Latest revision as of 20:32, 24 May 2020

Neurodegenerative diseases is a big part of neuropathology. It includes some discussion of dementia.

Overview

Neurodegenerative disease = essentially progressive and selective neuron loss.
Clinically, they are not unique, e.g. dementia can be caused by several diseases (with different molecular etiologies).
- Each syndrome (e.g. dementia, parkinsonism, ataxia) has a most common etiology and a DDx.
They are defined by molecular pathology.^[1]
- The diseases are due to the accumulation of abnormal protein.
  - The amino acid sequence of the protein may be completely normal. The problem may just be folding/protein conformation.

Molecular schema of neurodegenerative disorders:^[1]

Neurodegenerative
disorders

Amyloidoses

Tauopathies

α-synucleinopathies

TDP-43

FUS/EWS/TAF15

Common diseases

Amyloidoses:

Alzheimer disease (Abeta).

'Pure' tauopathies:

Progressive supranuclear palsy.
Pick's disease.
Corticobasal degeneration.
FTDP-17.
Dementia pugilistica.

Synucleinopathies:^[2]

TDP-43 proteinopathies:

Amyotrophic lateral sclerosis.
Frontotemporal lobar degeneration with TDP-43 (FTLD-TDP).

FET proteinopathies:

Basophilic inclusion body disease (BIBD).
Neuronal intermediate filament inclusion disease (NIFID).
Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (atypical FTLD-U).

Prionopathies:

Creutzfeldt-Jakob disease (PrP).

Note: Some people consider α-synuclein as a prion-like protein.^[3]

Table

Disease/pathology/clinical correlation based on Dickson:^[1]

Disease	Deposited protein	Distribution	Clinical	Histology	Image
Alzheimer disease	Abeta (mutated APP)	corticolimbic, usu. spares occipital	dementia	plaques, neurofibrillary tangles	[1]
Creutzfeldt-Jakob disease	PrP^res (mutated PrP)	cortical & basal ganglia	dementia (rapid progression), movement disorder	cytoplasmic vacuolization, PrP+ve plaques, Kuru plaques (MV2 variant)	[2]
Parkinson disease	alpha-synuclein	brainstem	parkinsonism	Lewy bodies in substantia nigra and locus coeruleus	[3] [4]
Dementia with Lewy bodies	alpha-synuclein	corticolimbic, brainstem	dementia + parkinsonism	Lewy bodies brainstem and cortical, tangles	[5] [6]
Multiple system atrophy	alpha-synuclein	basal ganglia, brainstem, cerebellum	parkinsonism, ataxia	Papp-Lantos inclusions (cytoplasmic deposits in oligodendrocytes)^[4]	[7]
Amyotrophic lateral sclerosis (ALS)	TDP-43	motor neurons	spasticity, weakness	motor neuron loss, TDP-43+ve, TAF15-ve, EWS-ve inclusions in motor neurons	[8]
Frontotemporal lobar degeneration with TDP-43 (FTLD-TDP)	TDP-43	cortex, basal ganglia	dementia, focal cortical syndromes	histology depends on (type 1-4), ubiquitin and TDP-43+ve, tau and FUS-ve	[9]
Frontotemporal lobar degeneration with FET (FTLD-FET)	FUS/EWS/TAF15	cortex, medulla, hippocampus, and motor cells of the spinal cord	dementia, cases classified as aFTLD-U, NIFID and BIBD	FUS+ve, TAF15+ve, EWS+ve cytoplasmic & intranuclear inclusions, neuritic threads	[10]
Progressive supranuclear palsy (FTLD-tau)	tau 4R	basal ganglia, brainstem	atypical parkinsonism with early gait instability, falls, and supranuclear gaze palsy	tau-positive globose neurofibrillary tangles in neurons, tufted astrocytes, coiled bodies in oligodendrocytes	[11]
Pick disease (FTLD-tau)	tau 3R	corticolimbic	dementia + focal cortical syndrome	Intraneuronal argyrophilic inclusions (Pick body)	[12]
Corticobasal degeneration (CBD) (FTLD-tau)	tau 4R	cortical, basal ganglia	dementia + movement disorder (Parkinson-plus syndrome)	ballooned neurons, astrocytic plaques, pretangles in basal nucleus	[13]
Argryophilic grain disease (AGD) (FTLD-tau)	tau 4R	medial temporal lobe, limbic structures	late-onset amnestic syndrome	Argyrophilic grains (also found unspecific in elederly)	[14]

