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Young-Onset Dementia (YOD) — Viva Crisp Notes

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DEFINITION

The boundary is not universal — some authorities use <65 for "young-onset." Know both and state what definition you are using.

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EPIDEMIOLOGY

• Prevalence ≈ 67–81/100,000 persons aged 45–64
• Represents ~5–9% of all dementia cases
• Often delayed diagnosis (mean delay 4–5 years) due to atypical presentations and low clinical suspicion

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CAUSES — FLOWCHART BY AGE

DEMENTIA ONSET
      │
      ├─── Age < 45 yrs (Kelley 2008, Mayo Clinic)
      │         Most common:
      │         1. Frontotemporal dementia (FTD)
      │         2. Huntington disease
      │         3. Multiple sclerosis
      │         4. Autoimmune/inflammatory encephalopathy
      │         5. Neuropsychiatric lupus
      │         6. Mitochondrial disease
      │         7. Lysosomal storage disease
      │         8. Prion disease (CJD)
      │         9. CNS vasculitis
      │
      └─── Age 30–65 yrs (Harvey 2003)
                Most common:
                1. Alzheimer dementia (most common >45)
                2. Vascular dementia
                3. Frontotemporal dementia
                4. Alcohol-related dementia
                5. Dementia with Lewy bodies (DLB)
                6. Huntington disease
                7. Multiple sclerosis
                8. Down syndrome dementia
                9. CBD / prion disease / Parkinson dementia

Mayo Clinic overall breakdown: Neurodegenerative 31.1% → Autoimmune/Inflammatory 21.3% → Metabolic 10.6% → Unknown 18.7%

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BROAD AETIOLOGICAL FRAMEWORK

YOD CAUSES
├── NEURODEGENERATIVE
│   ├── Alzheimer disease (dominant if >45)
│   ├── Frontotemporal dementia (dominant if <45)
│   ├── Dementia with Lewy bodies
│   ├── Corticobasal degeneration (CBD)
│   └── Huntington disease (CAG repeat ↑)
│
├── VASCULAR
│   ├── Multi-infarct dementia
│   ├── Binswanger disease (subcortical)
│   └── CADASIL (Notch3 mutation — classic YOD cause)
│
├── AUTOIMMUNE / INFLAMMATORY
│   ├── Autoimmune encephalitis (anti-NMDAR, VGKC, LGI1)
│   ├── CNS vasculitis
│   ├── Neuropsychiatric SLE
│   └── MS / neurosarcoidosis
│
├── METABOLIC / TOXIC
│   ├── Wernicke-Korsakoff (thiamine ↓)
│   ├── Vitamin B12 deficiency
│   ├── Wilson disease (copper)
│   ├── Mitochondrial disorders (MELAS)
│   ├── Alcohol-related
│   └── Drug toxicity (lithium, methotrexate)
│
├── INFECTIOUS
│   ├── HIV dementia
│   ├── Neurosyphilis
│   ├── Viral encephalitis
│   ├── Cryptococcal meningitis
│   ├── Tuberculosis
│   └── Whipple disease (PAS+ macrophages)
│
├── PRION
│   └── CJD (sporadic/variant/familial/iatrogenic)
│       — Rapidly progressive, myoclonus, EEG periodic complexes
│
├── NEOPLASTIC
│   ├── CNS lymphoma
│   ├── Gliomatosis cerebri
│   └── Paraneoplastic / cancer-associated encephalopathy
│
├── STRUCTURAL
│   ├── Normal-pressure hydrocephalus (triad: gait, incontinence, dementia)
│   ├── Chronic subdural hematoma
│   └── Intracranial tumours (meningioma)
│
└── STORAGE / GENETIC
    ├── Niemann-Pick type C
    ├── Metachromatic leukodystrophy
    ├── CADASIL
    └── Down syndrome (Trisomy 21)

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CLINICAL APPROACH — FLOWCHART

