modification
                         ↓
Monocyte recruitment → macrophages → foam cells
                         ↓
               Fatty streak formation
                         ↓
 Smooth-muscle-cell migration + collagen deposition
                         ↓
        Fibrofatty atherosclerotic plaque
                         ↓
  Stenosis / plaque rupture / thrombosis / embolism
                         ↓
       MI, stroke, peripheral arterial disease

Pathogenesis of hypertriglyceridaemia

Obesity / diabetes / alcohol / high refined-carbohydrate diet
                          ↓
              ↑ Hepatic VLDL production
                          +
               ↓ Lipoprotein lipase activity
                          ↓
     Reduced clearance of triglyceride-rich particles
                          ↓
                Hypertriglyceridaemia
                          ↓
        Atherogenic remnant particles and low HDL
                          ↓
      Atherosclerotic cardiovascular disease risk

Very severe triglyceride elevation
                          ↓
 Pancreatic lipase releases free fatty acids in pancreas
                          ↓
       Pancreatic inflammation → acute pancreatitis

Risk Factors

Non-modifiable factors

• Increasing age
• Male sex
• Family history of premature cardiovascular disease
• Genetic dyslipidemia
• Familial hypercholesterolaemia
• Raised lipoprotein(a)

Modifiable factors

• Unhealthy diet
• Obesity
• Physical inactivity
• Smoking
• Diabetes mellitus
• Hypertension
• Excess alcohol
• Hypothyroidism
• Chronic kidney disease
• Drug-induced dyslipidemia

Features suggesting familial hypercholesterolaemia

• Very high LDL-C from a young age
• Tendon xanthomas, especially Achilles tendon
• Xanthelasma at a young age
• Corneal arcus at a young age
• Premature coronary artery disease in patient or first-degree relative
• Family history of markedly elevated cholesterol

Clinical Features

• Xanthelasma
• Tendon xanthomas
• Tuberous xanthomas
• Corneal arcus in young persons
• Lipemia retinalis in severe hypertriglyceridaemia
• Obesity and acanthosis nigricans in insulin resistance

• Angina or myocardial infarction
• Transient ischaemic attack or stroke
• Intermittent claudication
• Aortic stenosis in familial hypercholesterolaemia
• Acute pancreatitis in very severe hypertriglyceridaemia

Investigations

1. Lipid profile

• Total cholesterol
• LDL-C
• HDL-C
• Triglycerides
• Non-HDL cholesterol

Common interpretation

2. Investigation for secondary causes

3. Further tests in selected patients

• ApoB
• Lipoprotein(a)
• Genetic testing for familial hypercholesterolaemia
• ECG, stress testing, echocardiography, or coronary imaging if cardiovascular disease is suspected
• Coronary artery calcium score in selected individuals when treatment decisions are uncertain

Diagnosis

Diagnostic approach

Abnormal lipid profile
        ↓
Repeat / confirm if needed
        ↓
Assess cardiovascular risk:
Age, BP, diabetes, smoking, CKD, family history, ASCVD
        ↓
Exclude secondary causes
        ↓
Classify:
Primary genetic / secondary acquired / mixed dyslipidemia
        ↓
Choose lifestyle and drug treatment according to risk

Important practical patterns

Prevention

Primordial prevention

• Encourage healthy eating from childhood.
• Avoid tobacco use.
• Promote regular exercise.
• Prevent obesity.
• Restrict alcohol.
• Screen individuals with family history of premature cardiovascular disease.

Primary prevention

1. Screen lipid profile according to age, risk factors, and family history.
2. Maintain healthy body weight and waist circumference.
3. Follow a heart-healthy diet.
4. Exercise regularly.
5. Treat diabetes, hypertension, hypothyroidism, kidney disease, and obesity.
6. Avoid smoking and excess alcohol.
7. Use lipid-lowering medicine when cardiovascular risk and lipid values indicate.

Secondary prevention

• Intensive LDL-C lowering
• Statin-based treatment unless contraindicated
• Blood-pressure control
• Diabetes management
• Smoking cessation
• Antiplatelet therapy when indicated
• Supervised cardiac rehabilitation or exercise programme
• Regular follow-up for adherence and lipid response

Treatment

Treatment goals

A. Lifestyle treatment

Dietary measures

• More vegetables, fruit, legumes, nuts, and whole grains
• More fibre-rich foods
• Fish and unsaturated fats
• Reduced saturated fat, trans-fat, processed meat, fried foods, and bakery products
• Lower refined sugar and refined carbohydrate intake, especially when triglycerides are high
• Restriction of alcohol in hypertriglyceridaemia
• Salt restriction if hypertension coexists
• Calorie deficit for overweight or obesity

Physical activity

• Regular aerobic physical activity
• Resistance exercise on appropriate days
• Reduce prolonged sitting
• Individualize for age, cardiac symptoms, and other disease

Weight reduction

• Triglycerides
• Insulin sensitivity
• Blood pressure
• Fatty liver disease
• Overall cardiovascular risk

Tobacco and alcohol

• Stop all tobacco exposure.
• Avoid or strictly limit alcohol, especially in high triglycerides.

B. Pharmacological treatment

1. Statins

• Reduce hepatic cholesterol synthesis
• Increase LDL receptor expression
• Lower LDL-C
• Stabilize atherosclerotic plaques
• Reduce myocardial infarction, stroke, and cardiovascular death

• Atorvastatin 40-80 mg/day
• Rosuvastatin 20-40 mg/day

2. Ezetimibe

3. PCSK9 inhibitors

4. Bempedoic acid and inclisiran

5. Fibrates

6. Prescription omega-3 fatty acids

7. Niacin

C. Management of severe hypertriglyceridaemia

Very high triglycerides
         ↓
Assess for abdominal pain / acute pancreatitis
         ↓
Urgent alcohol cessation
         ↓
Strict reduction in dietary fat and refined carbohydrates
         ↓
Control diabetes and secondary causes
         ↓
Consider triglyceride-lowering therapy under medical supervision
         ↓
Prevent acute pancreatitis

Ayurvedic Perspective

Important clarification

• Medoroga
• Medovriddhi
• Medovaha Srotodushti
• Abaddha Medas
• Ama
• Santarpanottha Vyadhi
• Kapha-Meda predominance

Ayurvedic definition and correlation

Medoroga / Medovriddhi

• Excess or vitiation of Meda dhatu
• Aggravation of Kapha dosha
• Impairment of Agni
• Formation of Ama
• Dysfunction of Medovaha srotas

Abaddha Medas

Ayurvedic Etiological Factors: Nidana

Aharaja nidana

• Excess consumption of sweet, heavy, oily, fried, and unctuous foods
• Excess dairy, bakery foods, refined flour, and sweets
• Repeated overeating
• Eating before digestion of the previous meal
• Excess alcohol
• Improper meal timing

Viharaja nidana

• Sedentary lifestyle
• Daytime sleeping, especially after heavy meals
• Lack of exercise
• Excessive rest
• Poor sleep pattern
• Chronic stress

Other factors

• Hereditary predisposition
• Ageing
• Obesity
• Diabetes-like metabolic disturbances
• Impaired Agni

Ayurvedic Samprapti: Pathogenesis

Kapha-Meda aggravating ahara and vihara
  (heavy, oily, sweet food; inactivity; day sleep)
                      ↓
                 Agnimandya
            impaired digestion/metabolism
                      ↓
                  Ama formation
                      ↓
             Meda dhatu dushti
             / Medovriddhi
                      ↓
       Medovaha srotodushti / srotorodha
                      ↓
      Abaddha Medas in circulation
                      ↓
Kapha predominance + altered Vata movement
                      ↓
  Medoroga and metabolic-cardiovascular risk

Dosha and dushya involved

Ayurvedic Prevention

Nidana parivarjana

• Avoid excessive oily, fried, sweet, heavy, and processed food.
• Avoid frequent overeating.
• Avoid prolonged inactivity.
• Avoid regular day sleep after meals.
• Avoid alcohol excess and tobacco.
• Maintain routine sleep and meal timings.

Ahara

• Light, fibre-rich, plant-based meals
• Vegetables, legumes, whole grains, and fruit
• Controlled portions
• Minimal fried and highly processed foods
• Reduction of excess sugar and fats

Vihara

• Regular exercise suited to ability
• Yoga and walking
• Weight control
• Stress reduction
• Adequate night sleep
• Avoidance of day sleep where clinically appropriate

Ayurvedic Management Principles

1. Nidana parivarjana: avoidance of causative diet and lifestyle factors
2. Langhana: selected lightening measures
3. Deepana and Pachana: approaches intended to improve Agni and address Ama
4. Lekhana: approaches intended to reduce excess Kapha and Meda
5. Medohara ahara-vihara: dietary and lifestyle regulation for Meda imbalance
6. Shodhana/Panchakarma: only if appropriate after individualized assessment by a qualified practitioner

Conclusion

Simple relationship diagram

Dyslipidemia
↑ LDL-C / ↑ triglyceride-rich remnants / ↓ HDL-C
                ↓
LDL retention and oxidation in arterial wall
                ↓
Inflammation + foam cells + fibrous plaque
                ↓
Atherosclerosis
                ↓
Angina / MI / stroke / PAD / aneurysm

Myopathies: Long Essay

Definition

• Neuropathy: nerve disorder, often with sensory loss, reduced reflexes, and distal weakness
• Neuromuscular-junction disorder: fluctuating or fatigable weakness
• Motor neuron disease: weakness with fasciculations, hyperreflexia, or mixed upper and lower motor-neuron signs

Basic clinical pattern

Primary muscle disease
        ↓
Muscle fibre injury / defective energy production / inflammation
        ↓
Weakness ± myalgia ± fatigue ± wasting
        ↓
Usually proximal and symmetrical weakness
        ↓
Difficulty climbing stairs, rising from a chair,
lifting arms, combing hair, or walking uphill

Causes of Myopathy

A. Inherited causes

1. Muscular dystrophies
2. Congenital myopathies
3. Metabolic myopathies
4. Mitochondrial myopathies
5. Channelopathies and periodic paralysis
6. Myotonic disorders

B. Acquired causes

1. Inflammatory or autoimmune myopathies
2. Drug-induced and toxic myopathies
3. Endocrine myopathies
4. Electrolyte-related myopathies
5. Infectious myopathies
6. Critical-illness myopathy
7. Nutritional and deficiency-related myopathies
8. Rhabdomyolysis due to exertion, heat, trauma, drugs, toxins, or metabolic disease

Types of Myopathies

Important Inflammatory Myopathies

1. Dermatomyositis

• Symmetrical proximal muscle weakness
• Characteristic skin rash
• Raised CK in many patients
• Possible dysphagia and interstitial lung disease
• Association with malignancy in adults

Characteristic skin findings

• Heliotrope rash: violet discoloration around eyelids
• Gottron papules: violaceous papules over knuckles
• Photosensitive rash over face, neck, chest, and shoulders
• “Shawl sign” or “V sign”
• Mechanic's hands in overlap/antisynthetase disease

2. Polymyositis

3. Immune-mediated necrotizing myopathy

• Severe proximal weakness
• Markedly elevated CK
• Prominent muscle-fibre necrosis
• Often little inflammatory infiltrate on biopsy
• May be associated with anti-HMGCR or anti-SRP antibodies
• Anti-HMGCR disease can occur after statin exposure

4. Antisynthetase syndrome

• Myositis
• Interstitial lung disease
• Inflammatory arthritis
• Fever
• Mechanic's hands
• Anti-Jo-1 or other antisynthetase antibodies

