Dementias | Bone Wizardry

01 · The Four Types

The Four Dementias

Different pathologies, different first symptoms, and one detail that changes everything on boards.

Alzheimer Disease (AD)

Most common dementia (60-80% of cases). Insidious onset, relentless progression.

Sequence of decline

Memory (hippocampus) → Language / Aphasia (temporal) → Visuospatial (posterior cortex) → Global impairment

Pathology

Beta-amyloid plaques (senile plaques) are extracellular deposits of amyloid-beta 42 peptide. They accumulate outside neurons, especially in the hippocampus and cortex.

Neurofibrillary tangles are intracellular aggregates of hyperphosphorylated tau protein. Tau normally stabilizes microtubules. When hyperphosphorylated, it detaches and clumps, destroying the neuron's transport system.

Cholinergic deficit: loss of acetylcholine-producing neurons in the nucleus basalis of Meynert (basal forebrain). This is the pharmacological target.

Genetics

ApoE4 (chromosome 19): biggest risk factor for sporadic AD. Does not cause AD outright but lowers age of onset.
Presenilin 1 (chr 14): most common cause of early-onset familial AD.
Presenilin 2 (chr 1): rare, later onset than PS1.
APP (chr 21): mutation causes familial AD. Explains why Down syndrome (trisomy 21 = 3 copies of APP) develops Alzheimer pathology by age 40.

Treatment

Mild-moderate: AChE inhibitors (donepezil, rivastigmine, galantamine). Increase ACh by blocking the enzyme that breaks it down.
Moderate-severe: Memantine (NMDA receptor antagonist). Blocks excitotoxic glutamate signaling.
Severe: Combination AChEI + memantine.

Memory first Tau tangles + A-beta plaques ApoE4 risk AChEI + memantine Trisomy 21 = early AD Nucleus basalis of Meynert

Lewy Body Dementia (DLB)

Second most common. The triad that separates it from everything else.

The Diagnostic Triad

Feature 1

Fluctuating Cognition

Waxes and wanes day-to-day. Looks like delirium. The patient can seem fine one day and profoundly confused the next. Distinguishes DLB from the steady decline of Alzheimer.

Feature 2

Recurrent Visual Hallucinations

Well-formed, vivid hallucinations. Often animals, children, or small people. Patients can describe them in detail. Occurs early in the disease, unlike Alzheimer where hallucinations appear late.

Feature 3

Parkinsonism

Bradykinesia, cogwheel rigidity, shuffling gait. Key rule: motor symptoms develop within 1 year of cognitive symptoms. If motor comes first by over a year, it is Parkinson disease dementia, not DLB.

Early clue (may precede dementia by years)

REM sleep behavior disorder (RBD): patients act out their dreams during REM sleep (may shout, kick, punch). RBD is the earliest prodromal marker of alpha-synuclein diseases (DLB, Parkinson disease, multiple system atrophy). When a patient presents with RBD years later develops cognitive decline and visual hallucinations, DLB is the answer.

Pathology and treatment

Pathology: cortical alpha-synuclein Lewy bodies (same protein as Parkinson disease, different distribution). In PD, Lewy bodies are in the substantia nigra. In DLB, they are throughout the cortex.

Treatment: AChE inhibitors for cognition. NEVER use typical antipsychotics (haloperidol). DLB patients have extreme neuroleptic sensitivity. Haloperidol can cause severe rigidity, irreversible Parkinsonism, or death. If agitation must be treated, use quetiapine (lowest D2 blockade) cautiously.

Board trap: DLB patient given haloperidol for "psychosis" = severe neuroleptic reaction. This is the most dangerous prescribing error in all of dementia management. If the question mentions antipsychotic selection in dementia with Parkinsonism or visual hallucinations, the answer is NEVER haloperidol.

Fluctuating cognition Visual hallucinations (early) Parkinsonism (within 1yr) REM sleep behavior disorder NO haloperidol Alpha-synuclein Lewy bodies

Frontotemporal Dementia (FTD)

Younger onset (50s-60s). Behavior or language changes before memory loss.

Two clinical variants

Variant 1 · More Common

Behavioral (bvFTD)

Frontal lobe dysfunction first: disinhibition (inappropriate social behavior, crude jokes), apathy, loss of empathy, compulsive or repetitive behaviors (same route, same food, same phrase). Patients seem "rude" or "changed" to family. Memory testing is relatively intact early.