Immunohistochemistry

Alpha-synuclein

Look for:

Lewy bodies (seen in Parkinson's Disease (PD), Dementia with Lewy bodies (DLB)) = round cytoplasmic eosinophilic body +/- pale halo.
Lewy neurites(seen in PD and DLB) = abnormal neurites with filaments similar to those found in Lewy bodies.
Glial cytoplasmatic inclusions (Papp-Lantos bodies) seen in mutisystem atrophy (MSA).
Beta amyloid in vessels seen in cerebral amyloid angiopathy (CAA).

Tau

AT8 = stains phosphorylated tau.^[5]
- AT = anti-tau.
- Stains tau 4R and tau 3R.^[6]

TDP-43

May accumulate due to a progranulin mutation.

Microscopic

TDP-43 - normally in the nucleus.
- Pathologic: Micrograph (label B) - neurites, skein-like formations (ama-assn.org)^[7]
  - Fibrillar or skein-like formations = cytoplasmic staining.
    - "Skein" = yarn or thread wound on a reel or flock of birds in flight.^[8]
  - Neurites = "squiggly appearance"; "worm-like appearance".

Ubiquitin

Marks proteins for recycling.
Stains Barr bodies in hippocampal granule cells^[9]

p62

p62; poli-ubiquitin-binding protein p62.^[5]

Microscopic

Look for:

Lewy bodies and extracellular pigment in neuromelanin-containing nuclei (SN, LC, DVN) -> PD.
Spongiform vacuolation in the neuropil (seen in Prion disease and FTLD-TDP).
Neurofibrillar tangles (pyramidal layer of dentate gyrus).
Granulovacuolar degeneration (granules within cytoplasmic vacuoles, mainly in the hippocampal pyramidal neurons, seen in AD).
Cores of amyloid plaqyes.
Cotton wool plaques (seen in familiar AD).
Pick cells (balloned neurons in frontal cortex).
Pick bodies (granular layer of dentate gyrus).
Extensive astrogliosis (striatonigral degeneration, hepatic encephalopathy).
Corpora amylacea in the cornu ammonis may be increased in neurodegenerative diseases. ^[10]

Lewy body
Cotton wool plaques
Neurofibrillary tangles
Spongiform vacuolation

Clinical perspective

Correlations between clinical signs and molecular can be poor.
- Example: The MAPT A152T gene mutation may cause clinical symptoms matching AD, CBD, PSP and LBD.^[11]

Dementia general (mostly useless) DDx

Alzheimer's dementia - most common.
Vascular.
- Multi-infarct dementia.
Parkinson's associated dementia.
Lewy body dementia.
Alcohol-related dementia.
Fronto-temporal dementia (Pick disease).
Multisystem atrophy.

Mnemonic

Dementia mnemonic VITAMIN D VEST:^[12]

Vitamin deficiency (B12, folate, thiamine).
Infection (HIV).
Trauma.
Anoxia.
Metabolic (Diabetes).
Intracranial tumour.
Normal pressure hydrocephalus.
Degenerative (Alzheimer's, Huntington's, CJD).
Vascular.
Endocrine.
Space occupying lesion (chronic subdural hematoma).
Toxins (alcohol).

Functional anatomy of dementia

Hippocampus (essential for forming new memories).
Frontal lobe (essential for retrieval of memories).