Patient < 65 yrs with cognitive decline
              │
              ▼
     EXCLUDE PSEUDODEMENTIA
     Depression (masked depression in elderly)
     Schizophrenia (usually younger, delusions prominent, memory intact)
              │
              ▼
     HISTORY
     ├── Pattern of onset (acute/subacute → vascular, autoimmune, prion)
     ├── Family history (Huntington, CADASIL, FAD, prion)
     ├── Drug/alcohol history
     ├── Systemic features (rash → SLE, chorea → Huntington)
     └── Rate of progression (weeks–months = rapidly progressive dementia)
              │
              ▼
     EXAMINATION
     ├── Frontal lobe signs → FTD
     ├── Chorea → Huntington disease
     ├── Parkinsonism → DLB, CBD, PSP
     ├── Myoclonus → prion, metabolic
     ├── Cerebellar signs → MSA, mitochondrial, prion
     └── Kayser-Fleischer rings → Wilson disease
              │
              ▼
     INVESTIGATIONS (TIERED)

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INVESTIGATIONS — FLOWCHART

TIER 1 — ALL YOD PATIENTS (Minimum workup)
├── FBC, ESR, CRP
├── Metabolic panel (renal, LFTs, glucose, calcium)
├── TFTs (hypothyroidism → reversible)
├── Vitamin B12, folate, thiamine
├── HIV serology
├── VDRL/TPPA (neurosyphilis)
├── Lipid profile
└── MRI brain (mandatory — rule out structural/vascular/atrophy pattern)

TIER 2 — BASED ON HISTORY/SUSPICION
├── EEG (non-convulsive status, prion)
├── Genetic testing: HTT CAG repeat (Huntington), NOTCH3 (CADASIL)
├── Autoimmune panel: ANA, ANCA, anti-dsDNA, complement
├── Paraneoplastic antibodies (anti-Hu, Yo, Ri, NMDAR, LGI1, CASPR2)
├── Copper/ceruloplasmin/24hr urine copper (Wilson disease)
├── Lactate/pyruvate, mitochondrial DNA (mitochondrial disease)
├── Lysosomal enzyme assays (storage diseases)
├── Chest X-ray / CT chest (sarcoidosis, TB, malignancy)
└── CSF analysis:
    ├── Cell count, protein, glucose, VDRL
    ├── 14-3-3 protein, tau, RT-QuIC (prion)
    ├── Amyloid-β, phospho-tau (Alzheimer)
    ├── Oligoclonal bands (MS)
    └── Cytology (CNS lymphoma, leptomeningeal)

TIER 3 — SPECIALIST/RESEARCH
├── PET: FDG-PET (metabolic pattern), amyloid PET, tau PET
├── SPECT: DaTscan (dopaminergic) for DLB
├── Brain biopsy (CNS vasculitis, lymphoma, prion if uncertain)
└── Skin biopsy (CADASIL — electron microscopy GOM deposits)

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KEY DIAGNOSTIC CLUES — VIVA TRAPS

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TREATABLE / REVERSIBLE CAUSES — MUST NOT MISS

REVERSIBLE YOD
├── Hypothyroidism
├── Vitamin B12 / thiamine deficiency
├── Wilson disease (penicillamine / trientine)
├── Neurosyphilis (penicillin)
├── HIV (antiretrovirals)
├── Autoimmune encephalitis (steroids, IVIG, plasma exchange)
├── CNS vasculitis (immunosuppression)
├── Normal-pressure hydrocephalus (VP shunt)
├── Chronic subdural haematoma (drainage)
├── CNS lymphoma (chemotherapy ± radiotherapy)
├── Cryptococcal meningitis (antifungals)
└── Drug toxicity (withdrawal of offending agent)

A key viva point: ~20% of YOD cases have potentially treatable aetiologies — this justifies a thorough workup in every case.

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GENETIC YOD — SUMMARY TABLE

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MANAGEMENT FLOWCHART

DIAGNOSIS CONFIRMED
      │
      ├─── SPECIFIC TREATMENT (if treatable cause)
      │
      ├─── SYMPTOMATIC PHARMACOLOGICAL
      │     ├── Cognitive: Cholinesterase inhibitors (AD, DLB)
      │     ├── Behavioural: SSRIs (FTD, depression)
      │     ├── Psychosis: Quetiapine (avoid typical antipsychotics in DLB)
      │     └── Chorea: Tetrabenazine (Huntington)
      │
      ├─── NON-PHARMACOLOGICAL
      │     ├── Cognitive stimulation therapy
      │     ├── Occupational therapy / ADL support
      │     ├── Speech & language therapy
      │     └── Carer education & support
      │
      ├─── SOCIAL / LEGAL
      │     ├── Driving cessation (early counselling)
      │     ├── Power of attorney / advance directives
      │     ├── Work/financial planning (younger patients still employed)
      │     └── Child/family counselling (genetic implications)
      │
      └─── SPECIALIST REFERRAL
            ├── Neurologist (diagnosis, imaging, genetic)
            ├── Neuropsychologist (formal testing)
            ├── Geriatric psychiatry (BPSD management)
            └── Genetic counsellor (hereditary causes)

