​​​​​​​During a genetic study, several members of a family are found to have an abnormality affecting a gene located on chromosome 21.  The gene encodes a cell surface protein that is processed by proteolytic enzyme cleavage.  In the affected individuals, there is an increased number of hydrophobic fragments of the protein, which are prone to aggregation into insoluble fibrils.  Which of the following is the most likely result of the genetic abnormality in these individuals? The amyloid precursor protein (APP) gene (located on chromosome 21) encodes a transmembrane protein that is normally involved in synaptic formation and repair.  APP is processed in 1 of 2 pathways by a series of secretases (proteolytic enzymes): processing via the alpha- and gamma-secretase pathway, which does not result in amyloidogenic proteins, or processing via the beta- and gamma-secretase pathway, which results in the production of beta amyloid. If beta amyloid is not sufficiently cleared by cellular processes, it can form insoluble fibrils and contribute to the generation of extracellular amyloid plaques that accumulate in the brain.  These aggregates of beta amyloid are neurotoxic and associated with the development and progression of Alzheimer dementia, a disease characterized by accelerated neurodegeneration leading to progressive cognitive dysfunction.  As a result, patients who have abnormal APP processing, impaired beta-amyloid clearance, or production of higher levels of APP (eg, trisomy 21 [Down syndrome]) are at increased risk of developing Alzheimer dementia. (Choice A)  Patients with trisomy 21 have an increased risk of hematologic malignancies such as acute lymphoblastic leukemia and acute megakaryoblastic leukemia.  This is thought to be related to the high susceptibility of megakaryocytic and B-cell precursors to increased dosage of chromosome 21 genes. (Choice C)  Erythrocyte membrane distortion most often occurs with abnormalities affecting either the cytoskeleton (eg, spectrin/ankyrin in hereditary spherocytosis) or hemoglobin (eg, beta globin in sickle cell disease). (Choice D)  Pulmonary elastic tissue loss can occur when there is excessive alveolar elastin degradation (eg, alpha-1 antitrypsin deficiency).  Alpha-1 antitrypsin is a serine protease inhibitor that is synthesized in the liver and released into the systemic circulation. (Choice E)  Skeletal myofiber disruption (eg, muscular & myotonic dystrophy) can occur with numerous mutations affecting the internal cytoskeletal system and contractile components (eg, sarcomere, costamere proteins).  However, it is not typically related to impaired proteolytic cleavage and does not result in precipitation of insoluble fibrils. Educational objective: The amyloid precursor protein (APP) gene is located on chromosome 21 and encodes a cell-surface protein that can be degraded into beta amyloid.  Abnormal APP processing, impaired beta-amyloid clearance, and production of higher levels of APP are associated with the increased formation of the neurotoxic plaques that characterize Alzheimer dementia. Convert this UWorld question into ultra high-yield USMLE notes: 1. Diagnosis: 2. Key clue from question stem (1 line): 3. Why correct answer (max 2 lines): 4. Why others wrong (1 line each): 5. Buzzword trigger: 6. Trap / trick tested: 7. One-liner memory hook: Make it extremely concise. No paragraphs.