5. Inclusion-body myositis

• Slowly progressive course
• Often asymmetric weakness
• Quadriceps weakness and finger-flexor weakness
• Falls and dysphagia
• Rimmed vacuoles on biopsy
• Poor response to immunosuppressive treatment

Pathogenesis

General pathogenesis

Genetic defect / autoimmunity / metabolic failure /
drug toxicity / endocrine disorder / infection
                       ↓
Disruption of muscle-fibre structure or energy metabolism
                       ↓
Muscle-fibre dysfunction
                       ↓
Necrosis, inflammation, mitochondrial dysfunction,
or defective regeneration
                       ↓
Weakness ± pain ± elevated CK ± wasting
                       ↓
Functional limitation and complications

A. Pathogenesis of inflammatory myopathy

Genetic susceptibility + environmental trigger
       ± infection / drug exposure / malignancy
                         ↓
                Immune dysregulation
                         ↓
Autoantibodies, T cells, cytokines and complement activation
                         ↓
 Muscle inflammation and/or microvascular injury
                         ↓
 Muscle-fibre necrosis and impaired regeneration
                         ↓
 Proximal weakness, myalgia, fatigue, dysphagia
                         ↓
 Chronic damage → atrophy, fibrosis and fatty replacement

Dermatomyositis

Complement-mediated microvascular injury
                 ↓
Damage to small intramuscular blood vessels
                 ↓
Muscle ischaemia
                 ↓
Perifascicular muscle-fibre atrophy
                 ↓
Proximal weakness + characteristic skin lesions

Polymyositis-like cellular injury

CD8+ cytotoxic T-cell activation
                 ↓
Direct invasion and injury of muscle fibres
                 ↓
Endomysial inflammation
                 ↓
Muscle-fibre necrosis and regeneration
                 ↓
Symmetrical proximal muscle weakness

Inclusion-body myositis

Age-related degenerative protein aggregation
      + chronic inflammatory changes
                 ↓
Rimmed vacuoles and abnormal protein deposits
                 ↓
Progressive quadriceps and finger-flexor weakness
                 ↓
Falls, hand-grip dysfunction and dysphagia

B. Pathogenesis of metabolic myopathy

Inherited enzyme defect
        ↓
Failure of glycogen, lipid, or mitochondrial energy metabolism
        ↓
Inadequate ATP during exercise, fasting, or illness
        ↓
Exercise intolerance, cramps and myalgia
        ↓
Muscle-fibre breakdown
        ↓
Myoglobinuria / rhabdomyolysis in severe episodes

C. Drug-induced myopathy

Drug or toxin exposure
        ↓
Direct myotoxicity / mitochondrial injury /
immune reaction / electrolyte disturbance
        ↓
Muscle-fibre dysfunction or necrosis
        ↓
Myalgia, weakness, raised CK or rhabdomyolysis

Risk Factors

General risk factors

• Family history of muscle disease
• Consanguinity in autosomal-recessive disorders
• Childhood onset of weakness or delayed milestones
• Older age for inclusion-body myositis
• Autoimmune disease
• Malignancy, especially in adult dermatomyositis
• Diabetes, thyroid disease, renal disease, or liver disease
• Alcohol misuse
• Malnutrition and vitamin deficiency
• Severe infection, sepsis, or ICU stay
• Strenuous unaccustomed exercise, heat exposure, or crush injury
• Exposure to myotoxic drugs

Risk factors for drug-induced myopathy

• High drug dose
• Older age and frailty
• Renal or liver impairment
• Hypothyroidism
• Drug interactions
• Combination of statin with certain interacting drugs
• Previous history of drug-related muscle symptoms
• Intensive exercise during treatment

Clinical Features

Symptoms

• Proximal muscle weakness
• Difficulty standing from sitting or floor
• Difficulty climbing stairs
• Difficulty lifting the arms above shoulders
• Difficulty combing hair or lifting objects
• Myalgia and muscle tenderness
• Cramps
• Exercise intolerance
• Fatigue
• Muscle wasting
• Falls
• Dysphagia
• Dyspnoea due to respiratory-muscle weakness
• Dark urine in rhabdomyolysis

Signs

• Symmetrical proximal weakness
• Preserved sensation in most primary myopathies
• Reflexes usually preserved until weakness becomes severe
• Muscle tenderness in inflammatory, infectious, or toxic causes
• Muscle hypertrophy or pseudohypertrophy in some dystrophies
• Contractures in muscular dystrophies
• Rash in dermatomyositis
• Distal finger-flexor and quadriceps weakness in inclusion-body myositis

Investigation

1. History and examination

• Age at onset and speed of progression
• Distribution of weakness: proximal, distal, facial, ocular, axial
• Family history
• Myalgia, cramps, exercise intolerance, dark urine
• Fever, weight loss, rash, arthritis, Raynaud phenomenon
• Dysphagia, aspiration, breathlessness
• Drug history, especially statins, steroids, antimalarials, colchicine, alcohol, and recreational substances
• Thyroid symptoms and diabetes
• Recent infection, trauma, fasting, exertion, heat exposure, or surgery

2. Blood investigations

CK can be normal in some myopathies, especially steroid myopathy, mitochondrial myopathy, some congenital myopathies, and advanced muscle wasting. A normal CK does not exclude myopathy.

3. Electrophysiology

Electromyography and nerve-conduction studies

• Short-duration, low-amplitude motor-unit potentials
• Early recruitment
• Spontaneous activity in inflammatory or necrotizing muscle disease

4. Imaging

Muscle MRI

• Muscle oedema suggesting active inflammation
• Fatty replacement
• Muscle atrophy
• A suitable site for biopsy

5. Muscle biopsy

• Inflammation
• Necrosis and regeneration
• Perifascicular atrophy in dermatomyositis
• Endomysial inflammation in some inflammatory myopathies
• Rimmed vacuoles in inclusion-body myositis
• Storage material in metabolic myopathy
• Mitochondrial abnormalities
• Dystrophic changes in muscular dystrophy

6. Genetic testing

• Muscular dystrophy
• Congenital myopathy
• Mitochondrial disease
• Metabolic myopathy
• Channelopathy

7. Systemic assessment

• ECG and echocardiography for cardiac involvement
• Pulmonary function tests and high-resolution CT for interstitial lung disease
• Swallow assessment for dysphagia and aspiration risk
• Cancer screening in adult dermatomyositis and selected inflammatory myopathies

Diagnosis

Diagnostic flowchart

Patient with muscle weakness / myalgia / high CK
                    ↓
Confirm true weakness and identify distribution
                    ↓
Exclude emergency causes:
rhabdomyolysis, severe hypokalaemia, respiratory weakness
                    ↓
History: drugs, family history, rash, systemic disease,
exercise-induced symptoms, endocrine symptoms
                    ↓
CK + electrolytes + renal function + thyroid tests
                    ↓
EMG/NCS and muscle MRI when indicated
                    ↓
Autoantibodies / genetic testing / muscle biopsy
                    ↓
Classify the myopathy:
Inherited / inflammatory / metabolic / endocrine /
toxic-drug-induced / infectious / critical illness
                    ↓
Cause-specific treatment and rehabilitation

Differential Diagnosis

Prevention

General preventive measures

• Genetic counselling for inherited muscle disorders
• Newborn, family, or carrier screening where available
• Avoid unnecessary exposure to myotoxic drugs
• Review drug interactions, especially with statins
• Correct hypothyroidism, electrolyte disturbances, and vitamin deficiency
• Limit alcohol and avoid illicit drugs
• Gradual exercise conditioning rather than sudden intense exertion
• Adequate hydration during prolonged exertion or heat exposure
• Early management of diabetes, kidney disease, and endocrine disorders
• Vaccination and infection prevention in vulnerable patients
• Physiotherapy, stretching, contracture prevention, and fall prevention

Treatment

General supportive treatment for all myopathies

1. Physiotherapy and graded exercise plan
2. Occupational therapy for activities of daily living
3. Nutrition support and adequate protein/calorie intake
4. Stretching, splints, and contracture prevention
5. Fall prevention and mobility aids when required
6. Management of pain and fatigue
7. Assessment and treatment of dysphagia
8. Respiratory and cardiac monitoring in appropriate disorders
9. Psychological support and genetic counselling

Cause-specific treatment

Emergency warning signs

• Dark or cola-coloured urine
• Severe muscle pain with weakness
• Rapidly progressive weakness
• Difficulty swallowing or choking
• Shortness of breath or weak cough
• Chest pain or palpitations
• Markedly reduced urine output
• Fever with focal muscle pain/swelling
• Severe electrolyte disturbance or suspected rhabdomyolysis

Ayurvedic Perspective

Important clarification

Ayurvedic correlation

Possible Nidana

• Excessive exertion or repetitive strain
• Inadequate nutrition or fasting
• Irregular eating habits
• Trauma
• Excessive exposure to cold and dryness
• Sleep deprivation
• Chronic illness and debility
• Ageing
• Emotional stress
• Vata-aggravating diet and lifestyle
• Metabolic impairment, often described through Agni disturbance and Ama formation

Ayurvedic Samprapti: Conceptual Pathogenesis

Vata-aggravating nidana
(excess exertion, fasting, irregular diet, cold, stress)
                    ↓
Agnimandya and/or dhatu-poshana disturbance
                    ↓
Mamsa dhatu kshaya or mamsa dhatu dushti
                    ↓
Vata prakopa in mamsa and related srotas
                    ↓
Mamsagata Vata / Mamsavrita Vata
                    ↓
Shoola, stambha, kampa, bala-kshaya,
mamsa-kshaya and impaired movement

Pitta-Rakta aggravation + Vata disturbance
                    ↓
Mamsa-Rakta dushti
                    ↓
Inflammatory pain, tenderness and weakness
                    ↓
Chronic disease → Mamsa kshaya and functional loss

Ayurvedic Preventive Principles

Ahara

• Adequate and balanced nutrition
• Avoid prolonged fasting and extreme diets
• Prefer easily digestible, nourishing foods when there is muscle wasting
• Avoid excessive alcohol and tobacco
• Adapt diet to metabolic disease, obesity, diabetes, and kidney disease where present

Vihara

• Avoid sudden overexertion
• Use graduated exercise rather than complete inactivity
• Ensure adequate sleep and recovery
• Maintain regular daily routine
• Use gentle yoga, stretching, and breathing exercises only within functional limits
• Prevent falls and injury

General principles

• Nidana Parivarjana: avoid known aggravating factors
• Attention to Agni and nutrition
• Individualized assessment of Vata, Pitta, Kapha, Ama, Bala, and Mamsa-dhatu status
• Rehabilitation-oriented approach for maintaining function

Ayurvedic Management Principles

1. Brimhana: nourishing approaches in Mamsa-kshaya and debility
2. Snehana: selected internal or external oleation approaches
3. Swedana: selected fomentation where appropriate
4. Basti: sometimes considered in chronic Vata disorders
5. Rasayana: supportive rejuvenative approaches
6. Abhyanga: massage-based supportive care in selected non-acute situations
7. Gentle rehabilitation, sleep regulation, and nutrition support

Safety cautions

• Do not delay medical review for progressive weakness, dysphagia, breathing difficulty, dark urine, or severe pain.
• Do not stop corticosteroids, immunosuppressants, statins, thyroid medicine, or other prescribed therapy without medical advice.
• Massage and vigorous exercise may be unsafe in acute inflammatory myositis, severe weakness, rhabdomyolysis, fractures, severe infection, or severe cardiopulmonary disease.
• Herbal medicines may interact with immunosuppressants, anticoagulants, diabetic medicines, and other drugs.