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VIVA KEY POINTS — CRISP ANSWERS

1. Definition: YOD = onset < 65 yrs; strict definition < 45 yrs (Mayo/Kelley)
2. Most common cause <45: Frontotemporal dementia + Huntington disease
3. Most common cause 45–65: Alzheimer disease
4. Most important distinction from late-onset: Higher proportion of treatable/reversible causes; genetic aetiology more prominent; social consequences more severe (employment, childcare, finances)
5. Why investigate thoroughly?: ~10–20% have treatable causes; missing them is catastrophic
6. Fastest to diagnose (must not miss): Autoimmune encephalitis, neurosyphilis, B12/thiamine, hypothyroidism, NPH, subdural haematoma
7. Rapidly progressive YOD → prion disease until proven otherwise; send RT-QuIC, 14-3-3, EEG
8. CSF biomarkers in AD: ↑ p-tau, ↑ t-tau, ↓ Aβ42
9. DLB: Never give typical antipsychotics — risk of severe neuroleptic sensitivity reaction
10. FTD vs AD: FTD = personality/behaviour change first, memory relatively preserved early; AD = memory loss first

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Approach to Inflammatory Myopathies — Viva Crisp Notes

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CLASSIFICATION (Current Framework)

INFLAMMATORY MYOPATHIES (IMs)
├── Dermatomyositis (DM) — including Juvenile DM
├── Polymyositis (PM) — rare as isolated entity
├── Immune-Mediated Necrotizing Myopathy (IMNM)
├── Antisynthetase Syndrome (ASyS)
├── Inclusion Body Myositis (IBM)
└── Others:
    ├── Overlap myositis (with CTD)
    ├── Checkpoint inhibitor myositis
    ├── Infectious myositis
    ├── Eosinophilic / Granulomatous myositis
    └── Paraneoplastic myositis

True isolated PM without overlap signs is now considered rare — many previously labelled PM were actually IMNM, IBM, or muscular dystrophies.

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EPIDEMIOLOGY AT A GLANCE

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STEP-BY-STEP CLINICAL APPROACH

PATIENT WITH MUSCLE WEAKNESS
          │
          ▼
STEP 1: LOCALISE THE LESION
├── UMN signs? → CNS
├── Wasting + fasciculations? → Anterior horn cell / MND
├── Sensory loss + areflexia? → Peripheral nerve
├── Ptosis + fatigability? → NMJ (MG)
└── Proximal weakness, NO sensory loss → MYOPATHY
          │
          ▼
STEP 2: IS IT INFLAMMATORY?
├── Subacute onset
├── Elevated CK
├── Elevated ESR/CRP
├── Skin rash (heliotrope, Gottron's)
├── Systemic features (ILD, arthritis, Raynaud's)
└── Auto-antibodies positive
          │
          ▼
STEP 3: WHICH SUBTYPE?

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SUBTYPE DIFFERENTIATION — FLOWCHART

SUSPECTED INFLAMMATORY MYOPATHY
              │
    ┌─────────┴─────────┐
    │                   │
Proximal > Distal    Finger flexor + Quadriceps weakness
weakness             (distal + proximal, asymmetric)
    │                   │
    ▼                   ▼
Has RASH?          Suspect IBM
    │               → See IBM pathway
  ┌─┴─┐
Yes   No
 │     │
 ▼     ▼
DM    PM / IMNM / ASyS
      │
   Has anti-HMGR or anti-SRP?
   │                    │
  Yes                  No
   │                    │
  IMNM            Anti-tRNA synthetase?
                  (anti-Jo-1, PL-7, PL-12, EJ, OJ)
                   │           │
                  Yes          No
                   │           │
                 ASyS          PM (or overlap)

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DERMATOMYOSITIS (DM)