Variant 2 · Language

Primary Progressive Aphasia

Language deteriorates before behavior or memory. Two subtypes: nonfluent/agrammatic (telegraphic speech, effortful) and semantic variant (loses word meanings, fluent but empty). Temporal lobe atrophy with language area involvement.

Key pathology and genetics

Pathology: TDP-43 inclusions (most common) or FUS protein inclusions. In Pick disease specifically: tau-positive Pick bodies in swollen neurons (Pick cells). MRI shows selective frontal and temporal lobe atrophy ("knife-edge" atrophy).

Genetics: C9ORF72 hexanucleotide repeat expansion is the most common genetic cause of FTD and also causes ALS. FTD-ALS overlap syndrome is well described, where patients develop both motor neuron disease and frontal dementia.

Boards tell: behavioral change (disinhibition, apathy, loss of empathy) with relatively preserved memory = FTD. Younger age, personality change noticed by family, inappropriate behavior in social settings. Alzheimer never presents with prominent disinhibition early.

Younger onset (50s-60s) Disinhibition / apathy Memory preserved early TDP-43 / FUS inclusions C9ORF72 (FTD + ALS link) Frontal + temporal atrophy

Vascular Dementia

Stepwise decline, not gradual. Each stroke = one step down, then plateau.

The key pattern

Stroke event → Sudden cognitive step-down → Plateau (stable) → Next stroke → Another step down

Compare to Alzheimer: gradual, continuous decline with no acute episodes. If the history includes strokes, TIAs, hypertension, diabetes, or atrial fibrillation and cognition drops abruptly, this is vascular dementia.

Clinical and imaging

Risk factors: HTN (biggest), diabetes, atrial fibrillation, dyslipidemia, smoking.
MRI findings: white matter hyperintensities (leukoaraiosis), lacunar infarcts in basal ganglia, thalamus, or internal capsule. Periventricular changes on T2/FLAIR.
First symptom: frontal-executive dysfunction (planning, working memory) is prominent early because white matter tracts connecting frontal lobes are vulnerable.
Treatment: control vascular risk factors (BP, blood sugar, anticoagulation for AFib). No specific dementia treatment.

Mixed dementia: Alzheimer + vascular is the most common combination in older patients. MRI with vascular changes does NOT rule out Alzheimer. The board tests pure vascular dementia with stepwise decline in a patient with heavy vascular risk factor history.

Stepwise progression White matter hyperintensities Lacunar infarcts on MRI Frontal-executive early Control risk factors HTN / DM / AFib history

02 · Always Rule Out First

Reversible Dementias

These mimic irreversible dementia but are treatable. Boards always test them.

The DEMENTIAS mnemonic covers all treatable causes: Drugs, Emotional (depression), Metabolic, Electrolytes, NPH, Tumor/Trauma, Infections, Anemia, Structural/Sleep apnea. In the real world AND on boards, rule these out before diagnosing an irreversible dementia.

Drugs and Depression ▸

Drugs (#1 cause of reversible dementia): polypharmacy, anticholinergics (diphenhydramine, tricyclics, bladder drugs), benzodiazepines, opioids. Any sedating medication in an older adult can cause apparent dementia. Stop the offender and cognition improves.

Depression (pseudodementia): depressed patients often complain of memory loss and score poorly on cognitive tests. Key distinguisher: a depressed patient says "I don't know" to every question (gives up, doesn't try). A demented patient confabulates (makes up plausible-sounding answers) or guesses. The depressed patient knows they're struggling. Treat depression first and reassess.

Normal Pressure Hydrocephalus ▸

Classic triad: "Wet, Wacky, Wobbly"
Wet = urinary incontinence
Wacky = cognitive impairment (subcortical pattern: slow, frontal-executive)
Wobbly = magnetic gait (wide-based, shuffling, feet seem stuck to floor, difficulty initiating steps)

Imaging: CT/MRI shows enlarged ventricles out of proportion to the degree of sulcal atrophy. This mismatch is the radiographic clue.

Diagnosis + treatment: large-volume LP (30-50 mL removed) causing improvement in gait is both diagnostic and temporarily therapeutic. Definitive treatment: ventriculoperitoneal (VP) shunt. Gait responds best to shunting. NPH is the most treatable cause of dementia.