​​​​​​​A 72-year-old woman comes to the office for a routine follow-up visit accompanied by her son.  The patient has experienced progressive memory loss over the last 2 years.  She now needs help with her daily activities, such as shopping and housekeeping.  The patient's son says, "She used to be such an independent person, but now she needs help with most things.  She even forgot my name the other day!"  Medical history includes hypertension, hyperlipidemia, and type 2 diabetes mellitus.  Family history includes major depressive disorder in her father.  MRI reveals diffuse cortical and hippocampal atrophy.  Which of the following biochemical changes is most likely contributing to this patient's condition? Clinical features of Alzheimer disease Early findings Anterograde memory loss (ie, immediate recall affected, distant memories preserved) Visuospatial deficits (eg, lost in own neighborhood) Language difficulties (eg, difficulty finding words) Cognitive impairment with progressive decline Late findings Neuropsychiatric (eg, hallucinations, wandering) Dyspraxia (eg, difficulty performing learned motor tasks) Lack of insight regarding deficits Noncognitive neurologic deficits (eg, pyramidal & extrapyramidal motor, myoclonus, seizures) Urinary incontinence Alzheimer disease (AD) is the most common cause of dementia.  It has the following characteristic features: Prevailing clinical symptom: slow, progressive memory loss Macroscopic brain appearance: mild-to-moderate generalized brain atrophy Microscopic brain changes: neurofibrillary tangles, senile plaques, and amyloid angiopathy Biochemical abnormalities: decreased acetylcholine levels in the hippocampus and nucleus basalis of Meynert The most important biochemical abnormality noted in AD is a decrease in the acetylcholine level.  This occurs due to a deficiency of choline acetyltransferase.  The decline in acetylcholine is most notable in the nucleus basalis of Meynert, which participates in memory and cognition.  This nucleus is located at the base of the forebrain and widely projects to the neocortex.  Another involved structure is the hippocampus:  The major function of the hippocampus is the formation of new memories. Symptomatic management of AD includes cholinesterase inhibitors, which target the acetylcholine deficit by inhibiting the degradation of acetylcholine at the synaptic cleft. (Choice B)  Loss of dopaminergic neurons in the substantia nigra is seen in Parkinson disease and dementia with Lewy bodies. (Choice C)  The raphe nuclei form the medial part of the brain stem's reticular formation (medulla, pons, and midbrain).  Many neurons in the nuclei are serotonergic.  Serotonin is implicated in the pathogenesis of anorexia, depression, and sleep disorders. (Choice D)  Atrophy of the caudate nucleus is seen in Huntington disease. (Choice E)  The locus ceruleus is thought to play a role in the pathogenesis of panic attacks and panic disorder.  It is located in the pons and contains cell bodies of noradrenergic neurons that synthesize norepinephrine. Educational objective: Alzheimer disease is characterized by decreased levels of acetylcholine in the nucleus basalis of Meynert and the hippocampus, caused by diminished activity of choline acetyltransferase.

​​​​​​​A 42-year-old woman comes to the office with her husband for evaluation of abnormal movements.  The patient has been having involuntary facial grimaces and extremity fidgeting.  She has no prior medical or psychiatric conditions, but her husband says she has had frequent anger outbursts over the past year.  The patient takes no medications.  She smoked cigarettes and used illicit drugs for several years during college but not since then.  Her father died of a neurological disorder at age 55.  Physical examination shows intermittent, fidgety, jerky movements of the hands.  MRI of the brain is ordered.  Which of the following neuroimaging findings is most likely to be seen in this patient? Huntington disease Pathogenesis Autosomal dominant inheritance Increased number of CAG repeats in HTT gene Anticipation: earlier onset, more severe disease in subsequent generations Gain of function mutation: protein accumulation toxic to neurons Decrease in GABA & acetylcholine in caudate nuclei Clinical features Chorea: involuntary, jerky movements of face & extremities Behavioral abnormalities (eg, aggressiveness, depression) Progressive dementia Confirmatory testing Neuroimaging: caudate atrophy with enlargement of the lateral ventricles Genetic testing for number of CAG repeats This patient with chorea (eg, fidgety, jerky, involuntary movements), behavioral abnormalities (eg, outbursts of anger), and a family history of a fatal neurological disease likely has Huntington disease (HD).  HD is an autosomal dominant, progressive neurodegenerative disorder that results in the production and accumulation of abnormal huntingtin protein, which is toxic to neurons. Although patients with HD display generalized cortical atrophy as the disease progresses, the most prominent atrophy is seen bilaterally in the caudate nucleus and putamen, leading to the enlargement of the frontal horns of the lateral ventricles.  The loss of inhibitory GABAergic neurons in these areas causes decreased regulation of the movement and behavioral centers of the cerebral cortex, resulting in the characteristic constellation of symptoms in patients with HD. (Choice A)  Diffuse ventriculomegaly without sulcal widening is seen in normal pressure hydrocephalus (eg, urinary incontinence, gait disturbance, cognitive impairment) due to an increase in cerebrospinal fluid volume.  