Parkinsonism causes

Parkinson's disease ^[13]
Dementia with Lewy bodies.
Multiple system atrophy (MSA).^[14]
Progressive supranuclear palsy (PSP).^[15]
Drug induced (valproic acid, MPTP).^[16]^[17]
Vascular. ^[18]
Postencephalitic. ^[19]
Tramuatic (Dementia pugilistica).^[20]

Amyloidoses

Alzheimer disease

General

Onset: episodic memory loss.
Diagnosis is clinical & pathologic.
- Pathologic finding alone are not diagnostic.
- Onset, rate of progression and the development of pathology are highly variable.
Defined by:
- Pathological accumulation of amyloid β (Aβ) into extracellular plaques.
- Abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs).
- Clinicopathological correlation better for NFT than for Aβ.^[21]
Seen in conjunction with vascular amyloid deposition; see cerebral amyloid angiopathy.
Evidence of possible iatrogenic transmission by cadaver-sourced growth hormone batches.^[22]^[23]

Genetics

Genes associated with Alzheimer disease:^[24]

Amyloid precursor protein (APP).
- On chromosome 21 - may explain why Trisomy 21 (Down syndrome) increases the risk of Alzheimer disease.^[25]
Presenilin 1 (PSEN1).^[26]
Presenilin 2 (PSEN2).^[27]
Apolipoprotein E (APOE)^[28] - specifically the epsilon-4 allele.

Gross

Features:

Temporal atrophy, esp. hippocampus.
Dilation of:
- Lateral ventricles.
- Third ventricle.

Gross/microscopic - disease spread by NF tangles (staging):^[29]

Alzheimer "spreads" in a reproducible pattern:
- Stage I-II: entorhinal cortex.
- Stage III-IV: inferior aspect of brain.
- Stage V-VI: limbic system.

Minimal sampling:

Frontal, parietal & temporal lobe
Hippocampus and entorhinal cortex

Additional sampling:

Basal ganglia
Cerebellum
Midbrain (including substantia nigra)
Occipital cortex

Images

Alzheimer's brain. (WC/NIH)
Alzheimer's brain macroscopy (top) vs control (bottom). (WC/Hersenbank)
Alois Alzheimer provided a first description of the pathology. (NLM)

Microscopic

Features:

Neurofibrillary tangles.
- Consists of tau.
- Location: hippocampus, cerebral cortex, hypothalamus.
- Dementia severity correlates better with NF tangles number than senile plaque number.^[30]
- Six-tiered scoring method to assess tangle load ^[31]
- Images: tangles - schematic (pakmed.net)^[32], tangle (washington.edu).^[33]
Senile plaques (AKA neuritic plaques).
- Consists of two components:
  1. Centre - radiates.
    - Consists of Abeta amyloid
  2. Neurites - swollen axons.
- Considered to be more specific for Alzheimer's than NF tangles.
  - How to remember: senile plaques = specific.
- There is a CERAD staging system for senile plaque load: 0 (none), I (mild), II (moderate), III (severe).^[34]
- Images: senile plaques (utah.edu)^[35] senile plaques - beta-APP - high mag. (WC).
Neuron loss.
+/-Cerebral amyloid angiopathy.

Images

Neuritic plaques with amyloid core in HE. (WC/jensflorian)
Neuritic plaques in Gallays silver impregnation. (WC/jensflorian)
Neuritic plaques with amyloid core in Bodian stain. (WC/KGH)
Plaques with Abeta IHC. (WC/Nephron)
Neurofibrillary tangles in HE. (WC/Patho)
Tau IHC highlighting tangles. (WC/Patho)
Tangles in Gallays silver impregnation.(WC/Patho)
HE stain with ghost tangles and Hirano bodies in AD. (WC/Patho)
HE stain with granulovaculolar degeneration in AD. (WC/Patho)

Classification

NIA/AA Guidelines: "ABC" scoring method ^[36]

(A) assessment of amyloid b deposits
(B) staging of neurofibrillary tangles
(C) scoring of neuritic plaques

(A) abeta plaques (Thal phase)^[37]	(B) Neurofibrillary tangles (Braak stage) ^[38]	(C) neuritic plaques (CERAD) ^[39]
(A0) 0	(B0) 0	(C0) none
(A1) 1 (temporal),2 (+frontal, +CA1)	(B1) I,II (transentorhinal)	(C1) sparse (1–5 neuritic plaques/1 mm2)
(A2) 3 (+diencephalon, +striatum)	(B2) III,IV (limbic)	(C2) moderate(6–19 neuritic plaques/1 mm2)
(A3) 4 (+brainstem),5 (+cerebellum, +pons)	(B3) V,VI (neocortical)	(C3) frequent(>20 neuritic plaques/1 mm2)

The ABC score is a good indicator for the likelihood of dementia.