Vitamin B12 Deficiency ▸

Mechanism: B12 (cobalamin) is required for myelin synthesis. Deficiency leads to subacute combined degeneration of the spinal cord (posterior columns = loss of proprioception/vibration; lateral corticospinal tracts = UMN signs) AND dementia from cortical involvement.

Labs: low serum B12, elevated homocysteine AND elevated methylmalonic acid. This dual elevation distinguishes B12 deficiency from folate deficiency (folate only elevates homocysteine, not MMA).

Causes: strict vegans (no animal products), pernicious anemia (anti-intrinsic factor antibodies block B12 absorption), long-term metformin, long-term PPIs, gastric bypass surgery.

Treatment: B12 supplementation. IM injection required if absorption is impaired (pernicious anemia, gastric bypass).

Creutzfeldt-Jakob Disease (CJD) ▸

Prion disease (misfolded PrP protein that converts normal PrP into misfolded form in a chain reaction). Technically not reversible, but tested alongside reversible causes because workup overlaps.

Clinical: Rapidly progressive dementia over weeks to months (not years). Myoclonus (especially startle myoclonus, exaggerated jerking response to noise or touch) is classic. Cerebellar ataxia, behavioral changes, visual disturbances.

Diagnostics:
EEG: periodic sharp wave complexes (1-2 Hz triphasic)
MRI DWI: cortical ribboning + basal ganglia hyperintensity
CSF: 14-3-3 protein elevated (marker of rapid neuronal destruction)

Variant CJD (vCJD): Bovine spongiform encephalopathy ("mad cow disease"). Younger patients. Psychiatric prodrome (depression, anxiety, personality change before cognitive decline). Pulvinar sign on MRI (thalamic hyperintensity). Universally fatal.

Board priority for reversible dementias: NPH = wet/wacky/wobbly + enlarged ventricles + responds to LP. B12 = elevated MMA (folate does NOT raise MMA). CJD = rapid dementia + myoclonus + EEG periodic sharp waves. Depression = "I don't know" pattern, not confabulation.

03 · Side by Side

Diagnosis and Workup

The one table that settles every board question about dementia type. Scroll horizontally on mobile.

Feature	Alzheimer	Lewy Body	Frontotemporal	Vascular
Onset	Gradual, insidious	Gradual	Gradual (younger)	Stepwise
First symptom	Memory	Fluctuating cognition	Behavior / personality	Executive dysfunction
Hallucinations	Late in disease	Early, visual, vivid	Uncommon	Uncommon
Parkinsonism	Late only	Early (within 1 yr)	Absent	Can occur (lacunes)
MRI	Hippocampal atrophy	Posterior cortex atrophy	Frontal/temporal atrophy	WM lesions, lacunes
Key biomarker	Amyloid PET, CSF A-beta/tau	DaTscan (dopamine imaging)	TDP-43 (biopsy/autopsy)	Vascular imaging
Pathology	Tau tangles + A-beta plaques	Alpha-synuclein Lewy bodies	TDP-43 or FUS inclusions	Infarcts, ischemia
Treatment	AChEI + memantine	AChEI + NO typicals	Behavioral management	Vascular risk factors

Lewy body = NEVER haloperidol. REM sleep behavior disorder = first clue (may predate dementia by years). Visual hallucinations = second clue. Parkinsonism within one year of cognitive onset = third clue. Any two of the three core features confirms DLB. DaTscan shows reduced dopamine uptake in striatum.

Memory first vs. behavior first: if memory is the first and dominant complaint, think Alzheimer. If personality or behavior changed first with relatively preserved memory, think FTD. If it fluctuates day-to-day like delirium, think Lewy body. If it steps down after strokes, think vascular.

04 · Elimination Game

Rule Out One by One

Use the clues to eliminate. One diagnosis survives.

Vignette A 68-year-old retired teacher has a 2-year history of progressive personality change and disinhibition. His daughter reports he made a crude joke at a funeral and cannot seem to understand why she was upset. He has started eating the same meal in the same restaurant every day. On cognitive testing, memory is relatively intact but verbal fluency is impaired. MRI shows prominent frontal and temporal lobe atrophy. He has no visual hallucinations and walks normally.

Alzheimer Disease

Lewy Body Dementia

Frontotemporal Dementia

Vascular Dementia

Clue 1 Behavioral changes (disinhibition, personality change, compulsive rituals) before memory loss = frontal lobe syndrome, not hippocampal. Alzheimer always leads with memory loss because the hippocampus is the first casualty. Here, memory is relatively preserved. Vascular dementia would require stroke history and stepwise deterioration, neither of which is present.