Conclusion

Comparison Table of Major Myopathies

1. Inflammatory and autoimmune myopathies

2. Inherited, metabolic, endocrine, and toxic myopathies

3. High-yield comparison: Statin myalgia versus statin-associated autoimmune necrotizing myopathy

One-glance pattern recognition diagram

Proximal symmetrical weakness + rash
             ↓
      Dermatomyositis

Proximal severe weakness + very high CK
             ↓
Immune-mediated necrotizing myopathy

Age >50 + quadriceps and finger-flexor weakness
             ↓
Inclusion-body myositis

Childhood onset + calf pseudohypertrophy + progressive weakness
             ↓
Duchenne/Becker muscular dystrophy

Exercise-induced cramps + dark urine after exertion/fasting
             ↓
Metabolic myopathy / rhabdomyolysis

Proximal weakness + endocrine symptoms or steroid exposure
             ↓
Endocrine or steroid myopathy

Core differentiating points

• Dermatomyositis: proximal weakness plus characteristic skin rash.
• IMNM: severe weakness with very high CK and muscle necrosis.
• IBM: older adult, finger-flexor and quadriceps weakness, poor immunotherapy response.
• Muscular dystrophy: inherited, slowly progressive, often childhood onset.
• Metabolic myopathy: exercise, fasting, or illness triggers episodic symptoms.
• Steroid myopathy: painless proximal weakness with often normal CK.
• Statin myopathy: consider drug timing, interactions, hypothyroidism, CK level, and persistent weakness after withdrawal.

Alzheimer’s Disease: Long Essay

Definition

1. Extracellular deposition of amyloid-beta (Aβ) plaques
2. Intracellular neurofibrillary tangles of hyperphosphorylated tau protein
3. Synaptic dysfunction, neuronal loss, brain atrophy, and neuroinflammation

Stages of Alzheimer’s Disease

Normal cognition
      ↓
Preclinical Alzheimer disease
(amyloid/tau pathology may be present without symptoms)
      ↓
Mild cognitive impairment due to AD
(memory decline but basic independence largely maintained)
      ↓
Mild Alzheimer dementia
      ↓
Moderate Alzheimer dementia
      ↓
Severe Alzheimer dementia
(complete dependence, immobility, dysphagia, infections)

1. Mild cognitive impairment due to AD

• Memory impairment greater than expected for age
• Person remains mostly independent in daily activities
• May misplace objects, repeat questions, or forget appointments
• Does not yet meet criteria for dementia

2. Alzheimer dementia

• Mild stage: recent-memory loss, word-finding difficulty, impaired finances and complex tasks
• Moderate stage: disorientation, wandering, agitation, sleep disturbance, impaired self-care
• Severe stage: loss of speech, swallowing difficulty, incontinence, immobility, recurrent infection, total dependence

Causes and Etiology

A. Sporadic late-onset AD

• Ageing
• APOE ε4 genotype
• Vascular disease
• Diabetes mellitus
• Hypertension
• Physical inactivity
• Low educational/cognitive reserve
• Smoking
• Obesity
• Hearing impairment
• Depression and social isolation
• Head injury

B. Early-onset familial AD

• APP gene on chromosome 21
• PSEN1
• PSEN2

C. Down syndrome

Risk Factors

A. Non-modifiable risk factors

B. Potentially modifiable risk factors

• Midlife hypertension
• Diabetes mellitus
• Dyslipidemia and obesity
• Smoking
• Physical inactivity
• Excess alcohol use
• Depression
• Social isolation
• Low cognitive stimulation
• Hearing loss
• Poor sleep and untreated sleep apnoea
• Traumatic brain injury
• Poorly controlled vascular risk factors

Pathogenesis

Main pathogenesis diagram

Ageing + genetic susceptibility + vascular/metabolic risk factors
                              ↓
Abnormal processing of amyloid precursor protein (APP)
                              ↓
Increased amyloid-beta, particularly Aβ42
                              ↓
Extracellular amyloid-beta oligomers and plaques
                              ↓
Synaptic dysfunction + microglial activation + inflammation
                              ↓
Tau hyperphosphorylation
                              ↓
Neurofibrillary tangles inside neurons
                              ↓
Disrupted microtubules and impaired axonal transport
                              ↓
Neuronal dysfunction and neuronal death
                              ↓
Hippocampal and cortical atrophy
                              ↓
Progressive memory loss and dementia

1. Amyloid-beta plaque formation

• Soluble oligomers
• Fibrils
• Extracellular amyloid plaques

2. Tau hyperphosphorylation

Normal tau
     ↓
Abnormal hyperphosphorylation
     ↓
Tau detaches from microtubules
     ↓
Microtubule instability
     ↓
Impaired axonal transport
     ↓
Paired helical filaments
     ↓
Neurofibrillary tangles
     ↓
Neuronal death

3. Neuroinflammation

4. Cholinergic deficiency

5. Brain atrophy

Early disease
Hippocampus + entorhinal cortex affected
               ↓
Recent-memory impairment
               ↓
Temporal and parietal cortex involvement
               ↓
Language and visuospatial impairment
               ↓
Frontal cortex involvement
               ↓
Executive dysfunction, personality and behavioural changes
               ↓
Widespread neuronal loss
               ↓
Severe dementia and complete dependence

Pathology

Gross pathology

• Diffuse cerebral cortical atrophy
• Marked medial temporal and hippocampal atrophy
• Widened sulci
• Narrowed gyri
• Enlarged ventricles due to ex vacuo dilatation

Microscopic pathology

Clinical Features

Cognitive features

1. Recent-memory loss is usually the earliest prominent feature.
2. Repetitive questions or statements
3. Difficulty learning new information
4. Misplacing objects
5. Word-finding difficulty and impaired naming
6. Impaired judgement and planning
7. Visuospatial problems, getting lost in familiar places
8. Difficulty handling money, medications, cooking, or driving
9. Impaired recognition in advanced disease
10. Loss of insight into illness, called anosognosia

Behavioural and psychological symptoms

• Apathy
• Depression
• Anxiety
• Irritability
• Agitation or aggression
• Delusions, especially theft or misidentification delusions
• Hallucinations, less typical early than in Lewy-body dementia
• Wandering
• Sleep-wake disturbance
• Sundowning

Late-stage complications

• Dysphagia and aspiration
• Weight loss and malnutrition
• Pressure ulcers
• Falls and fractures
• Urinary and faecal incontinence
• Immobility and contractures
• Pneumonia and other infections
• Delirium

Investigations

1. History

• Onset and progression of memory impairment
• Difficulty in daily activities
• Repetition of questions
• Safety concerns: driving, cooking, finances, medication errors
• Behavioural symptoms and sleep
• Depression, hallucinations, delusions
• Alcohol and drug use
• Family history of early dementia
• Vascular risk factors
• Head trauma
• Current medicines, especially anticholinergic and sedative drugs

2. Cognitive assessment

3. Functional assessment

• Medication management
• Financial management
• Cooking
• Shopping
• Driving
• Personal hygiene
• Dressing and toileting

Cognitive decline without loss of independence
          ↓
Mild cognitive impairment

Cognitive decline interfering with independent daily function
          ↓
Major neurocognitive disorder / dementia

4. Laboratory investigations

5. Brain imaging

CT or MRI brain

• Subdural hematoma
• Brain tumour
• Normal-pressure hydrocephalus
• Large stroke
• Extensive vascular disease
• Other structural causes

6. Biomarker testing

Diagnosis

Clinical diagnosis of probable Alzheimer disease

1. Insidious onset
2. Gradual progressive decline
3. Objective impairment in memory and at least one additional cognitive domain
4. Decline interfering with independent functioning
5. No better explanation, such as delirium, major depression, stroke, medication effect, or another dementia syndrome

Diagnostic flowchart

Memory complaint or observed cognitive decline
                    ↓
History from patient and caregiver
                    ↓
Cognitive screening + functional assessment
                    ↓
Exclude delirium, depression, medication effects,
thyroid disease, B12 deficiency and metabolic causes
                    ↓
MRI/CT brain to exclude structural causes
                    ↓
Assess vascular and psychiatric comorbidity
                    ↓
Probable Alzheimer clinical syndrome
                    ↓
CSF / amyloid PET / tau biomarkers if diagnostic
uncertainty or disease-modifying treatment is considered

Differential diagnosis

Prevention and Risk Reduction

Preventive measures

1. Control vascular risk factors

• Treat hypertension
• Control diabetes
• Treat dyslipidemia when indicated
• Maintain healthy body weight
• Stop smoking
• Manage atrial fibrillation and stroke risk

2. Regular physical exercise

• Regular aerobic activity
• Strength and balance training
• Avoid prolonged sedentary behaviour

3. Brain-healthy diet

• Vegetables, fruit, legumes, nuts, whole grains
• Fish and unsaturated fats
• Less processed food, saturated fat, refined sugar, and excess salt

4. Cognitive and social activity

• Reading, learning, puzzles, music, and educational activities
• Social interaction
• Community involvement
• Continued intellectual engagement

5. Sleep and hearing

• Treat hearing loss
• Evaluate and treat sleep apnoea
• Maintain regular sleep schedule

6. Avoid head injury and harmful substances

• Use seat belts and helmets
• Prevent falls
• Avoid tobacco
• Limit alcohol
• Avoid unnecessary sedative or anticholinergic medicines

Treatment

Alzheimer management
       ↓
1. Cognitive symptom treatment
2. Disease-modifying therapy in selected early AD
3. Management of behavioural symptoms
4. Family, caregiver and safety support

A. Cognitive symptom treatment

1. Cholinesterase inhibitors

• Nausea
• Vomiting
• Diarrhoea
• Loss of appetite
• Weight loss
• Bradycardia and syncope
• Sleep disturbance

2. Memantine

• Dizziness
• Constipation
• Headache
• Confusion in some patients

B. Anti-amyloid disease-modifying therapy

Lecanemab

• Early-stage AD only
• Confirmation of amyloid pathology by CSF testing or amyloid PET
• MRI before treatment and serial MRI monitoring
• Discussion of APOE ε4 status and risk
• Specialist supervision

Important adverse effect: ARIA

• ARIA-E: brain oedema or effusions
• ARIA-H: microhaemorrhages or superficial siderosis

Anti-amyloid therapy is not a cure and is not suitable for every patient. Eligibility, monitoring, cost, availability, comorbidities, and bleeding risk require specialist assessment.