In contrast, neurodegenerative disorders such as Huntington disease typically present with both ventriculomegaly and sulcal widening due to generalized cortical atrophy. (Choice C)  A hypoplastic cerebellar vermis with cystic dilation of the fourth ventricle and a posterior fossa cyst is characteristic of congenital Dandy-Walker malformation.  Although the diagnosis of Dandy-Walker malformation can be delayed into early adulthood, patients typically have a long history of chronic headaches and neurologic abnormalities (eg, unsteady gait, facial palsy). (Choices D and E)  Early-onset Alzheimer disease (eg, bilateral hippocampal atrophy) or frontotemporal dementia (eg, frontal/temporal lobe atrophy) can present in patients as early as the fourth decade.  However, changes in memory, speech, or behavior are the predominant symptoms at presentation; movement abnormalities (eg, myoclonus, akinesia, hyperreflexia) typically develop later in the disease course. Educational objective: Huntington disease is an autosomal dominant neurodegenerative disorder that manifests with chorea (eg, involuntary, jerky, fidgety movements) and behavioral abnormalities (eg, aggressiveness, depression).  Characteristic neuroimaging findings include atrophy of the caudate nuclei which results in enlargement of the frontal horns of the lateral ventricles.

​​​​​​​A 54-year-old man is brought to the office by his daughter.  She says that her father has been acting strangely over the past 2 years.  He makes inappropriate sexual jokes, has little regard for social rules, is often irritable, and is borderline aggressive at times.  The patient denies that his personality is any different from normal.  When speaking with the patient, the physician notices that he has minimal verbal output and repeats "it is what it is" when asked questions about his strange behavior.  On physical examination, he appears unkempt but otherwise has no significant findings.  This patient most likely has a condition that predominantly involves which of the following structures? Explanation Differential diagnosis of dementia subtypes Alzheimer disease Early, insidious short-term memory loss Language deficits & spatial disorientation Later personality changes Vascular dementia Stepwise decline Early executive dysfunction Cerebral infarction &/or deep white matter changes on neuroimaging Frontotemporal dementia Early personality changes Apathy, disinhibition & compulsive behavior Frontotemporal atrophy on neuroimaging Dementia with Lewy bodies Visual hallucinations Spontaneous parkinsonism Fluctuating cognition Rapid eye movement behavior disorder Normal pressure hydrocephalus Ataxia early in disease Urinary incontinence Dilated ventricles on neuroimaging Prion disease Behavioral changes Rapid progression Myoclonus &/or seizures This patient's personality and behavioral changes (eg, disinhibition, apathy, social inappropriateness, compulsive behaviors) and altered speech patterns (eg, paucity of speech, repeated phrases) are consistent with a diagnosis of behavioral variant frontotemporal dementia (FTD).  Personality and behavioral changes present early in the disease course with neurocognitive deficits occurring later.  FTD is highly heritable and a common cause of early-onset dementia. FTD is characterized by initial degeneration of the prefrontal cortex that eventually progresses to include the anterior temporal cortex.  Loss of function in the prefrontal cortex can cause inappropriate behavior, impaired judgment, and poor problem-solving skills (ie, executive dysfunction). (Choice B)  The caudate nucleus and putamen are basal ganglia structures that together form the dorsal striatum, which regulates voluntary movements.  Huntington disease causes atrophy of the dorsal striatum (there is greater relative atrophy of the caudate) and presents with choreiform movements, psychiatric symptoms (eg, irritability, depression), and dementia.  This patient's prominent personality changes and lack of a movement disorder are not characteristic of Huntington disease. (Choice C)  Neuronal loss in the locus ceruleus and substantia nigra is seen in Parkinson disease, which typically presents with tremor, bradykinesia, and rigidity.  The locus ceruleus is a pontine structure that is one of the primary areas of norepinephrine synthesis in the brain.  The substantia nigra, located in the midbrain, contains dopaminergic neurons whose axons project to the striatum (nigrostriatal pathway) and participate in regulation of voluntary movements. (Choice D)  Damage to the mammillary bodies and medial thalamus is characteristic of chronic Wernicke encephalopathy and Korsakoff syndrome.  Both disorders result from chronic thiamine deficiency, most often in the context of heavy alcohol use. (Choice E)  Medial temporal and parietal cortical atrophy is characteristic of Alzheimer disease.  The medial temporal lobe contains the hippocampus, a structure involved in the formation of new memories. (Choice F)  Disproportionate atrophy of the parietal and occipital cortices is seen in posterior cortical atrophy, an atypical variant of Alzheimer disease with prominent visual symptoms. Educational objective: Frontotemporal dementia is associated with pronounced atrophy of the prefrontal cortex with later degeneration of the anterior temporal cortex.  It manifests initially with changes in personality, social behavior, and language that progress over time to a more global dementia with obvious neurocognitive deficits.