Clue 2 No Parkinsonism, no visual hallucinations, no fluctuating cognition = not Lewy body. Frontal and temporal atrophy on MRI with preserved posterior cortex rules out the posterior-predominant Lewy body pattern. This patient has bilateral frontal and anterior temporal atrophy, the signature of behavioral variant FTD (bvFTD). The disinhibition, loss of empathy, compulsive eating behavior, and preserved memory are exactly the frontal syndrome of bvFTD.

Frontotemporal Dementia (bvFTD)

Behavioral change before memory loss + frontal/temporal atrophy + disinhibition + compulsive behaviors + preserved memory = the bvFTD phenotype. TDP-43 inclusions on pathology. Look for C9ORF72 mutation if family history of FTD or ALS.

05 · Retrieval Practice

Quiz

Four board-style questions. Original vignettes. Commit to your answer before reading the explanation.

Question 1 of 4

A 77-year-old woman with dementia and visual hallucinations develops agitation and is given haloperidol 2 mg by the covering physician. Within 24 hours she is severely rigid, nearly unresponsive, and febrile with a creatine kinase of 12,000 U/L.

What is the MOST likely explanation for this complication?

AAcute extrapyramidal reaction from dopamine blockade in a neurologically intact patient

BSerotonin syndrome from an unrecognized drug interaction

CNeuroleptic sensitivity reaction in a patient with Lewy body dementia

DMalignant hyperthermia triggered by haloperidol

Tempting to give a typical antipsychotic for visual hallucinations in a demented patient, since haloperidol is a standard antipsychotic choice. The trap in DLB is that the dopamine tank is nearly empty from alpha-synuclein pathology in the substantia nigra. Think of blocking dopamine receptors in a DLB patient like slamming the brakes on a car that already has almost no engine power: the motor system locks up completely, giving catastrophic rigidity, autonomic crisis, and elevated CK. In a normal patient you just slow down; in DLB you stall the engine entirely. Correct: C. Neuroleptic sensitivity in Lewy body dementia. Patients with DLB have profoundly reduced nigrostriatal dopamine due to Lewy body pathology in the substantia nigra. Blocking the remaining dopamine receptors with a typical antipsychotic (haloperidol) precipitates catastrophic Parkinsonism-like rigidity, reduced consciousness, autonomic instability, and elevated CK resembling NMS. This is distinct from true NMS and is caused by the underlying alpha-synuclein pathology. Visual hallucinations in a demented patient should prompt immediate consideration of DLB before ANY antipsychotic is prescribed. Break it down: DLB = alpha-synuclein Lewy bodies in substantia nigra = severely depleted nigrostriatal dopamine; any D2 blocker in DLB = catastrophic rigidity, autonomic instability, elevated CK; visual hallucinations plus dementia = suspect DLB before ANY antipsychotic; if antipsychotic needed in DLB = use quetiapine or clozapine (low D2 affinity).

Question 2 of 4

An 80-year-old man is brought in by his family for urinary incontinence, memory impairment, and a progressively worsening gait. His wife says he shuffles with very small steps and has fallen twice. CT head shows markedly enlarged ventricles disproportionate to the cortical atrophy. A large-volume lumbar puncture is performed, removing 40 mL of CSF.

Which component of the classic triad responds BEST to ventriculoperitoneal shunting?

AUrinary incontinence

BGait disturbance

CCognitive impairment

DAll three respond equally well

Tempting to pick cognitive impairment: the family brought the patient in for memory problems, and improving cognition seems most important. The trap is that NPH cognition has a fixed component that shunting cannot reverse, while gait responds most consistently and is the most reliable predictor of surgical benefit. Think of the NPH triad as three workers buried under pressure: the gait worker climbs out first and most fully when pressure is released (CSF drained), the incontinence worker partially climbs out, and the cognition worker may be too deep to fully resurface. Correct: B. Gait disturbance responds best to VP shunting in NPH and is also the most reliable predictor of who will benefit from surgery. The magnetic gait (wide-based, small shuffling steps, difficulty initiating movement, feet appear stuck) is the hallmark feature and the one that improves most consistently. Cognitive impairment may partially improve but often has a fixed component. Urinary incontinence can improve but is less reliable. When the board asks "which symptom indicates a good shunt response" or "which responds best," gait is always the answer. Break it down: NPH classic triad = gait (magnetic/apractic) + urinary incontinence + cognitive impairment (wet, wacky, wobbly); shunt response = gait improves most + most reliably; incontinence partially improves; cognition partially improves but often has fixed component; gait improvement = best predictor of surgical success.