Example: Cerebellar abeta deposits (A3) + tangles in entorhinal cortex and few temporal (B2), + 15 neuritic plaques per 1 mm2 (C2) -> (A3, B3, C2): intermediate AD level change.

Notes:

Abeta amyloid:
- Derived from amyloid precursor protein (APP).
  - APP:
    - Rapid axonal transport - useful as a marker of axonal injury.
    - Function currently not known.
Tau:
- Important in microtubule assembly.

Prion diseases

General

Etiology:^[40]

Misfolded cell-surface protein called PrP^SC.
- This is derived from the protein PrP^C encoded by the PRNP gene.
Different genetics strains are associated with varying clinical phenotype.^[41]

Includes:

Creutzfeldt-Jakob disease (CJD).
Sporadic fatal insomnia (sFI).^[40]
Fatal familial insomnia (FFI).^[42]^[43]
Gestmann-Straussler-Scheinker syndrome (GSS) - due to PRNP gene mutations.^[44]

IHC

PrP^C:^[42]

Congo red +ve.
PAS +ve.

Creutzfeldt-Jakob disease

Commonly abbreviated as CJD.

General

Rare.
Incurable disease.

Usually diagnosed clinically:

Characteristic findings:
- Very rapid decline (3-4 months).
- Characteristic (cortex findings on) neuroradiology.

Variant Creutzfeldt-Jakob disease

Abbreviated vCJD.

General

Associated with bovine spongiform encephalopathy (AKA mad cow disease).
Should sample: spleen, lymph nodes, tonsils.^[45]

Microscopic

Features:

Spongy appearance (cytoplasmic vacuolization^[46]).

Note:

Spongiform changes may be seen in ALS, Alzheimer's disease and Lewy body disease (e.g. Parkinson disease); however, the changes are only in the upper cortex and not diffuse.^[47]

Molecular

The CJD phenotype is associated with a PRNP D178N mutation and valine polymorphism at codon 129 (D178N-129V).
- Note: A Met129 polymorphism will cause Fatal familiar insomnia in the setting of the same PRNP D178N mutation. ^[48]

CJD. (WC/DRdoubleB)
Spongiform changes in CJD. (CDC/ Teresa Hammett)
Florid plaques in vCJD. (WC/Sbrandner)
Florid plaques in vCJD - low mag. (WC/CDC.gov)
vCJD - prion protein immunostain tonsil. (WC/Sbrandner)
sCJD - prion protein immunostain cortex. (WC/jensflorian)
sCJD - prion protein immunostain cerebellum. (WC/jensflorian)

CJD - several cases (upmc.edu).

Alpha-synucleinopathies

Without clincial information Parkinson's disease and Dementia with Lewy bodies cannot separated in histology.

Dementia with Lewy bodies

General

Clinical features:

Parkinsonian features.
Hallucinations (visual).
Progressive cognitive decline with fluctuations.

Microscopic

Features:

Lewy bodies.
Lewy neurites.

Note: Cortical Lewy bodies are easily missed in HE.

IHC

Alpha-synuclein +ve.

Images

Lewy bodies in frontal cortex of DLB. (WC/jensflorian)
Alpha-synculein IHC showing cortical Lewy bodies. (WC/jensflorian)
Alpha-synculein IHC showing Lewy Neurites in DLB. (WC/jensflorian)

Parkinson disease

General

Common - often sporadic.
May be genetic.

Clinical TRAP:^[49]

Tremor.
Rigidity.
Akinesia.
Postural instability.

Genetics:^[50]

LRRK2 gene^[51] - autosomal dominant.
PARK2 gene (parkin)^[52] - autosomal recessive.

Gross

Features:^[53]

Abnormally pale substantia nigra.
- Pigmentation increases with age.
Pale locus ceruleus.

Notes:

Substantia nigra is a midbrain structure.
- Image: Midbrain - schematic (WC).

