NeuroDegenerative Master Clinical Reference

Proteinopathies • Approach • Diagnosis • Investigations • Treatment • Pathognomonic Signs

Neurology Board & Clinical Practice Compendium

Neurodegenerative Disorders: Approach, Diagnosis, Investigations, Treatment & Pathognomonic Signs

Complete evidence-based monographs for AD, DLB, FTD, IPD, PSP, MSA, CBS/CBD, ALS/MND, Huntington's Disease, sCJD, and iNPH — including 2022–2024 diagnostic criteria, MRI/PET hallmarks, CSF/Plasma biomarkers (p-tau217, RT-QuIC, NfL), and disease-modifying therapies (Lecanemab, Donanemab, Tofersen).

ADCognitive & Dementia

Alzheimer's Disease (AD)

Extracellular β-Amyloid (Aβ42) plaques + Intracellular Hyperphosphorylated Tau (3R+4R) Neurofibrillary Tangles

DLBCognitive & Dementia

Dementia with Lewy Bodies (DLB)

Alpha-Synuclein (Lewy bodies & Lewy neurites in neocortex, limbic cortex, and brainstem) + frequent co-existent AD amyloid pathology

FTD / FTLDCognitive & Dementia

Frontotemporal Degeneration (bvFTD, svPPA, nfvPPA)

FTLD-TDP (TDP-43, ~50%), FTLD-Tau (3R Pick bodies or 4R Tau, ~45%), or FTLD-FUS (~5%)

IPDParkinsonism & Synucleinopathies

Idiopathic Parkinson's Disease (IPD)

Alpha-Synuclein (Lewy bodies in Substantia Nigra pars compacta [SNpc], ascending via Braak Stages 1–6 from dorsal motor nucleus of vagus & olfactory bulb)

PSPAtypical Parkinsonism & Tauopathies

Progressive Supranuclear Palsy (PSP)

4-Repeat (4R) Tauopathy ("Tufted Astrocytes" & globose neurofibrillary tangles in midbrain, STN, globus pallidus, and dentate nucleus)

MSAParkinsonism & Synucleinopathies

Multiple System Atrophy (MSA-P & MSA-C)

Alpha-Synucleinopathy inside Oligodendrocytes — Papp-Lantos Glial Cytoplasmic Inclusions (GCIs) causing striatonigral degeneration & olivopontocerebellar atrophy

CBD / CBSAtypical Parkinsonism & Tauopathies

Corticobasal Degeneration / Syndrome (CBD / CBS)

4-Repeat (4R) Tauopathy ("Astrocytic Plaques", ballooned achromatic neurons, and corticobasal bodies); Note: Clinical CBS can also be caused by AD, PSP, or TDP-43 pathology

ALS / MNDMotor Neuron & Repeat Disorders

Amyotrophic Lateral Sclerosis (ALS / Motor Neuron Disease)

TDP-43 Cytoplasmic Inclusions + Bunina Bodies (~97% of all ALS); SOD1 (~2%, lacks TDP-43!) or FUS (~1%)

HDMotor Neuron & Repeat Disorders

Huntington's Disease (HD)

Mutant Huntingtin Protein (mHTT) with expanded polyglutamine (PolyQ) tract causing selective loss of GABAergic Medium Spiny Neurons in the Caudate & Putamen (Striatum)

sCJDPrion & Rapidly Progressive / Mimics

Sporadic Creutzfeldt-Jakob Disease (sCJD / Prion Disease)

Misfolded Protease-Resistant Prion Protein (PrP^Sc converting normal α-helical cellular PrP^C into β-sheet rich PrP^Sc) causing spongiform encephalopathy

iNPHPrion & Rapidly Progressive / Mimics

Idiopathic Normal Pressure Hydrocephalus (iNPH — Reversible Mimic)

Impaired CSF dynamics & glymphatic clearance (Non-obstructive communicating hydrocephalus; ~30–40% have co-existent AD or vascular pathology on cortical biopsy)

ADCognitive & Dementia

Onset: Late-onset (>65 yrs, ~95%); Early-onset (<65 yrs, ~5%)

Alzheimer's Disease (AD)

Core Clinical Signature / Hallmark Triad

Insidious anterograde episodic memory loss (hippocampal type: poor free recall NOT rescued by cueing) + visuospatial/language/executive decline.

Proteinopathy & Pathology

Extracellular β-Amyloid (Aβ42) plaques + Intracellular Hyperphosphorylated Tau (3R+4R) Neurofibrillary Tangles

Key Associated Genes

APP (Chr 21)PSEN1 (Chr 14 - most common early-onset AD)PSEN2 (Chr 1)APOE ε4 (Risk allele, dose-dependent)

Pathognomonic & Hallmark Signs (AD)

1. Bedside Clinical Signs

•Head-Turning Sign: Patient immediately turns to look at caregiver when asked a direct history question
•Hippocampal Amnestic Pattern: Failure to benefit from semantic cues on delayed recall testing (unlike FTD/subcortical dementia)

2. MRI / Neuroimaging Signs

•MTA (Medial Temporal Lobe Atrophy) Score ≥2–3 on Coronal T1 MRI: Disproportionate hippocampal, parahippocampal, and entorhinal cortex atrophy with widened choroid fissure
•Posterior Cingulate & Precuneus Atrophy / Hypometabolism (especially prominent in early-onset AD)
•Koedam Posterior Parietal Atrophy in PCA variant

3. Biomarker / PET / EMG Signs

•AT(N) Biomarker Profile: Decreased CSF Aβ42 (or Aβ42/Aβ40 ratio <0.06) + Increased CSF p-tau181 / Plasma p-tau217 + Increased t-tau/NfL
•Amyloid PET (Florbetapir, Flutemetamol, Pittsburgh Compound B) diffuse cortical uptake & Tau PET (Flortaucipir) Braak stage propagation
•FDG-PET: Temporoparietal + Posterior Cingulate / Precuneus hypometabolism (sparing primary sensorimotor and occipital cortex)