A 52-year-old man is brought to the office due to social withdrawal and inability to care for himself.  The patient is divorced and lives alone, and he was found to be living in disarray by his daughter, who is visiting from out of state.  His neighbors and friends say the patient rarely comes out of the house or contacts them.  During previous visits, his daughter noticed fidgety movements of his hands, but now he has marked jerky movements of his extremities with frequent facial grimaces.  He has a history of depression with frequent angry outbursts that led to his divorce several years ago.  The patient has no other medical conditions and does not use tobacco, alcohol, or illicit drugs.  He was adopted and his family history is unknown.  On physical examination, the patient is forgetful and has slowed mental processing.  Involuntary, spasmodic movements of the hands and facial muscles are present.  Deep tendon reflexes and sensation are normal.  The loss of neurons supplying which of the following neurotransmitters is most specific for this patient's disease process? his patient with behavioral abnormalities (eg, mood changes, withdrawal), cognitive impairment, and chorea (eg, jerky, fidgety, involuntary movements) most likely has Huntington disease (HD).  HD is a neurodegenerative disorder inherited as an autosomal dominant trait and classically manifests between ages 30 and 50.  Excessive CAG trinucleotide repeats cause a gain-of-function mutation that leads to the accumulation of abnormal huntingtin protein in neural cells. The inhibitory GABAergic neurons in the caudate nuclei (striatum) are especially vulnerable and atrophy early in the course of the disease.  These neurons play an important role in regulating both emotional and motor impulses from the cerebral cortex, and their loss is central to the behavioral and movement changes in HD.  As HD progresses, neuronal atrophy becomes more widespread.  Patients display features of advanced dementia (eg, memory loss, facial agnosia, incontinence) with bradykinesia and near-total absence of voluntary movement. (Choice A)  The largest concentration of acetylcholine-producing neurons in the brain is found in the amygdala (eg, nucleus basalis of Meynert).  Although there are lower levels of acetylcholine in the amygdalas of patients with HD, this change is not specific to the disease (it also occurs in Alzheimer and Lewy body dementia), and atrophy of these neurons does not occur until late in the clinical course. (Choice B)  In HD, dopamine is typically increased, likely due to the loss of regulation by inhibitory GABA-producing neurons.  Loss of dopaminergic neurons in the substantia nigra and striatum is found in Parkinson disease. (Choices D and E)  Reduced concentrations of norepinephrine and serotonin in the CNS are associated with depression, which can be treated with agents (eg, SSRIs, SNRIs) that block the reuptake or degradation of these neurotransmitters. Educational objective: Huntington disease is an autosomal dominant neurodegenerative disease that leads to the accumulation of abnormal, toxic huntingtin protein in neural cells.  Inhibitory GABAergic neurons in the caudate nuclei are most susceptible, and their loss is responsible for the characteristic manifestations of Huntington disease (eg, chorea, behavioral abnormalities).