Microscopic

Features:^[53]

Loss of pigmented (catecholaminergic) neurons in the substantia nigra and locus ceruleus.
Gliosis - due to neuron loss.
Lewy bodies (in remaining neurons) - key feature.
- Eosinophilic cytoplasmic inclusion with "dense" (darker) core and pale (surrounding) halo.
  - Consist of filaments composed of alpha-synuclein.
Lewy neurites - alpha-synuclein positive processes.

IHC

Alpha-synuclein +ve.

Images

Schematic progression of PD (PLOSone/Jubault et al.).
Lewy body (HE, left) and Lewy neurite (aSyn IHC, right).
Alpha-synculein positive Lewy body (WC/Marvin101).
Lewy body and Lewy neurites (WC/Suraj Rajan).

Molecular

Hereditary forms in less than 10% of the cases
- Involved genes are consecutively labeled PARK1, PARK2....

Multiple system atrophy

Multiple system atrophy is a neurodegenerative disease of the parkinsonism-plus disorder group.

General

Clinical findings variable:

Parkinsonism (stiatonigral degeneration, MSA-P).
Ataxia (olivo-ponto-cerebellar degeneration, MSA-C).
Autonomic dysfunction (Shy-Drager syndrome, depreceated).
Clinical onset between 40-60 years.
Progedient tremor, atxia, laryngeal paresis, wakness, cognitive decline.
Patients usually succumb after 6 years from aspiration pneumonia.

DDx:

Macroscopy

Cerebral (mild) & cerebellar atrophy.
greenish putamen.
Discoloration Substantia nigra and Locus coeruleus

Microscopic

Features:

Inclusions cerebral, subcortical white matter, cerebellar.
Neuronal loss and gliosis (absent in minimal-change MSA).
Alpha-synuclein-rich glial and neuronal cytoplasmic inclusions in white matter (finding at autopsy).^[54]
- Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.^[55]^[56]
- Inclusions usu. abundant in basal ganglia, substantia nigra, pontine nuclei, medulla and cerebellum.
Pons and Putamen:
- Nuclear inclusions (sparse in most cases).
- Neuropil threads (alpha-synuclein).
Loss of myelinated fibers from external capsule, striatum and pallidum.

Images

Gray-brown discoloration in putamen of a striatonigral-type MSA (WC/jensflorian).
Gallays silver stain showing MSA-typic inclusions (WC/jensflorian).
a-synuclein IHC showing Glial and neuronal cytoplasmic inclusion in the pons of a MSA case (WC/jensflorian).

Molecular

No known alpha-synuclein mutation.
Genetic variants of SNCA gene assoicated with MSA. ^[57]

Tauopathies

More than 20 different degenerative disorders can be classiﬁed as tauopathies.^[58] FTLD-tau is an umbrella term used for tauopathies including PSP, CBD, PiD and GGT. ^[59]

Argyrophilic grain disease

Corticobasal degeneration

AKA CBD.
Symptoms may vary:
- Progressive asymmetrical rigidity and apraxia, progressive aphasia or dementia.
Neuronal and glial Tau-positive inclusions.^[60]
- Astrocytic plaques.
- Thread-like lesions and coiled bodies.
- Ballooned neurons +/-.
Pathology is cortical and striatal and Gallyas-positive.
Neuronal loss in the substantia nigra.

DD: PSP (widespread neurofibrillary degeneration, with characteristic globose NFT).

Globular glial tauopathies

Commonly abbreviated GGT.
AKA sporadic multiple system tauopathy.
Rare disease.^[61]
Combination of frontotemporal dementia and motor neuron disease or only part thereof.
4-repeat tauopathy.

Microscopic

Globular oligodendroglial and astrocytic Tau inclusions.
Absence of tufted astrocytes.
Mostly Gallyas-negative.

Progressive supranuclear palsy

Commonly abbreviated PSP.
AKA Steele-Richardson-Olszewski syndrome.