C. Management of behavioural and psychological symptoms

Non-drug measures first

• Identify pain, infection, constipation, urinary retention, hunger, loneliness, sleep disturbance, or medication side effects
• Provide a predictable routine
• Use calm communication
• Reduce noise and overstimulation
• Ensure adequate lighting and familiar surroundings
• Use reassurance and redirection rather than confrontation
• Maintain caregiver support

Medicines

• SSRIs may be considered for depression or anxiety
• Antipsychotics may be used cautiously for severe dangerous psychosis/agitation
• Antipsychotics have significant risks in dementia, including sedation, falls, stroke, and increased mortality

D. Supportive and safety care

• Advance-care planning
• Driving assessment and advice
• Medication supervision
• Fall prevention
• Home safety modifications
• Wandering prevention
• Nutrition and swallowing assessment
• Legal and financial planning
• Caregiver education, respite care, and support groups
• Physiotherapy and occupational therapy
• Management of urinary incontinence, pressure sores, and aspiration risk in late stages

Ayurvedic Perspective

Important clarification

• Smriti Bhramsha: impairment or loss of memory
• Medha Kshaya: decline in intellect/cognitive capacity
• Dhi, Dhriti, Smriti Bhramsha
• Jara: ageing-related degeneration
• Vatavyadhi
• Majja Dhatu Kshaya
• Manovaha Srotodushti
• Pragya Aparadha, depending on the context

Ayurvedic conceptual understanding

Smriti Bhramsha

Dhi, Dhriti, Smriti

Ayurvedic Nidana: Possible Contributory Factors

• Ageing, or Jara
• Excessive worry, fear, grief, anger, and stress
• Sleep deprivation
• Daytime sleep and disturbed sleep routine
• Inadequate nutrition or excessive fasting
• Alcohol and substance use
• Sedentary lifestyle
• Recurrent illness and debility
• Head injury
• Vata-aggravating food and lifestyle
• Mental overexertion or lack of mental stimulation
• Metabolic disorders and poor vascular health

Ayurvedic Samprapti: Conceptual Pathogenesis

Jara (ageing) + Vata-aggravating factors
   + stress + sleep disturbance + poor nutrition
                     ↓
Vata prakopa
                     ↓
Disturbance of Manovaha and Majjavaha Srotas
                     ↓
Majja dhatu kshaya / impaired nourishment of higher functions
                     ↓
Dhi, Dhriti and Smriti impairment
                     ↓
Smriti Bhramsha, Medha Kshaya,
confusion and functional decline

Ageing and tissue depletion
          ↓
Vata predominance
          ↓
Neurocognitive decline and functional instability
          ↓
Memory loss, impaired judgement, sleep disturbance,
anxiety, wandering and reduced independence

Ayurvedic Preventive Approach

1. Dinacharya and Ritucharya

• Regular daily routine
• Regular meals
• Adequate night sleep
• Physical activity suited to age and ability
• Social interaction
• Avoidance of excessive strain and irregular lifestyle

2. Ahara

• Excess alcohol
• Tobacco
• Highly processed food
• Excess sugar
• Excess saturated fat
• Extreme fasting or malnutrition

3. Mental health and cognitive stimulation

• Reading, music, memory exercises, learning, meditation, and social engagement
• Stress-management practices
• Yoga and breathing exercises adapted to physical ability

Ayurvedic Management Principles

1. Nidana Parivarjana: avoiding factors that aggravate symptoms
2. Medhya Rasayana: traditionally used cognitive-support approaches
3. Rasayana: supportive measures aimed at healthy ageing
4. Snehana: selected oleation practices in appropriate persons
5. Abhyanga: gentle massage for comfort, sleep, and relaxation where safe
6. Yoga, pranayama, meditation, and routine-based care
7. Support of sleep, nutrition, mobility, bowel/bladder function, and caregiver well-being

• Evidence for treating established Alzheimer’s disease is limited.
• They should not replace diagnosis, cholinesterase inhibitors, memantine, anti-amyloid therapy in eligible patients, or medical management of comorbidities.
• Herbal products may interact with anticoagulants, antidiabetic drugs, antihypertensives, sedatives, and psychiatric medicines.

Integrative Care Model

Evidence-based dementia assessment
     + cognitive testing + imaging/biomarkers when needed
                         ↓
Modern medical treatment
     + vascular-risk control + caregiver support
                         ↓
Supportive lifestyle measures
     + exercise + healthy diet + sleep + social stimulation
                         ↓
Optional safe Ayurvedic wellness measures
under qualified supervision
                         ↓
Better quality of life and safer long-term care

Conclusion

Atherosclerosis

Definition

Arteriosclerosis versus atherosclerosis

• Arteriosclerosis: General term for thickening and loss of elasticity of arteries.
• Atherosclerosis: A specific form of arteriosclerosis involving intimal plaques with lipid accumulation.
• Other forms include:
  • Arteriolosclerosis
  • Medial calcific sclerosis of Mönckeberg

Common sites

1. Abdominal aorta
2. Coronary arteries
3. Popliteal arteries
4. Internal carotid arteries
5. Circle of Willis
6. Renal arteries

Risk factors

A. Non-modifiable risk factors

1. Increasing age
   Lesions develop gradually over decades and commonly become clinically apparent in middle or old age.
2. Male sex
   Men are affected earlier than women. Premenopausal women have relative protection; risk rises after menopause.
3. Family history and genetic factors
   Includes familial hypercholesterolemia and inherited predisposition to hypertension, diabetes, or dyslipidaemia.

B. Major modifiable risk factors

1. Hyperlipidaemia, particularly increased LDL cholesterol
2. Hypertension
3. Cigarette smoking
4. Diabetes mellitus
5. Inflammation, including chronic inflammatory diseases

C. Additional or emerging factors

• Obesity and sedentary lifestyle
• Diet rich in saturated fat and trans-fat
• Low HDL cholesterol
• Hypertriglyceridaemia
• Elevated lipoprotein(a)
• Metabolic syndrome
• Hyperhomocysteinaemia
• Chronic kidney disease
• Psychological stress

Pathogenesis: response-to-injury hypothesis

Sequence of events

1. Endothelial dysfunction or injury

• Hyperlipidaemia
• Hypertension
• Smoking
• Diabetes
• Turbulent blood flow
• Inflammatory mediators

• Increased permeability to lipoproteins
• Increased leukocyte and platelet adhesion
• Reduced nitric oxide production
• Pro-inflammatory and pro-thrombotic activity

2. Accumulation and modification of LDL in intima

• Is toxic to endothelial cells and smooth muscle cells
• Attracts monocytes
• Promotes inflammation
• Is readily ingested by macrophages

3. Monocyte adhesion and foam-cell formation

• Monocytes adhere to endothelial cells via adhesion molecules.
• They migrate into the intima and become macrophages.
• Macrophages engulf oxidized LDL through scavenger receptors.
• Lipid-laden macrophages are called foam cells.

4. Platelet activation and cytokine release

• PDGF
• FGF
• TGF-β
• IL-1
• TNF

5. Smooth-muscle-cell migration and proliferation

• Collagen
• Elastin
• Proteoglycans

6. Formation of fibrofatty plaque

• Central lipid-rich necrotic core
• Fibrous cap overlying the core
• Inflammatory cells, especially macrophages and T cells
• Calcification in advanced lesions
• Neovascularization from the vasa vasorum

Morphology

1. Fatty streak

• Earliest lesion of atherosclerosis
• Appears as flat, yellow streaks in the intima
• Composed mainly of foam cells
• Begins in childhood and may progress or regress
• Does not significantly obstruct blood flow

2. Atheromatous or fibrofatty plaque

3. Complicated plaque

• Calcification
• Ulceration or erosion
• Rupture of fibrous cap
• Intraplaque hemorrhage
• Superimposed thrombosis
• Atheroembolism
• Aneurysm formation due to weakening of the arterial media

Stable and vulnerable plaques

Clinical consequences and complications

1. Progressive luminal narrowing

• Coronary artery narrowing → stable angina, chronic ischemic heart disease
• Carotid artery narrowing → transient ischemic attacks
• Peripheral arterial narrowing → intermittent claudication
• Renal artery narrowing → renovascular hypertension
• Mesenteric artery narrowing → intestinal angina

2. Acute plaque rupture, erosion, or ulceration

• Acute myocardial infarction
• Unstable angina
• Sudden cardiac death
• Ischaemic stroke
• Acute limb ischemia

3. Thrombosis

4. Atheroembolism

5. Aneurysm formation

• Aortic aneurysm
• Mural thrombosis
• Rupture
• Embolization

Prevention and management principles

1. Stop smoking.
2. Maintain healthy body weight and regular physical activity.
3. Consume a diet low in saturated fat and trans-fat, with fruits, vegetables, whole grains, and unsaturated fats.
4. Control hypertension.
5. Control diabetes mellitus.
6. Reduce LDL cholesterol with lifestyle measures and lipid-lowering therapy, especially statins when indicated.
7. Use antiplatelet therapy only when clinically indicated, particularly in established atherosclerotic cardiovascular disease.
8. Screen and manage high-risk individuals, including those with diabetes, familial hypercholesterolaemia, or established cardiovascular disease.

Conclusion

Definition

Arteriosclerosis is a general term for thickened and stiff arteries.
Atherosclerosis is the specific form in which lipid-rich plaques form in the arterial intima.

Sites commonly affected

1. Abdominal aorta
2. Coronary arteries
3. Popliteal arteries
4. Internal carotid arteries
5. Circle of Willis and cerebral arteries
6. Renal arteries
7. Mesenteric arteries

Causes and Etiology

Important causal mechanisms

• Endothelial dysfunction or injury
• Accumulation of LDL cholesterol in arterial intima
• Oxidation and modification of LDL
• Inflammatory-cell recruitment
• Macrophage foam-cell formation
• Smooth-muscle-cell migration and collagen deposition
• Plaque growth, rupture, thrombosis, and embolization

Risk Factors

A. Non-modifiable risk factors

B. Major modifiable risk factors

1. Hyperlipidaemia, especially raised LDL cholesterol
2. Hypertension
3. Cigarette smoking and tobacco exposure
4. Diabetes mellitus
5. Chronic inflammation

C. Additional factors

• Obesity and central adiposity
• Physical inactivity
• Diet high in saturated fats, trans fats, refined carbohydrate, and salt
• Low HDL cholesterol
• Raised triglycerides
• Elevated lipoprotein(a)
• Metabolic syndrome
• Chronic kidney disease
• Excess alcohol intake
• Psychosocial stress
• Sleep disorders, including obstructive sleep apnoea

Pathogenesis

Response-to-injury hypothesis

Flow diagram of atherogenesis

Risk factors
  ↓
Hyperlipidaemia, hypertension, diabetes, smoking, turbulent blood flow
  ↓
Endothelial dysfunction / injury
  ↓
↑ Permeability to LDL + ↑ leukocyte adhesion + ↓ nitric oxide
  ↓
LDL enters arterial intima
  ↓
LDL oxidation / modification
  ↓
Monocyte adhesion → migration into intima → macrophage formation
  ↓
Macrophages engulf oxidized LDL
  ↓
Foam cells form
  ↓
Fatty streak
  ↓
Smooth-muscle-cell migration and proliferation
  ↓
Collagen and extracellular-matrix deposition
  ↓
Fibrofatty atherosclerotic plaque
  ↓
Stable plaque                 Vulnerable plaque
(chronic stenosis)            (rupture/erosion)
   ↓                                ↓
Chronic ischaemia             Thrombosis / embolism

Steps in detail

1. Endothelial dysfunction

• Increased endothelial permeability to lipoproteins
• Increased expression of leukocyte adhesion molecules
• Reduced nitric oxide production
• Increased vasoconstriction
• Pro-inflammatory and pro-thrombotic state

2. LDL accumulation and oxidation

• Is toxic to endothelial cells
• Attracts monocytes
• Promotes cytokine release
• Is easily ingested by macrophages
• Promotes foam-cell formation

3. Monocyte migration and foam-cell formation

4. Inflammation

5. Smooth-muscle-cell migration and extracellular matrix formation

• Collagen
• Elastin
• Proteoglycans
• Other extracellular-matrix components

6. Mature plaque and its complications

              Arterial lumen
                   ↓
       ┌──────────────────────┐
       │ Fibrous cap          │
       │ Collagen + smooth    │
       │ muscle cells         │
       ├──────────────────────┤
       │ Macrophages /        │
       │ inflammatory cells   │
       ├──────────────────────┤
       │ Lipid-rich necrotic  │
       │ core: cholesterol,   │
       │ foam cells, debris   │
       └──────────────────────┘
              Arterial media

Morphology

1. Fatty streak

• Earliest lesion
• Flat, yellow streaks in intima
• Mainly composed of macrophage foam cells
• Begins in childhood or adolescence
• Usually does not obstruct blood flow

2. Fibrofatty or atheromatous plaque

• Raised intimal lesion
• Yellow-white in appearance
• Has a fibrous cap and lipid-rich necrotic core
• Progressively narrows arterial lumen
• May calcify