Clinical Presentation & Disease Evolution

Early / Prodromal Phase

• Impaired episodic memory for recent events (repeating questions, misplacing items)
• Anomia / word-finding pauses and loss of semantic fluency (animals > letter fluency)
• Topographical disorientation (getting lost in familiar routes)

Core Established Syndrome

• Amnestic Syndrome of Hippocampal Type: impaired encoding/consolidation — cueing does NOT normalize recall
• Atypical Non-Amnestic Variants: Posterior Cortical Atrophy (PCA - Balint/Gerstmann), Logopenic PPA (lvPPA - impaired sentence repetition), Frontal/Dysexecutive AD
• Ideomotor apraxia and visuospatial constructional deficits (clock drawing)

Advanced / Autonomic Features

• Behavioral & psychological symptoms of dementia (BPSD): apathy, agitation, delusions of theft
• Myoclonus and late-onset focal or generalized seizures
• Loss of ambulation, dysphagia, and mutism in end-stage

Red Flags Against AD (Think Alternative Diagnosis)

• Early prominent parkinsonism or recurrent visual hallucinations within 1 year (think DLB)
• Early behavioral disinhibition, hyperorality, or apathy with spared memory (think bvFTD)
• Stepwise deterioration with focal pyramidal signs or acute onset (think Vascular Dementia)
• Rapid progression over weeks to months with myoclonus (think CJD or Autoimmune Encephalitis)

Diagnostic Criteria

NIA-AA (2018/2024 Revised Criteria) & IWG-2 Criteria

Core Requirements:

• Insidious onset and gradual progression of cognitive impairment over ≥6 months
• Core 1 Biomarkers (sufficient for biological AD diagnosis): Amyloid PET positive, CSF Aβ42/40 + p-tau181 ratio, or high-accuracy Plasma p-tau217
• Core 2 Biomarkers (staging & prognosis): Tau PET (neocortical tangle burden)

Supportive Features:

• Amnestic presentation or classic non-amnestic syndromic variant (PCA, lvPPA)
• APOE ε4 homozygosity or autosomal dominant mutation (PSEN1, PSEN2, APP)
• Hippocampal volume loss on volumetric MRI

Exclusions / Mimics to Rule Out:

• Substantial concomitant cerebrovascular disease temporally related to cognitive onset
• Core features of DLB, bvFTD, or reversible metabolic/infectious encephalopathies

Diagnostic Investigations Workup

1. Structural MRI:Brain MRI (T1 coronal hippocampal protocol, FLAIR, SWI): Assess Scheltens MTA score, rule out mass/NPH/vascular burden, and screen for baseline microbleeds/cortical superficial siderosis before anti-amyloid mAb therapy (ARIA risk).

2. Functional PET / SPECT:FDG-PET shows bilateral temporoparietal and posterior cingulate/precuneus hypometabolism. Amyloid PET & Tau PET confirm in vivo pathology.

3. CSF & Blood Biomarkers:Plasma p-tau217 (highest diagnostic accuracy >90%), CSF low Aβ42/Aβ40 ratio + elevated p-tau181 and total tau.

4. Neurophysiology & Genetics:APOE genotyping MUST be performed prior to starting anti-amyloid therapy (APOE ε4/ε4 homozygotes have markedly elevated ARIA-E and ARIA-H risk). PSEN1/PSEN2/APP panel if onset <60 yrs.

Evidence-Based Treatment & Pharmacotherapy

CLARITY-AD (Lecanemab 2023)TRAILBLAZER-ALZ 2 (Donanemab 2023)DOMINO-AD (Donepezil + Memantine)

Disease-Modifying / Survival Therapy

• Lecanemab (IV q2w): Anti-Aβ protofibril mAb for MCI / Mild AD with confirmed amyloid; slows decline by 27% at 18m (CLARITY-AD). Requires serial MRI monitoring for ARIA-E (edema) and ARIA-H (hemorrhage).
• Donanemab (IV q4w): Anti-pyroglutamate Aβ plaque mAb for early symptomatic AD; slows decline by 35% in low/medium tau population (TRAILBLAZER-ALZ 2); can stop dosing once amyloid plaque clearance achieved.

First-Line Symptomatic Management

• Acetylcholinesterase Inhibitors (AChEIs) for Mild-to-Severe AD: Donepezil (5–10 mg OD; 23 mg in moderate-severe), Rivastigmine (oral or 4.6–13.3 mg/24h transdermal patch), Galantamine (8–24 mg/d).
• NMDA Receptor Antagonist for Moderate-to-Severe AD: Memantine (titrate 5 mg/d weekly to 10 mg BID; reduces glutamate excitotoxicity).
• Brexpiprazole (FDA-approved for agitation in AD) or SSRIs (Citalopram/Sertraline) for neuropsychiatric symptoms.

Non-Pharmacological & Multidisciplinary Care

• Aerobic exercise, Mediterranean/MIND diet, hearing aid correction (Lancet Commission modifiable risk factor)
• Cognitive stimulation therapy and structured caregiver support

Contraindicated / Drugs to Strictly Avoid

• Anticholinergics (Oxybutynin, Diphenhydramine, TCAs: Amitriptyline) — directly worsen cholinergic deficit and precipitate delirium
• Benzodiazepines and Z-drugs (paradoxical agitation, falls)
• Systemic thrombolytics (tPA/TNK) and therapeutic anticoagulation require extreme caution in patients on Lecanemab/Donanemab due to fatal intracerebral hemorrhage risk with ARIA