General

Diagnosis - clinical.^[62]

Clinical:

Impaired control of gaze, esp. difficulty looking up and down (supranuclear palsy).^[63]
Parkinsonism.^[15]

Microscopic

Features:^[1]^[62]^[64]

Globose neurofibrillary tangles in neurons.
Coiled bodies in oligodendrocytes.
- Wire coil-like structure around the nucleus.
Tufted astrocytes.
- Near impossible to see without IHC - specifically AT8.
- Cellular processes filled with crap.
- Star-like appearance; looks like a road network where all the roads lead to one place (Parisian star).
Grumose degeneration of the cerebellar dentate nucleus.
- Granular eosinophilic material adjacent to nuclei; once thought to be pathognomonic for PSP.^[65]^[66]

Images:

PSP - several images (upmc.edu).

Pick disease

General

Dementia.

Gross

Frontal and temporal lobe atrophy.^[67]
- May be called "walnut brain"^[68] - as it resembles a walnut.

Microscopic

Features:^[67]

Pick cells = large ballooned neurons.
Pick bodies = round, homogenous, intracytoplasmic inclusions, size ~10 micrometers.

Image(s):

Pick body (nature.com).^[69]

TDP Proteinopathies

FTLD-TDP

Accounts for about 50% of all FTLD cases.
Degeneration of frontal and temporal lobes.
Inclusions not seen in HE or silver stains.
TDP43-positive
- Neuronal cytoplasmic inclusions.
- Neuronal intranuclear inclusions.
- Dystrophic neurites.
Ubiquitin+ve.
p62+ve.
aSynculein-ve.
Tau-ve.
FUS-ve.
Four FTLD-TDP subtypes
- Type A: compact nuclear/cytoplasmatic inclusions, associated with GRN mutations.
- Type B: diffuse nuclear/cytoplasmatic inclusions most often seen in C9orf72 expansion.
- Type C: dystrophic neurites.
- Type D: Lentiform nuclear inclusions, only in cases with VCP mutations.
C9orf72 mutated show additional DPR+ve staining of TDP‐43‐ve inclusions.
- These addtional inclusions are ubiquitin+ve and p62+ve

FTLD-FET

Clinical manifestations depend on the distribution of the pathologic alterations in the CNS
Currently 3 disorders among the FTLD-FET subgroup.
In contrast to ALS-FUS, no genetic alterations of FUS have been reported to date for cases within the FTLD-FUS group.
5–10% of all FTLD cases
Deposited Proteins: FUS, EWS, TAF-15.
FUS‐positive inclusions in FTLD cases show co‐aggregation of TAF15 and EWS
- (Different from ALS-FUS)

DDx (also FUS+ve):

Spinocerebellar Ataxia (SCA)
Huntington Disease (SD)

Atypical FTLD‐U

Early onset frontotemporal dementia, rapidly progressive psycho‐behavioural changes.
Neuronal cytoplasmic inclusions in hippocampus and frontotemporal lobes.
Ubiquitin+ve, tau/TDP‐ve.
FET+ve inclusions
- Unique vermiform filamentous neuronal nuclear inclusions.
Caudate nucleus head degeneration and hippocampal sclerosis.

Basophilic inclusion body disease

AKA: BIBD.
Variable clinic (behavioral, cognitive alterations, parkinsonism, motor neuron diseases, ALS-like).
Age of onset: 35-70 years.
Intraneuronal cytoplasmic basophilic inclusion bodies.
FUS+ve (universally).
EWS+ve.
TAF15+ve.
alpha-Internexin+ve.

Neuronal Intermediate Filament Inclusion Disease

AKA: NIFID.
Sporadic early‐onset frontotemporal dementia, motor neuron disease, extrapyramidal motor symptoms.
Hyaline conglomerates (brightly eosinophilic branching fibrillar structures embedded in a round, well-delineated, glassy vacuole).
Deposits in cerebral cortex, hippocampus, basal ganglia, thalamus, cerebellar dentate, numerous brainstem nuclei and lower motor neurons.
FUS+ve/EWS+ve/TAF15+ve (heterogenous).
- FET+ve filamentous nuclear inclusions in the hippocampus.
Ubiquitin +/-ve.
NF +ve (some subunits).
p62 +/-ve.
TDP43-ve.
Tau-ve.
α-synuclein-ve.