Skin Features — Must Know

Pathology

• Perimysial + perivascular inflammation
• Inflammatory infiltrate: CD4+ T cells, B cells, dendritic cells, macrophages
• MAC (complement C5b-9) deposition on capillaries
• MxA expression on fibres — marker of type-I interferon signature (DM-specific)
• Perifascicular atrophy — hallmark

MSAs in DM

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POLYMYOSITIS (PM)

• Proximal > distal symmetric weakness, no rash
• Endomysial inflammation (vs perimysial in DM)
• Infiltrate: CD8+ T cells + macrophages (cytotoxic T-cell mediated — invade non-necrotic fibres)
• MHC-I ubiquitously upregulated on muscle fibres
• Diagnose by exclusion — must rule out IBM, IMNM, muscular dystrophy
• ⚠️ Many "PM" diagnoses historically were actually IMNM or IBM

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IMMUNE-MEDIATED NECROTIZING MYOPATHY (IMNM)

Key Features

• Acute/insidious proximal > distal weakness
• CK markedly elevated (>10× ULN, often 5000–50,000 U/L)
• Minimal inflammatory infiltrate on biopsy — predominantly necrotic fibres
• MAC deposition on non-necrotic fibres + MHC-I upregulation

Two MSA-defined subtypes

Statin toxic myopathy: improves with cessation. Anti-HMGR IMNM: does NOT improve — requires immunotherapy

• 90% require 2nd-line agent within 6 months — start early
• Anti-HMGR IMNM: IVIG may work as monotherapy (useful if steroids contraindicated)

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ANTISYNTHETASE SYNDROME (ASyS)

The Antisynthetase Triad (Classic)

1. Inflammatory myopathy
2. Interstitial lung disease (ILD) — can be life-threatening
3. Inflammatory arthritis

Additional Features

• Mechanic's hands (hyperkeratotic, fissured lateral fingers)
• Raynaud's phenomenon
• Fever
• Anti-Jo-1 most common (others: anti-PL-7, PL-12, EJ, OJ, KS)

Anti-MDA5 ≠ ASyS — anti-MDA5 is a DM-MSA with amyopathic DM + rapidly progressive ILD

• ASyS frequently fails corticosteroid monotherapy — early 2nd-line agent needed

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INCLUSION BODY MYOSITIS (IBM)

Clinical Pearls

• Most common myopathy in >50 years; M > F
• Distal + proximal involvement — asymmetric
• Characteristic pattern: deep finger flexors (flexor pollicis longus) + quadriceps
• Wrist/finger flexors > extensors
• Facial weakness + dysphagia in 1/3
• No myalgia
• Mimics MND (asymmetry + large MUPs on EMG) — but no fasciculations, no intrinsic hand wasting, reflexes preserved/reduced

Biopsy Hallmarks

• Endomysial inflammation + CD8+ T-cell invasion (similar to PM)
• Rimmed vacuoles (red rim on modified Gomori trichrome)
• TDP-43 inclusions — very specific
• p62 inclusions — very sensitive
• EM: tubulofilamentous inclusions 15–21 nm diameter

Antibody

• Anti-cN-1A (anti-NT5c1A): present in ~70% — specificity >90% for IBM vs other myopathies

Treatment

• No disease-modifying treatment proven effective
• Prednisone, IVIG, MTX, alemtuzumab — all negative in trials
• Management = supportive: fall prevention, ankle supports, gait aids, tendon transfer for hand function