3. Complicated plaque

• Calcification
• Plaque ulceration
• Plaque erosion
• Rupture of fibrous cap
• Intraplaque haemorrhage
• Superimposed thrombosis
• Cholesterol embolization
• Aneurysm formation

Stable and Vulnerable Plaques

Clinical Features and Complications

Major mechanisms of complications

Atherosclerotic plaque
       ↓
1. Progressive stenosis → chronic ischaemia
2. Plaque rupture/erosion → thrombosis → acute occlusion
3. Plaque debris → cholesterol emboli
4. Medial weakening → aneurysm and rupture

Investigations

1. Clinical evaluation

History

• Exertional chest pain, dyspnoea, palpitations
• Transient weakness, facial deviation, speech difficulty, visual loss
• Calf pain on walking, rest pain, cold feet, non-healing ulcers
• Postprandial abdominal pain and weight loss
• Smoking, dietary habits, physical activity
• Diabetes, hypertension, kidney disease
• Family history of premature cardiovascular disease

Examination

• Blood pressure in both arms
• Body mass index and waist circumference
• Carotid, abdominal, and femoral bruits
• Peripheral pulse status
• Cool limbs, trophic skin changes, ulcers, gangrene
• Cardiac signs of ischaemic heart disease or heart failure

2. Laboratory investigations

3. Non-invasive vascular tests

4. Invasive tests

Conventional catheter angiography

• Defines arterial anatomy and stenosis
• Often performed when intervention is likely
• Allows angioplasty and stent placement in the same setting
• Has risks including bleeding, contrast nephropathy, embolization, and vascular injury

Intravascular ultrasound and optical coherence tomography

Diagnosis

Risk-factor assessment
        +
Symptoms and physical signs
        +
Evidence of plaque, stenosis, ischaemia, or infarction on imaging/tests
        =
Clinical diagnosis of atherosclerotic cardiovascular disease

Diagnostic examples

Prevention

Primordial prevention

• Healthy food habits from childhood
• Regular physical activity
• Avoiding tobacco and vaping
• Maintaining normal weight
• Limiting alcohol
• Adequate sleep and stress control

Primary prevention

1. Assess cardiovascular risk.
2. Control blood pressure.
3. Detect and treat diabetes.
4. Treat dyslipidaemia according to overall cardiovascular risk.
5. Encourage a heart-healthy diet.
6. Advise physical activity.
7. Stop smoking.
8. Use statins when overall risk and LDL level justify treatment.

Secondary prevention

• High-intensity statin or maximally tolerated statin
• Strict blood-pressure control
• Diabetes management
• Smoking cessation
• Antiplatelet therapy where clinically indicated
• Cardiac rehabilitation or supervised exercise where appropriate
• Regular follow-up and medication adherence

Treatment

A. Lifestyle management

Diet

• Vegetables, fruits, whole grains, legumes, nuts
• Fish and unsaturated fats
• Reduced saturated fat and trans-fat
• Reduced processed meat, added sugar, and refined carbohydrates
• Salt restriction, especially in hypertension
• Appropriate calorie intake for weight reduction if overweight

Physical activity

• Regular aerobic activity plus resistance training
• Individualize exercise for age, symptoms, and cardiac status
• Supervised exercise therapy is useful in symptomatic peripheral arterial disease

Tobacco cessation

• Strongly advise complete cessation
• Use counselling, nicotine replacement, varenicline, or bupropion where appropriate
• Avoid second-hand smoke

B. Control of associated risk factors

C. Lipid-lowering treatment

1. Statins

• Lower LDL cholesterol
• Improve endothelial function
• Reduce vascular inflammation
• Stabilize plaques
• Reduce myocardial infarction, stroke, and cardiovascular death

• Atorvastatin 40-80 mg/day
• Rosuvastatin 20-40 mg/day

2. Add-on treatment

• Ezetimibe
• PCSK9 inhibitors
• Other specialist-directed lipid-lowering treatments

D. Antiplatelet treatment

• Low-dose aspirin is commonly used for secondary prevention if not contraindicated.
• Clopidogrel is an alternative when aspirin cannot be used.
• Dual antiplatelet therapy is used for a defined period after acute coronary syndrome or coronary stenting under specialist guidance.

Antiplatelet drugs should not be self-started for everyone with risk factors because bleeding risk must be considered.

E. Symptom-directed treatment

Coronary artery disease

• Beta-blockers
• Calcium-channel blockers
• Nitrates
• Other antianginal medicines as appropriate
• Revascularization for selected patients

Peripheral arterial disease

• Supervised exercise programme
• Antiplatelet therapy where indicated
• Statin treatment
• Wound and foot care in diabetes
• Revascularization for severe claudication not responding to medical therapy or for critical limb ischaemia

F. Revascularization

• Percutaneous coronary intervention with balloon angioplasty and stent
• Coronary artery bypass grafting
• Carotid endarterectomy
• Carotid stenting in selected cases
• Peripheral angioplasty/stenting
• Surgical bypass grafting

Ayurvedic Perspective

Important note

• Dhamani Pratichaya
• Medoroga / Medovriddhi
• Srotorodha
• Kaphaja Hridroga
• In advanced disease, possible involvement of Vata due to obstruction, often discussed as Avarana of Vata

1. Dhamani Pratichaya

2. Samprapti: Ayurvedic pathogenesis

Nidana: causative factors

• Excessive guru, snigdha, madhura, and abhishyandi ahara
• Excess intake of fried food, heavy food, excess dairy, sweets, and processed foods
• Sedentary lifestyle, day sleep, and lack of exercise
• Overeating and frequent eating before digestion of the previous meal
• Mental stress, anger, worry, and disturbed sleep
• Hereditary predisposition
• Ageing and impaired metabolic capacity

Samprapti diagram

Kapha-Meda aggravating ahara and vihara
   + sedentary lifestyle + day sleep + stress
                     ↓
                 Agnimandya
           (impaired metabolism)
                     ↓
       Ama formation + Meda dushti / Medovriddhi
                     ↓
     Abaddha Medas and altered lipid metabolism
                     ↓
   Srotorodha / Dhamani Pratichaya
   (obstruction and thickening of channels)
                     ↓
    Vata avarana and impaired circulation
                     ↓
 Hridroga / dhamani-related manifestations
      comparable to atherosclerotic disease

3. Dosha and dushya involvement

4. Ayurvedic preventive principles

Ahara

• Avoid excess fried, oily, heavy, sweet, and processed foods.
• Avoid overeating and irregular food timing.
• Prefer vegetables, legumes, whole grains, fruit, and fibre-rich meals.
• Limit excess salt, sugar, alcohol, and tobacco.
• Use an individualized dietary plan based on comorbidities, body constitution, and modern nutrition advice.

Vihara

• Daily physical activity appropriate to capacity
• Avoid day sleep, especially after heavy meals
• Maintain proper sleep routine
• Weight management
• Stress reduction through breathing practices, yoga, mindfulness, or meditation
• Avoid tobacco in all forms

Dinacharya and Ritucharya

5. Ayurvedic management concepts

• Nidana parivarjana: removal of causative diet and lifestyle factors
• Langhana: lightening measures where appropriate
• Deepana and Pachana: measures aimed at improving digestive/metabolic function
• Lekhana: conceptual approach to reduction of excessive Meda/Kapha
• Medohara ahara-vihara
• Shodhana, including selected Panchakarma approaches, only after individual assessment

Herbs and formulations

• Guggulu preparations
• Arjuna
• Garlic
• Turmeric/curcumin
• Triphala
• Pushkarmoola-based formulations

Integrative Conclusion

Evidence-based cardiovascular diagnosis and treatment
                  +
Diet, exercise, weight control, tobacco cessation
                  +
Stress management and safe individualized Ayurvedic lifestyle measures
                  =
Better long-term prevention and adherence

Definition

• Raised total cholesterol
• Raised low-density lipoprotein cholesterol, LDL-C
• Raised triglycerides
• Reduced high-density lipoprotein cholesterol, HDL-C
• Raised non-HDL cholesterol, apolipoprotein B, or lipoprotein(a)

Normal Lipoprotein Transport

Diagram: Lipoprotein pathway

Dietary fat
    ↓
Intestine
    ↓
Chylomicrons ──→ triglycerides delivered to muscle and adipose tissue
    ↓ remnants
Liver
    ↓
VLDL ──→ IDL ──→ LDL
                    ↓
       LDL enters arterial wall
                    ↓
      Oxidation + inflammation
                    ↓
        Atherosclerotic plaque

HDL ──→ removes cholesterol from tissues/artery wall
          ↓
        Liver → bile excretion

Classification

1. Primary dyslipidemia

• Familial hypercholesterolaemia
• Familial combined hyperlipidaemia
• Familial hypertriglyceridaemia
• Familial chylomicronaemia syndrome
• Elevated inherited lipoprotein(a)

2. Secondary dyslipidemia

Causes

A. Dietary and lifestyle causes

• Diet high in saturated fats, trans fats, refined carbohydrates, and excess calories
• Obesity, particularly central obesity
• Sedentary lifestyle
• Excess alcohol, especially with high triglycerides
• Smoking
• Poorly controlled diabetes
• Metabolic syndrome

B. Endocrine and metabolic conditions

• Diabetes mellitus and insulin resistance
• Hypothyroidism
• Cushing syndrome
• Polycystic ovarian syndrome
• Obesity
• Pregnancy

C. Renal and hepatic disorders

• Chronic kidney disease
• Nephrotic syndrome
• Cholestatic liver disease
• Non-alcoholic fatty liver disease

D. Drugs causing dyslipidemia

• Thiazide diuretics
• Some beta-blockers
• Corticosteroids
• Oral oestrogens
• Retinoids
• Protease inhibitors
• Cyclosporine and tacrolimus
• Certain antipsychotics
• Immunosuppressive drugs

E. Genetic causes

• Familial hypercholesterolaemia
• Familial combined hyperlipidaemia
• ApoB defects
• LDL receptor defects
• Lipoprotein lipase deficiency
• ApoC-II deficiency

Pathogenesis

Pathogenesis of raised LDL cholesterol

Genetic tendency / unhealthy diet / diabetes / hypothyroidism
                         ↓
       ↑ LDL production or ↓ LDL receptor clearance
                         ↓
             Increased circulating LDL-C
                         ↓
       LDL enters and is retained in arterial intima
                         ↓
            LDL oxidation and modification
                         ↓
Monocyte recruitment → macrophages → foam cells
                         ↓
               Fatty streak formation
                         ↓
 Smooth-muscle-cell migration + collagen deposition
                         ↓
        Fibrofatty atherosclerotic plaque
                         ↓
  Stenosis / plaque rupture / thrombosis / embolism
                         ↓
       MI, stroke, peripheral arterial disease

Pathogenesis of hypertriglyceridaemia

Obesity / diabetes / alcohol / high refined-carbohydrate diet
                          ↓
              ↑ Hepatic VLDL production
                          +
               ↓ Lipoprotein lipase activity
                          ↓
     Reduced clearance of triglyceride-rich particles
                          ↓
                Hypertriglyceridaemia
                          ↓
        Atherogenic remnant particles and low HDL
                          ↓
      Atherosclerotic cardiovascular disease risk

Very severe triglyceride elevation
                          ↓
 Pancreatic lipase releases free fatty acids in pancreas
                          ↓
       Pancreatic inflammation → acute pancreatitis

Risk Factors

Non-modifiable factors

• Increasing age
• Male sex
• Family history of premature cardiovascular disease
• Genetic dyslipidemia
• Familial hypercholesterolaemia
• Raised lipoprotein(a)