Question 3 of 4

A 65-year-old man with newly diagnosed Alzheimer disease is started on donepezil. His son asks which brain region is responsible for the cholinergic deficit that makes this medication effective.

Which structure is the primary source of cortical cholinergic innervation that is lost in Alzheimer disease?

ALocus coeruleus

BDorsal raphe nucleus

CNucleus basalis of Meynert

DSubstantia innominata exclusively

Tempting to pick substantia innominata since it sounds familiar and is in the right ballpark: the nucleus basalis of Meynert actually lives within the substantia innominata. The trap is that substantia innominata is the anatomical container, not the cell population that provides cholinergic projections. Think of the nucleus basalis as a specific broadcasting tower housed within a larger building (substantia innominata). Picking the building instead of the tower gives you the wrong answer for the specific mechanism. Locus coeruleus is the norepinephrine tower. Dorsal raphe is the serotonin tower. The cholinergic tower is the nucleus basalis. Correct: C. The nucleus basalis of Meynert (within the substantia innominata of the basal forebrain) is the primary source of cholinergic projections to the entire cortex and hippocampus. Selective neuronal loss here accounts for the cholinergic deficit that underlies Alzheimer's cognitive symptoms and is the pharmacological basis for AChE inhibitors. Locus coeruleus provides norepinephrine. Dorsal raphe provides serotonin. The substantia innominata is the anatomical location containing the nucleus basalis, not a separate answer. Knowing this structure by name is a direct board question. Break it down: nucleus basalis of Meynert = primary source of cortical and hippocampal cholinergic projections; located within substantia innominata of basal forebrain; Alzheimer disease selectively destroys these neurons; loss = cholinergic deficit = pharmacological basis for AChE inhibitors (donepezil, rivastigmine); locus coeruleus = NE; dorsal raphe = serotonin.

Question 4 of 4

A 58-year-old woman develops rapidly progressive dementia over 6 weeks. She now has difficulty walking and involuntary jerking movements of her limbs triggered by sudden sounds in the room. An EEG is performed.

Which EEG finding is MOST characteristic of this patient's diagnosis?

AGeneralized 3 Hz spike-and-wave discharges

BTemporal lobe sharp waves with secondary generalization

CPeriodic sharp wave complexes at 1-2 Hz

DDiffuse slowing with frontal intermittent rhythmic delta activity

Tempting to pick diffuse slowing since any dementia involves widespread cortical dysfunction and slow background activity is expected. The trap is that diffuse slowing is nonspecific, found in metabolic encephalopathy, toxic states, and many dementias. CJD has its own specific EEG signature that no other dementia shares. Think of EEG patterns as ID barcodes: diffuse slowing is a smudged barcode that tells you the printer is broken but not which product was being printed. Periodic sharp wave complexes at 1-2 Hz are a very specific barcode that belongs to one product only: CJD. Correct: C. Creutzfeldt-Jakob disease. Rapidly progressive dementia over weeks to months + myoclonus (especially startle myoclonus) + EEG showing periodic sharp wave complexes (1-2 Hz, often biphasic or triphasic) = CJD until proven otherwise. Confirm with MRI DWI showing cortical ribboning and basal ganglia hyperintensity, and CSF 14-3-3 protein. This is universally fatal. Generalized 3 Hz spike-wave is absence epilepsy. Temporal sharp waves suggest focal temporal lobe epilepsy or limbic encephalitis. Diffuse delta slowing is nonspecific (encephalopathy, metabolic, toxic). Break it down: CJD EEG = periodic sharp wave complexes at 1-2 Hz, biphasic or triphasic; rapidly progressive dementia over weeks plus myoclonus plus this EEG = CJD; confirm with MRI DWI cortical ribboning + CSF 14-3-3 protein; 3 Hz spike-wave = absence epilepsy; diffuse delta slowing = nonspecific encephalopathy; CJD EEG pattern is pathognomonic and boards-tested.

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Board-Style Walkthrough

Original board-style vignettes. Shuffled, never-repeat, full explanations for every choice.