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INVESTIGATIONS FLOWCHART

INVESTIGATIONS
│
├── BLOODS
│   ├── CK — key screening + monitoring marker
│   ├── LDH, AST, ALT (muscle enzyme panel)
│   ├── ESR, CRP, CBC
│   ├── ANA (screen for CTD overlap)
│   └── Myositis-specific antibodies (MSA) + myositis-associated antibodies (MAA)
│
├── EMG/NCS
│   ├── Fibrillation potentials + PSWs (irritable myopathy)
│   ├── Small short polyphasic MUPs (myopathic)
│   ├── IBM: MIXED pattern (small + large MUPs — mimics neurogenic)
│   └── Guides biopsy site (avoid EMG'd muscle)
│
├── MRI MUSCLE (STIR)
│   ├── Oedema/inflammation = bright signal
│   ├── PM: rectus femoris prominent
│   ├── IBM: vastus lateralis/medialis with relative sparing of rectus femoris
│   └── Guides biopsy to most active area
│
├── MUSCLE BIOPSY — Gold Standard
│   ├── DM: perimysial + perivascular; perifascicular atrophy; MAC on capillaries
│   ├── PM: endomysial CD8+ T cells; MHC-I expression
│   ├── IMNM: necrosis >> inflammation; MAC on non-necrotic fibres
│   ├── IBM: rimmed vacuoles; TDP-43; tubulofilaments on EM
│   └── SKIN BIOPSY: for DM diagnosis (± muscle biopsy)
│
├── PULMONARY
│   ├── CXR + HRCT chest (ILD screen — all new IMs)
│   └── PFTs (FVC, DLCO)
│
└── MALIGNANCY SCREEN (all adult DM, especially anti-TIF1-γ)
    ├── CT chest/abdomen/pelvis
    ├── FDG-PET (increasing utility)
    ├── PSA, mammogram, colonoscopy (age/sex appropriate)
    └── Repeat at 3 years (malignancy can precede or follow DM)

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TREATMENT FLOWCHART

Treatment Summary

DM / PM / IMNM WITH MUSCLE WEAKNESS
│
├── FIRST LINE
│   Prednisone 0.7–1 mg/kg/day (up to 60 mg/day) × 2–4 months
│   OR IV methylprednisolone 1 g/day × 3–5 days (severe disease)
│   → Maintain until strength improves + CK normalises
│   → Then slow taper: 10 mg/month → reach 20 mg → taper more slowly
│   → Monitor: glucose, K+, BP, eyes annually, bones (Ca + Vit D)
│
├── SECOND LINE (add if: poor response 2–4 months, relapse on taper, steroid toxicity)
│   ├── Methotrexate: 7.5 mg/week → titrate to 20 mg/week + folic acid 1 mg/day
│   ├── Azathioprine: 1–3 mg/kg/day
│   ├── Mycophenolate mofetil: 2–3 g/day
│   └── IVIG: 2 g/kg over 2–5 days (Grade A evidence in DM)
│
├── THIRD LINE / REFRACTORY
│   ├── Rituximab (anti-CD20)
│   ├── Cyclophosphamide (severe ILD)
│   ├── Tacrolimus / ciclosporin
│   └── Plasma exchange
│
├── DM SKIN ONLY
│   ├── Topical steroids
│   ├── Hydroxychloroquine / chloroquine
│   └── Sun protection
│
└── IBM
    └── SUPPORTIVE ONLY (no immunotherapy shown effective)
        ├── Avoid falls
        ├── AFOs / gait aids
        └── Tendon transfer (hand function)

Antibody-guided treatment

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MALIGNANCY ASSOCIATION — VIVA MUST

• DM: 18–32% associated with malignancy (highest risk 3 yrs before/after diagnosis)
• PM: ~10–15%
• IBM: No significant malignancy association
• IMNM: can be paraneoplastic (anti-SRP less so; HMGR less so)
• Most common cancers: ovary, lung, GI, breast, lymphoma
• Anti-TIF1-γ = strongest malignancy predictor in adult DM

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SYSTEMIC COMPLICATIONS

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KEY VIVA TRAPS

1. IBM vs PM on biopsy: Both show endomysial CD8+ infiltrate — rimmed vacuoles + TDP-43 = IBM
2. IBM vs MND: IBM has finger flexor > extensor weakness, no true fasciculations, no UMN signs, no intrinsic hand wasting
3. IMNM is NOT the same as toxic statin myopathy — toxic myopathy resolves on stopping statin; IMNM persists and needs immunotherapy
4. Anti-MDA5 = amyopathic DM + rapidly progressive ILD — muscle CK may be normal
5. Perifascicular atrophy = DM even without inflammation visible on biopsy
6. MAC on capillaries = DM; MAC on non-necrotic fibres = IMNM
7. DM infiltrate = CD4+ / B cells / macrophages; PM/IBM = CD8+ T cells (cytotoxic)
8. IVIG has Grade A RCT evidence in DM (NEJM 2022 trial — Aggarwal et al.)
9. IBM never responds to immunotherapy — do not treat with steroids expecting benefit
10. Juvenile DM: Calcinosis is prominent; vasculitis more common; skin can precede weakness by months

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