Modifiable factors

• Unhealthy diet
• Obesity
• Physical inactivity
• Smoking
• Diabetes mellitus
• Hypertension
• Excess alcohol
• Hypothyroidism
• Chronic kidney disease
• Drug-induced dyslipidemia

Features suggesting familial hypercholesterolaemia

• Very high LDL-C from a young age
• Tendon xanthomas, especially Achilles tendon
• Xanthelasma at a young age
• Corneal arcus at a young age
• Premature coronary artery disease in patient or first-degree relative
• Family history of markedly elevated cholesterol

Clinical Features

• Xanthelasma
• Tendon xanthomas
• Tuberous xanthomas
• Corneal arcus in young persons
• Lipemia retinalis in severe hypertriglyceridaemia
• Obesity and acanthosis nigricans in insulin resistance

• Angina or myocardial infarction
• Transient ischaemic attack or stroke
• Intermittent claudication
• Aortic stenosis in familial hypercholesterolaemia
• Acute pancreatitis in very severe hypertriglyceridaemia

Investigations

1. Lipid profile

• Total cholesterol
• LDL-C
• HDL-C
• Triglycerides
• Non-HDL cholesterol

Common interpretation

2. Investigation for secondary causes

3. Further tests in selected patients

• ApoB
• Lipoprotein(a)
• Genetic testing for familial hypercholesterolaemia
• ECG, stress testing, echocardiography, or coronary imaging if cardiovascular disease is suspected
• Coronary artery calcium score in selected individuals when treatment decisions are uncertain

Diagnosis

Diagnostic approach

Abnormal lipid profile
        ↓
Repeat / confirm if needed
        ↓
Assess cardiovascular risk:
Age, BP, diabetes, smoking, CKD, family history, ASCVD
        ↓
Exclude secondary causes
        ↓
Classify:
Primary genetic / secondary acquired / mixed dyslipidemia
        ↓
Choose lifestyle and drug treatment according to risk

Important practical patterns

Prevention

Primordial prevention

• Encourage healthy eating from childhood.
• Avoid tobacco use.
• Promote regular exercise.
• Prevent obesity.
• Restrict alcohol.
• Screen individuals with family history of premature cardiovascular disease.

Primary prevention

1. Screen lipid profile according to age, risk factors, and family history.
2. Maintain healthy body weight and waist circumference.
3. Follow a heart-healthy diet.
4. Exercise regularly.
5. Treat diabetes, hypertension, hypothyroidism, kidney disease, and obesity.
6. Avoid smoking and excess alcohol.
7. Use lipid-lowering medicine when cardiovascular risk and lipid values indicate.

Secondary prevention

• Intensive LDL-C lowering
• Statin-based treatment unless contraindicated
• Blood-pressure control
• Diabetes management
• Smoking cessation
• Antiplatelet therapy when indicated
• Supervised cardiac rehabilitation or exercise programme
• Regular follow-up for adherence and lipid response

Treatment

Treatment goals

A. Lifestyle treatment

Dietary measures

• More vegetables, fruit, legumes, nuts, and whole grains
• More fibre-rich foods
• Fish and unsaturated fats
• Reduced saturated fat, trans-fat, processed meat, fried foods, and bakery products
• Lower refined sugar and refined carbohydrate intake, especially when triglycerides are high
• Restriction of alcohol in hypertriglyceridaemia
• Salt restriction if hypertension coexists
• Calorie deficit for overweight or obesity

Physical activity

• Regular aerobic physical activity
• Resistance exercise on appropriate days
• Reduce prolonged sitting
• Individualize for age, cardiac symptoms, and other disease

Weight reduction

• Triglycerides
• Insulin sensitivity
• Blood pressure
• Fatty liver disease
• Overall cardiovascular risk

Tobacco and alcohol

• Stop all tobacco exposure.
• Avoid or strictly limit alcohol, especially in high triglycerides.

B. Pharmacological treatment

1. Statins

• Reduce hepatic cholesterol synthesis
• Increase LDL receptor expression
• Lower LDL-C
• Stabilize atherosclerotic plaques
• Reduce myocardial infarction, stroke, and cardiovascular death

• Atorvastatin 40-80 mg/day
• Rosuvastatin 20-40 mg/day

2. Ezetimibe

3. PCSK9 inhibitors

4. Bempedoic acid and inclisiran

5. Fibrates

6. Prescription omega-3 fatty acids

7. Niacin

C. Management of severe hypertriglyceridaemia

Very high triglycerides
         ↓
Assess for abdominal pain / acute pancreatitis
         ↓
Urgent alcohol cessation
         ↓
Strict reduction in dietary fat and refined carbohydrates
         ↓
Control diabetes and secondary causes
         ↓
Consider triglyceride-lowering therapy under medical supervision
         ↓
Prevent acute pancreatitis

Ayurvedic Perspective

Important clarification

• Medoroga
• Medovriddhi
• Medovaha Srotodushti
• Abaddha Medas
• Ama
• Santarpanottha Vyadhi
• Kapha-Meda predominance

Ayurvedic definition and correlation

Medoroga / Medovriddhi

• Excess or vitiation of Meda dhatu
• Aggravation of Kapha dosha
• Impairment of Agni
• Formation of Ama
• Dysfunction of Medovaha srotas

Abaddha Medas

Ayurvedic Etiological Factors: Nidana

Aharaja nidana

• Excess consumption of sweet, heavy, oily, fried, and unctuous foods
• Excess dairy, bakery foods, refined flour, and sweets
• Repeated overeating
• Eating before digestion of the previous meal
• Excess alcohol
• Improper meal timing

Viharaja nidana

• Sedentary lifestyle
• Daytime sleeping, especially after heavy meals
• Lack of exercise
• Excessive rest
• Poor sleep pattern
• Chronic stress

Other factors

• Hereditary predisposition
• Ageing
• Obesity
• Diabetes-like metabolic disturbances
• Impaired Agni

Ayurvedic Samprapti: Pathogenesis

Kapha-Meda aggravating ahara and vihara
  (heavy, oily, sweet food; inactivity; day sleep)
                      ↓
                 Agnimandya
            impaired digestion/metabolism
                      ↓
                  Ama formation
                      ↓
             Meda dhatu dushti
             / Medovriddhi
                      ↓
       Medovaha srotodushti / srotorodha
                      ↓
      Abaddha Medas in circulation
                      ↓
Kapha predominance + altered Vata movement
                      ↓
  Medoroga and metabolic-cardiovascular risk

Dosha and dushya involved

Ayurvedic Prevention

Nidana parivarjana

• Avoid excessive oily, fried, sweet, heavy, and processed food.
• Avoid frequent overeating.
• Avoid prolonged inactivity.
• Avoid regular day sleep after meals.
• Avoid alcohol excess and tobacco.
• Maintain routine sleep and meal timings.

Ahara

• Light, fibre-rich, plant-based meals
• Vegetables, legumes, whole grains, and fruit
• Controlled portions
• Minimal fried and highly processed foods
• Reduction of excess sugar and fats

Vihara

• Regular exercise suited to ability
• Yoga and walking
• Weight control
• Stress reduction
• Adequate night sleep
• Avoidance of day sleep where clinically appropriate

Ayurvedic Management Principles

1. Nidana parivarjana: avoidance of causative diet and lifestyle factors
2. Langhana: selected lightening measures
3. Deepana and Pachana: approaches intended to improve Agni and address Ama
4. Lekhana: approaches intended to reduce excess Kapha and Meda
5. Medohara ahara-vihara: dietary and lifestyle regulation for Meda imbalance
6. Shodhana/Panchakarma: only if appropriate after individualized assessment by a qualified practitioner

Conclusion

Simple relationship diagram

Dyslipidemia
↑ LDL-C / ↑ triglyceride-rich remnants / ↓ HDL-C
                ↓
LDL retention and oxidation in arterial wall
                ↓
Inflammation + foam cells + fibrous plaque
                ↓
Atherosclerosis
                ↓
Angina / MI / stroke / PAD / aneurysm

Definition

• Neuropathy: nerve disorder, often with sensory loss, reduced reflexes, and distal weakness
• Neuromuscular-junction disorder: fluctuating or fatigable weakness
• Motor neuron disease: weakness with fasciculations, hyperreflexia, or mixed upper and lower motor-neuron signs

Basic clinical pattern

Primary muscle disease
        ↓
Muscle fibre injury / defective energy production / inflammation
        ↓
Weakness ± myalgia ± fatigue ± wasting
        ↓
Usually proximal and symmetrical weakness
        ↓
Difficulty climbing stairs, rising from a chair,
lifting arms, combing hair, or walking uphill

Causes of Myopathy

A. Inherited causes

1. Muscular dystrophies
2. Congenital myopathies
3. Metabolic myopathies
4. Mitochondrial myopathies
5. Channelopathies and periodic paralysis
6. Myotonic disorders

B. Acquired causes

1. Inflammatory or autoimmune myopathies
2. Drug-induced and toxic myopathies
3. Endocrine myopathies
4. Electrolyte-related myopathies
5. Infectious myopathies
6. Critical-illness myopathy
7. Nutritional and deficiency-related myopathies
8. Rhabdomyolysis due to exertion, heat, trauma, drugs, toxins, or metabolic disease

Types of Myopathies

Important Inflammatory Myopathies

1. Dermatomyositis

• Symmetrical proximal muscle weakness
• Characteristic skin rash
• Raised CK in many patients
• Possible dysphagia and interstitial lung disease
• Association with malignancy in adults

Characteristic skin findings

• Heliotrope rash: violet discoloration around eyelids
• Gottron papules: violaceous papules over knuckles
• Photosensitive rash over face, neck, chest, and shoulders
• “Shawl sign” or “V sign”
• Mechanic's hands in overlap/antisynthetase disease

2. Polymyositis

3. Immune-mediated necrotizing myopathy

• Severe proximal weakness
• Markedly elevated CK
• Prominent muscle-fibre necrosis
• Often little inflammatory infiltrate on biopsy
• May be associated with anti-HMGCR or anti-SRP antibodies
• Anti-HMGCR disease can occur after statin exposure

4. Antisynthetase syndrome

• Myositis
• Interstitial lung disease
• Inflammatory arthritis
• Fever
• Mechanic's hands
• Anti-Jo-1 or other antisynthetase antibodies

5. Inclusion-body myositis

• Slowly progressive course
• Often asymmetric weakness
• Quadriceps weakness and finger-flexor weakness
• Falls and dysphagia
• Rimmed vacuoles on biopsy
• Poor response to immunosuppressive treatment

Pathogenesis

General pathogenesis

Genetic defect / autoimmunity / metabolic failure /
drug toxicity / endocrine disorder / infection
                       ↓
Disruption of muscle-fibre structure or energy metabolism
                       ↓
Muscle-fibre dysfunction
                       ↓
Necrosis, inflammation, mitochondrial dysfunction,
or defective regeneration
                       ↓
Weakness ± pain ± elevated CK ± wasting
                       ↓
Functional limitation and complications

A. Pathogenesis of inflammatory myopathy

Genetic susceptibility + environmental trigger
       ± infection / drug exposure / malignancy
                         ↓
                Immune dysregulation
                         ↓
Autoantibodies, T cells, cytokines and complement activation
                         ↓
 Muscle inflammation and/or microvascular injury
                         ↓
 Muscle-fibre necrosis and impaired regeneration
                         ↓
 Proximal weakness, myalgia, fatigue, dysphagia
                         ↓
 Chronic damage → atrophy, fibrosis and fatty replacement

