STEPTRACKERNERVOUS SYSTEM | PATHOLOGY + PHARMACOLOGY + GENETICS | HIGH-YIELD REVIEW

Dementias

Progressive loss of cognition — each degenerative dementia has its own protein, first symptom and pattern of atrophy; some causes are reversible.

FOCUS ON
Alzheimer: memory first; Aβ plaques + tau tangles, hippocampal atrophy, ↓ ACh; APOE4, Down syndrome. Frontotemporal: personality/language first, younger, Pick bodies. Lewy body: visual hallucinations, fluctuations, parkinsonism, antipsychotic sensitivity. Vascular: stepwise. Always rule out reversible causes: B12, thyroid, syphilis, NPH, depression, thiamine.
DISORDER
MECHANISM · PATHOLOGY
FEATURES
CLUE · TREATMENT
Alzheimer disease
most common
Extracellular Aβ plaques (from APP, chr 21) + intracellular neurofibrillary tangles (hyperphosphorylated tau); ↓ ACh (nucleus basalis of Meynert)
Gradual short-term memory loss → language, visuospatial, executive, behavior; hippocampal/temporoparietal atrophy
Tangles correlate with severity · Hirano bodies, granulovacuolar degeneration
Alzheimer — genetics
Early onset: APP (Down syndrome), PSEN1, PSEN2 · late onset: APOE4 ↑ risk, APOE2 protective
Down syndrome → Alzheimer by 40s (extra APP)
Also cerebral amyloid angiopathy
Alzheimer — treatment
Boost ACh; block excitotoxicity; clear amyloid
AChE inhibitors (donepezil, rivastigmine, galantamine); memantine (NMDA antagonist); anti-amyloid antibodies (lecanemab)
Anti-amyloid → ARIA (edema, microbleeds)
Frontotemporal dementia
Frontal/temporal lobe degeneration; Pick bodies (round tau aggregates), TDP-43; C9orf72 (with ALS)
Age 50s–60s: early personality change, disinhibition, apathy, hyperorality, compulsions, or progressive aphasia; memory spared early
"Knife-edge" frontotemporal atrophy
Dementia with Lewy bodies
Cortical α-synuclein Lewy bodies
Dementia + visual hallucinations + fluctuating attention + parkinsonism within a year; REM sleep behavior disorder
Severe reactions to antipsychotics
Vascular dementia
Multiple infarcts or diffuse small-vessel disease
Stepwise decline, focal signs, executive dysfunction; HTN, diabetes, smoking
MRI: infarcts, white-matter changes
Creutzfeldt-Jakob disease
Prion; spongiform change
Very rapid dementia + startle myoclonus
Detail: 16.07
Wernicke-Korsakoff
Thiamine deficiency (alcoholism, malnutrition, hyperemesis) → mammillary bodies, medial thalamus
Wernicke: confusion, ophthalmoplegia, ataxia · Korsakoff: anterograde + retrograde amnesia, confabulation
Give thiamine before glucose
Reversible causes
Treatable conditions that mimic dementia
B12 deficiency, hypothyroidism, neurosyphilis, NPH, depression (pseudodementia), drugs (anticholinergics, benzodiazepines), HIV
Check B12, TSH, RPR in every workup
HIV-associated neurocognitive disorder
Infected microglia/macrophages; microglial nodules, multinucleated giant cells
Subcortical dementia: slowness, apathy, motor problems
Improves with ART
Delirium vs dementia
Delirium: acute brain dysfunction from systemic illness, drugs, withdrawal
Acute onset, fluctuating attention and consciousness, hallucinations; reversible
Abnormal EEG (diffuse slowing) · find the cause

Mechanism — amyloid and tau

APPMembrane protein
→
α-secretaseNon-amyloidogenic
β- then γ-secretaseAβ42 (PSEN = γ-secretase)
→
Oligomers → plaques
Aβ toxicity
→
Tau hyperphosphorylationMicrotubules collapse
→
Tangles, neuron loss↓ ACh, atrophy

Dementias compared

TYPE
PROTEIN
FIRST SIGN
DISTINCT CLUE
Alzheimer
Aβ, tau
Memory
Hippocampal atrophy
Frontotemporal
Tau, TDP-43
Behavior / language
Younger, Pick bodies
Lewy body
α-synuclein
Hallucinations, fluctuations
Parkinsonism early
Parkinson dementia
α-synuclein
Motor first (> 1 year)
Dementia late
Vascular
—
Executive, stepwise
Infarcts on MRI
CJD
Prion
Rapid decline
Myoclonus, EEG

How it's tested

COMMON CONFUSIONLewy body dementia vs Parkinson disease dementia: the "one-year rule" — cognitive symptoms before or within a year of parkinsonism = Lewy body dementia.
THE TRAPHaloperidol for hallucinations in Lewy body dementia can cause severe rigidity and neuroleptic malignant–like reactions.
YOUR APPROACHAcute or chronic (delirium vs dementia) → reversible screen → first domain affected → time course (gradual, stepwise, rapid) → associated signs → protein and drug.

If you see… think…

75-year-old losing recent memories over years, hippocampal atrophy → Alzheimer disease
Down syndrome adult with early dementia → Alzheimer (extra APP on chr 21)
Gene variant that raises late-onset Alzheimer risk → APOE4
55-year-old with new disinhibition and compulsive eating → frontotemporal dementia
Dementia, vivid visual hallucinations, fluctuating alertness, rigidity → Lewy body dementia
Stepwise decline after several small strokes → vascular dementia
Alcoholic with ataxia, confusion and nystagmus → Wernicke — thiamine first
Memory loss with confabulation, mammillary body atrophy → Korsakoff syndrome
Dementia with macrocytosis and ↓ vibration sense → B12 deficiency
NMDA antagonist for moderate–severe Alzheimer → memantine