Dermatomyositis

Complement-mediated microvascular injury
                 ↓
Damage to small intramuscular blood vessels
                 ↓
Muscle ischaemia
                 ↓
Perifascicular muscle-fibre atrophy
                 ↓
Proximal weakness + characteristic skin lesions

Polymyositis-like cellular injury

CD8+ cytotoxic T-cell activation
                 ↓
Direct invasion and injury of muscle fibres
                 ↓
Endomysial inflammation
                 ↓
Muscle-fibre necrosis and regeneration
                 ↓
Symmetrical proximal muscle weakness

Inclusion-body myositis

Age-related degenerative protein aggregation
      + chronic inflammatory changes
                 ↓
Rimmed vacuoles and abnormal protein deposits
                 ↓
Progressive quadriceps and finger-flexor weakness
                 ↓
Falls, hand-grip dysfunction and dysphagia

B. Pathogenesis of metabolic myopathy

Inherited enzyme defect
        ↓
Failure of glycogen, lipid, or mitochondrial energy metabolism
        ↓
Inadequate ATP during exercise, fasting, or illness
        ↓
Exercise intolerance, cramps and myalgia
        ↓
Muscle-fibre breakdown
        ↓
Myoglobinuria / rhabdomyolysis in severe episodes

C. Drug-induced myopathy

Drug or toxin exposure
        ↓
Direct myotoxicity / mitochondrial injury /
immune reaction / electrolyte disturbance
        ↓
Muscle-fibre dysfunction or necrosis
        ↓
Myalgia, weakness, raised CK or rhabdomyolysis

Risk Factors

General risk factors

• Family history of muscle disease
• Consanguinity in autosomal-recessive disorders
• Childhood onset of weakness or delayed milestones
• Older age for inclusion-body myositis
• Autoimmune disease
• Malignancy, especially in adult dermatomyositis
• Diabetes, thyroid disease, renal disease, or liver disease
• Alcohol misuse
• Malnutrition and vitamin deficiency
• Severe infection, sepsis, or ICU stay
• Strenuous unaccustomed exercise, heat exposure, or crush injury
• Exposure to myotoxic drugs

Risk factors for drug-induced myopathy

• High drug dose
• Older age and frailty
• Renal or liver impairment
• Hypothyroidism
• Drug interactions
• Combination of statin with certain interacting drugs
• Previous history of drug-related muscle symptoms
• Intensive exercise during treatment

Clinical Features

Symptoms

• Proximal muscle weakness
• Difficulty standing from sitting or floor
• Difficulty climbing stairs
• Difficulty lifting the arms above shoulders
• Difficulty combing hair or lifting objects
• Myalgia and muscle tenderness
• Cramps
• Exercise intolerance
• Fatigue
• Muscle wasting
• Falls
• Dysphagia
• Dyspnoea due to respiratory-muscle weakness
• Dark urine in rhabdomyolysis

Signs

• Symmetrical proximal weakness
• Preserved sensation in most primary myopathies
• Reflexes usually preserved until weakness becomes severe
• Muscle tenderness in inflammatory, infectious, or toxic causes
• Muscle hypertrophy or pseudohypertrophy in some dystrophies
• Contractures in muscular dystrophies
• Rash in dermatomyositis
• Distal finger-flexor and quadriceps weakness in inclusion-body myositis

Investigation

1. History and examination

• Age at onset and speed of progression
• Distribution of weakness: proximal, distal, facial, ocular, axial
• Family history
• Myalgia, cramps, exercise intolerance, dark urine
• Fever, weight loss, rash, arthritis, Raynaud phenomenon
• Dysphagia, aspiration, breathlessness
• Drug history, especially statins, steroids, antimalarials, colchicine, alcohol, and recreational substances
• Thyroid symptoms and diabetes
• Recent infection, trauma, fasting, exertion, heat exposure, or surgery

2. Blood investigations

CK can be normal in some myopathies, especially steroid myopathy, mitochondrial myopathy, some congenital myopathies, and advanced muscle wasting. A normal CK does not exclude myopathy.

3. Electrophysiology

Electromyography and nerve-conduction studies

• Short-duration, low-amplitude motor-unit potentials
• Early recruitment
• Spontaneous activity in inflammatory or necrotizing muscle disease

4. Imaging

Muscle MRI

• Muscle oedema suggesting active inflammation
• Fatty replacement
• Muscle atrophy
• A suitable site for biopsy

5. Muscle biopsy

• Inflammation
• Necrosis and regeneration
• Perifascicular atrophy in dermatomyositis
• Endomysial inflammation in some inflammatory myopathies
• Rimmed vacuoles in inclusion-body myositis
• Storage material in metabolic myopathy
• Mitochondrial abnormalities
• Dystrophic changes in muscular dystrophy

6. Genetic testing

• Muscular dystrophy
• Congenital myopathy
• Mitochondrial disease
• Metabolic myopathy
• Channelopathy

7. Systemic assessment

• ECG and echocardiography for cardiac involvement
• Pulmonary function tests and high-resolution CT for interstitial lung disease
• Swallow assessment for dysphagia and aspiration risk
• Cancer screening in adult dermatomyositis and selected inflammatory myopathies

Diagnosis

Diagnostic flowchart

Patient with muscle weakness / myalgia / high CK
                    ↓
Confirm true weakness and identify distribution
                    ↓
Exclude emergency causes:
rhabdomyolysis, severe hypokalaemia, respiratory weakness
                    ↓
History: drugs, family history, rash, systemic disease,
exercise-induced symptoms, endocrine symptoms
                    ↓
CK + electrolytes + renal function + thyroid tests
                    ↓
EMG/NCS and muscle MRI when indicated
                    ↓
Autoantibodies / genetic testing / muscle biopsy
                    ↓
Classify the myopathy:
Inherited / inflammatory / metabolic / endocrine /
toxic-drug-induced / infectious / critical illness
                    ↓
Cause-specific treatment and rehabilitation

Differential Diagnosis

Prevention

General preventive measures

• Genetic counselling for inherited muscle disorders
• Newborn, family, or carrier screening where available
• Avoid unnecessary exposure to myotoxic drugs
• Review drug interactions, especially with statins
• Correct hypothyroidism, electrolyte disturbances, and vitamin deficiency
• Limit alcohol and avoid illicit drugs
• Gradual exercise conditioning rather than sudden intense exertion
• Adequate hydration during prolonged exertion or heat exposure
• Early management of diabetes, kidney disease, and endocrine disorders
• Vaccination and infection prevention in vulnerable patients
• Physiotherapy, stretching, contracture prevention, and fall prevention

Treatment

General supportive treatment for all myopathies

1. Physiotherapy and graded exercise plan
2. Occupational therapy for activities of daily living
3. Nutrition support and adequate protein/calorie intake
4. Stretching, splints, and contracture prevention
5. Fall prevention and mobility aids when required
6. Management of pain and fatigue
7. Assessment and treatment of dysphagia
8. Respiratory and cardiac monitoring in appropriate disorders
9. Psychological support and genetic counselling

Cause-specific treatment

Emergency warning signs

• Dark or cola-coloured urine
• Severe muscle pain with weakness
• Rapidly progressive weakness
• Difficulty swallowing or choking
• Shortness of breath or weak cough
• Chest pain or palpitations
• Markedly reduced urine output
• Fever with focal muscle pain/swelling
• Severe electrolyte disturbance or suspected rhabdomyolysis

Ayurvedic Perspective

Important clarification

Ayurvedic correlation

Possible Nidana

• Excessive exertion or repetitive strain
• Inadequate nutrition or fasting
• Irregular eating habits
• Trauma
• Excessive exposure to cold and dryness
• Sleep deprivation
• Chronic illness and debility
• Ageing
• Emotional stress
• Vata-aggravating diet and lifestyle
• Metabolic impairment, often described through Agni disturbance and Ama formation

Ayurvedic Samprapti: Conceptual Pathogenesis

Vata-aggravating nidana
(excess exertion, fasting, irregular diet, cold, stress)
                    ↓
Agnimandya and/or dhatu-poshana disturbance
                    ↓
Mamsa dhatu kshaya or mamsa dhatu dushti
                    ↓
Vata prakopa in mamsa and related srotas
                    ↓
Mamsagata Vata / Mamsavrita Vata
                    ↓
Shoola, stambha, kampa, bala-kshaya,
mamsa-kshaya and impaired movement

Pitta-Rakta aggravation + Vata disturbance
                    ↓
Mamsa-Rakta dushti
                    ↓
Inflammatory pain, tenderness and weakness
                    ↓
Chronic disease → Mamsa kshaya and functional loss

Ayurvedic Preventive Principles

Ahara

• Adequate and balanced nutrition
• Avoid prolonged fasting and extreme diets
• Prefer easily digestible, nourishing foods when there is muscle wasting
• Avoid excessive alcohol and tobacco
• Adapt diet to metabolic disease, obesity, diabetes, and kidney disease where present

Vihara

• Avoid sudden overexertion
• Use graduated exercise rather than complete inactivity
• Ensure adequate sleep and recovery
• Maintain regular daily routine
• Use gentle yoga, stretching, and breathing exercises only within functional limits
• Prevent falls and injury

General principles

• Nidana Parivarjana: avoid known aggravating factors
• Attention to Agni and nutrition
• Individualized assessment of Vata, Pitta, Kapha, Ama, Bala, and Mamsa-dhatu status
• Rehabilitation-oriented approach for maintaining function

Ayurvedic Management Principles

1. Brimhana: nourishing approaches in Mamsa-kshaya and debility
2. Snehana: selected internal or external oleation approaches
3. Swedana: selected fomentation where appropriate
4. Basti: sometimes considered in chronic Vata disorders
5. Rasayana: supportive rejuvenative approaches
6. Abhyanga: massage-based supportive care in selected non-acute situations
7. Gentle rehabilitation, sleep regulation, and nutrition support

Safety cautions

• Do not delay medical review for progressive weakness, dysphagia, breathing difficulty, dark urine, or severe pain.
• Do not stop corticosteroids, immunosuppressants, statins, thyroid medicine, or other prescribed therapy without medical advice.
• Massage and vigorous exercise may be unsafe in acute inflammatory myositis, severe weakness, rhabdomyolysis, fractures, severe infection, or severe cardiopulmonary disease.
• Herbal medicines may interact with immunosuppressants, anticoagulants, diabetic medicines, and other drugs.

Conclusion

1. Inflammatory and autoimmune myopathies

2. Inherited, metabolic, endocrine, and toxic myopathies

3. High-yield comparison: Statin myalgia versus statin-associated autoimmune necrotizing myopathy

One-glance pattern recognition diagram

Proximal symmetrical weakness + rash
             ↓
      Dermatomyositis

Proximal severe weakness + very high CK
             ↓
Immune-mediated necrotizing myopathy

Age >50 + quadriceps and finger-flexor weakness
             ↓
Inclusion-body myositis

Childhood onset + calf pseudohypertrophy + progressive weakness
             ↓
Duchenne/Becker muscular dystrophy

Exercise-induced cramps + dark urine after exertion/fasting
             ↓
Metabolic myopathy / rhabdomyolysis

Proximal weakness + endocrine symptoms or steroid exposure
             ↓
Endocrine or steroid myopathy

Core differentiating points

• Dermatomyositis: proximal weakness plus characteristic skin rash.
• IMNM: severe weakness with very high CK and muscle necrosis.
• IBM: older adult, finger-flexor and quadriceps weakness, poor immunotherapy response.
• Muscular dystrophy: inherited, slowly progressive, often childhood onset.
• Metabolic myopathy: exercise, fasting, or illness triggers episodic symptoms.
• Steroid myopathy: painless proximal weakness with often normal CK.
• Statin myopathy: consider drug timing, interactions, hypothyroidism, CK level, and persistent weakness after withdrawal.

Definition

1. Extracellular deposition of amyloid-beta (Aβ) plaques
2. Intracellular neurofibrillary tangles of hyperphosphorylated tau protein
3. Synaptic dysfunction, neuronal loss, brain atrophy, and neuroinflammation

Stages of Alzheimer’s Disease

Normal cognition
      ↓
Preclinical Alzheimer disease
(amyloid/tau pathology may be present without symptoms)
      ↓
Mild cognitive impairment due to AD
(memory decline but basic independence largely maintained)
      ↓
Mild Alzheimer dementia
      ↓
Moderate Alzheimer dementia
      ↓
Severe Alzheimer dementia
(complete dependence, immobility, dysphagia, infections)

1. Mild cognitive impairment due to AD

• Memory impairment greater than expected for age
• Person remains mostly independent in daily activities
• May misplace objects, repeat questions, or forget appointments
• Does not yet meet criteria for dementia

2. Alzheimer dementia

• Mild stage: recent-memory loss, word-finding difficulty, impaired finances and complex tasks
• Moderate stage: disorientation, wandering, agitation, sleep disturbance, impaired self-care
• Severe stage: loss of speech, swallowing difficulty, incontinence, immobility, recurrent infection, total dependence

Causes and Etiology

A. Sporadic late-onset AD

• Ageing
• APOE ε4 genotype
• Vascular disease
• Diabetes mellitus
• Hypertension
• Physical inactivity
• Low educational/cognitive reserve
• Smoking
• Obesity
• Hearing impairment
• Depression and social isolation
• Head injury

B. Early-onset familial AD

• APP gene on chromosome 21
• PSEN1
• PSEN2

C. Down syndrome

Risk Factors

A. Non-modifiable risk factors

B. Potentially modifiable risk factors

• Midlife hypertension
• Diabetes mellitus
• Dyslipidemia and obesity
• Smoking
• Physical inactivity
• Excess alcohol use
• Depression
• Social isolation
• Low cognitive stimulation
• Hearing loss
• Poor sleep and untreated sleep apnoea
• Traumatic brain injury
• Poorly controlled vascular risk factors

Pathogenesis

Main pathogenesis diagram

Ageing + genetic susceptibility + vascular/metabolic risk factors
                              ↓
Abnormal processing of amyloid precursor protein (APP)
                              ↓
Increased amyloid-beta, particularly Aβ42
                              ↓
Extracellular amyloid-beta oligomers and plaques
                              ↓
Synaptic dysfunction + microglial activation + inflammation
                              ↓
Tau hyperphosphorylation
                              ↓
Neurofibrillary tangles inside neurons
                              ↓
Disrupted microtubules and impaired axonal transport
                              ↓
Neuronal dysfunction and neuronal death
                              ↓
Hippocampal and cortical atrophy
                              ↓
Progressive memory loss and dementia

1. Amyloid-beta plaque formation

• Soluble oligomers
• Fibrils
• Extracellular amyloid plaques

2. Tau hyperphosphorylation

Normal tau
     ↓
Abnormal hyperphosphorylation
     ↓
Tau detaches from microtubules
     ↓
Microtubule instability
     ↓
Impaired axonal transport
     ↓
Paired helical filaments
     ↓
Neurofibrillary tangles
     ↓
Neuronal death

3. Neuroinflammation

4. Cholinergic deficiency

5. Brain atrophy

Early disease
Hippocampus + entorhinal cortex affected
               ↓
Recent-memory impairment
               ↓
Temporal and parietal cortex involvement
               ↓
Language and visuospatial impairment
               ↓
Frontal cortex involvement
               ↓
Executive dysfunction, personality and behavioural changes
               ↓
Widespread neuronal loss
               ↓
Severe dementia and complete dependence

Pathology

Gross pathology

• Diffuse cerebral cortical atrophy
• Marked medial temporal and hippocampal atrophy
• Widened sulci
• Narrowed gyri
• Enlarged ventricles due to ex vacuo dilatation

Microscopic pathology

Clinical Features

Cognitive features

1. Recent-memory loss is usually the earliest prominent feature.
2. Repetitive questions or statements
3. Difficulty learning new information
4. Misplacing objects
5. Word-finding difficulty and impaired naming
6. Impaired judgement and planning
7. Visuospatial problems, getting lost in familiar places
8. Difficulty handling money, medications, cooking, or driving
9. Impaired recognition in advanced disease
10. Loss of insight into illness, called anosognosia

Behavioural and psychological symptoms

• Apathy
• Depression
• Anxiety
• Irritability
• Agitation or aggression
• Delusions, especially theft or misidentification delusions
• Hallucinations, less typical early than in Lewy-body dementia
• Wandering
• Sleep-wake disturbance
• Sundowning

Late-stage complications

• Dysphagia and aspiration
• Weight loss and malnutrition
• Pressure ulcers
• Falls and fractures
• Urinary and faecal incontinence
• Immobility and contractures
• Pneumonia and other infections
• Delirium

Investigations

1. History

• Onset and progression of memory impairment
• Difficulty in daily activities
• Repetition of questions
• Safety concerns: driving, cooking, finances, medication errors
• Behavioural symptoms and sleep
• Depression, hallucinations, delusions
• Alcohol and drug use
• Family history of early dementia
• Vascular risk factors
• Head trauma
• Current medicines, especially anticholinergic and sedative drugs

2. Cognitive assessment

3. Functional assessment

• Medication management
• Financial management
• Cooking
• Shopping
• Driving
• Personal hygiene
• Dressing and toileting

Cognitive decline without loss of independence
          ↓
Mild cognitive impairment

Cognitive decline interfering with independent daily function
          ↓
Major neurocognitive disorder / dementia

4. Laboratory investigations

5. Brain imaging

CT or MRI brain

• Subdural hematoma
• Brain tumour
• Normal-pressure hydrocephalus
• Large stroke
• Extensive vascular disease
• Other structural causes

6. Biomarker testing

Diagnosis

Clinical diagnosis of probable Alzheimer disease

1. Insidious onset
2. Gradual progressive decline
3. Objective impairment in memory and at least one additional cognitive domain
4. Decline interfering with independent functioning
5. No better explanation, such as delirium, major depression, stroke, medication effect, or another dementia syndrome

Diagnostic flowchart

Memory complaint or observed cognitive decline
                    ↓
History from patient and caregiver
                    ↓
Cognitive screening + functional assessment
                    ↓
Exclude delirium, depression, medication effects,
thyroid disease, B12 deficiency and metabolic causes
                    ↓
MRI/CT brain to exclude structural causes
                    ↓
Assess vascular and psychiatric comorbidity
                    ↓
Probable Alzheimer clinical syndrome
                    ↓
CSF / amyloid PET / tau biomarkers if diagnostic
uncertainty or disease-modifying treatment is considered

Differential diagnosis

Prevention and Risk Reduction

Preventive measures

1. Control vascular risk factors

• Treat hypertension
• Control diabetes
• Treat dyslipidemia when indicated
• Maintain healthy body weight
• Stop smoking
• Manage atrial fibrillation and stroke risk

2. Regular physical exercise

• Regular aerobic activity
• Strength and balance training
• Avoid prolonged sedentary behaviour

3. Brain-healthy diet

• Vegetables, fruit, legumes, nuts, whole grains
• Fish and unsaturated fats
• Less processed food, saturated fat, refined sugar, and excess salt

4. Cognitive and social activity

• Reading, learning, puzzles, music, and educational activities
• Social interaction
• Community involvement
• Continued intellectual engagement

5. Sleep and hearing

• Treat hearing loss
• Evaluate and treat sleep apnoea
• Maintain regular sleep schedule

6. Avoid head injury and harmful substances

• Use seat belts and helmets
• Prevent falls
• Avoid tobacco
• Limit alcohol
• Avoid unnecessary sedative or anticholinergic medicines

Treatment

Alzheimer management
       ↓
1. Cognitive symptom treatment
2. Disease-modifying therapy in selected early AD
3. Management of behavioural symptoms
4. Family, caregiver and safety support

A. Cognitive symptom treatment

1. Cholinesterase inhibitors

• Nausea
• Vomiting
• Diarrhoea
• Loss of appetite
• Weight loss
• Bradycardia and syncope
• Sleep disturbance

2. Memantine

• Dizziness
• Constipation
• Headache
• Confusion in some patients

B. Anti-amyloid disease-modifying therapy

Lecanemab

• Early-stage AD only
• Confirmation of amyloid pathology by CSF testing or amyloid PET
• MRI before treatment and serial MRI monitoring
• Discussion of APOE ε4 status and risk
• Specialist supervision

Important adverse effect: ARIA

• ARIA-E: brain oedema or effusions
• ARIA-H: microhaemorrhages or superficial siderosis

Anti-amyloid therapy is not a cure and is not suitable for every patient. Eligibility, monitoring, cost, availability, comorbidities, and bleeding risk require specialist assessment.

C. Management of behavioural and psychological symptoms

Non-drug measures first

• Identify pain, infection, constipation, urinary retention, hunger, loneliness, sleep disturbance, or medication side effects
• Provide a predictable routine
• Use calm communication
• Reduce noise and overstimulation
• Ensure adequate lighting and familiar surroundings
• Use reassurance and redirection rather than confrontation
• Maintain caregiver support

Medicines

• SSRIs may be considered for depression or anxiety
• Antipsychotics may be used cautiously for severe dangerous psychosis/agitation
• Antipsychotics have significant risks in dementia, including sedation, falls, stroke, and increased mortality

D. Supportive and safety care

• Advance-care planning
• Driving assessment and advice
• Medication supervision
• Fall prevention
• Home safety modifications
• Wandering prevention
• Nutrition and swallowing assessment
• Legal and financial planning
• Caregiver education, respite care, and support groups
• Physiotherapy and occupational therapy
• Management of urinary incontinence, pressure sores, and aspiration risk in late stages

Ayurvedic Perspective

Important clarification

• Smriti Bhramsha: impairment or loss of memory
• Medha Kshaya: decline in intellect/cognitive capacity
• Dhi, Dhriti, Smriti Bhramsha
• Jara: ageing-related degeneration
• Vatavyadhi
• Majja Dhatu Kshaya
• Manovaha Srotodushti
• Pragya Aparadha, depending on the context

Ayurvedic conceptual understanding

Smriti Bhramsha

Dhi, Dhriti, Smriti

Ayurvedic Nidana: Possible Contributory Factors

• Ageing, or Jara
• Excessive worry, fear, grief, anger, and stress
• Sleep deprivation
• Daytime sleep and disturbed sleep routine
• Inadequate nutrition or excessive fasting
• Alcohol and substance use
• Sedentary lifestyle
• Recurrent illness and debility
• Head injury
• Vata-aggravating food and lifestyle
• Mental overexertion or lack of mental stimulation
• Metabolic disorders and poor vascular health

Ayurvedic Samprapti: Conceptual Pathogenesis

Jara (ageing) + Vata-aggravating factors
   + stress + sleep disturbance + poor nutrition
                     ↓
Vata prakopa
                     ↓
Disturbance of Manovaha and Majjavaha Srotas
                     ↓
Majja dhatu kshaya / impaired nourishment of higher functions
                     ↓
Dhi, Dhriti and Smriti impairment
                     ↓
Smriti Bhramsha, Medha Kshaya,
confusion and functional decline

Ageing and tissue depletion
          ↓
Vata predominance
          ↓
Neurocognitive decline and functional instability
          ↓
Memory loss, impaired judgement, sleep disturbance,
anxiety, wandering and reduced independence

Ayurvedic Preventive Approach

1. Dinacharya and Ritucharya