Other

Chronic traumatic encephalopathy

Abbreviated CTE.

Main article: Chronic traumatic encephalopathy

Huntington disease

General

Autosomal dominant inheritance.
Mutation in Huntington gene (HTT):^[70]
- 11-34 CAG repeat = normal.^[71]
- >42 CAG repeat = Huntington disease.

Clinical:^[72]

Early onset dementia.
Involuntary movements (chorea) - both arms and legs.
Behaviour changes, e.g. grimacing.
Speech changes.

Gross

Severe caudate atrophy.^[73]
- Prominent frontal horns of the lateral ventricles.^[74]

Note:

A normal caudate bulges into the ventricle.

Images:

Microscopic

Features:^[72]

Neuron loss.
Gliosis.

Binswanger disease

General

Multi-infarct dementia affecting subcortical white matter.
Waste-basket diagnosis; diagnosed if CADASIL and amyloidosis have been excluded.
Diagnosis has been controversial -- most with this entity (in the past) were diagnosed with Alzheimer's disease.

Microscopic

Features:

Subcortical lesions that replace the myelin consisting of macrophages.

Frontotemporal lobar degeneration with ubiquitinated inclusions

Abbreviated FTLD with ubiquitinated inclusions or FTLD-TDP43.

General

There are several forms of frontotemporal dementia.
Related to amyotrophic lateral sclerosis (ALS); also a TDP-43 pathology.^[75]
- There are several subtypes of FTLD with TDP-43.

Gross

Frontal and temporal lobe atrophy.

Image:

FTLD (WC).

Amyotrophic lateral sclerosis

Abbreviated ALS.

General

AKA Lou Gehrig's disease.
Characterized by motor neuron death.
May be familial and associated with C9orf72 expansion, or SOD1, FUS and TARDBP mutations.^[76]^[77]
Pathological protein aggregates cause dysfunction of RNA-binding proteins.

Clinical

Peak incidence: 50-60yrs.
2-5 per 100,000 individuals worldwide.
Dead after disease onset: Usu. 2-5yrs.
Weakness (Progressive bulbar, limb, thoracic, and abdominal muscle atrophy).
About 20% of ALS cases develop frontotemporal lobar degeneration (FTLD).
Environmental toxins are discussed (Guam ALS).^[78]

Microscopic

Features:^[76]^[79]

Loss of the giant cells of Betz.
Motor neurons with eosinophilic inclusions (Bunina bodies).
- PAS positive cytoplasmic inclusions.
Motor neuron loss + reactive gliosis + neurogenic muscular atrophy.
- Loss of myelinated axons in the lateral and anterior columns of the spinal cord.
Ubiquitinated cytoplasmic inclusions.^[80]
TDP-43 proteinopathy in motor neurons (90% of all sporadic ALS cases).
- SOD1-mutant cases are TDP-43-ve.^[81]
C9orf72 expansion cases: p62+ve, TDP-43-ve inclusions in the dentate gyrus, neocortex, and cerebellum.^[82]
- FUS-mutant cases show FUS+ve, p62+ve (few) and TDP-43-ve inclusions.^[83]

Images:

Motor neuron loss in ALS-TDP. (WC)
pTDP-43 positive inclusions in neurons. (WC)

DDx:

Spinal muscular atrophy.
Primary Lateral Sclerosis.
Hereditary Spastic Paraparesis (HSP).

Hallervorden-Spatz disease

AKA pantothenate kinase-associated neurodegeneration.

General

Uncommon.

Microscopic

Features:^[85]

Axonal spheroids.
Iron deposition.

Images:

HSD - several images (upmc.edu).

Stains

Prussian blue +ve.

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Dickson DW (2009). "Neuropathology of non-Alzheimer degenerative disorders". Int J Clin Exp Pathol 3 (1): 1–23. PMC 2776269. PMID 19918325. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776269/?tool=pubmed.
↑ Uversky, VN. (Oct 2008). "Alpha-synuclein misfolding and neurodegenerative diseases.". Curr Protein Pept Sci 9 (5): 507-40. PMID 18855701.
↑ Watts, JC. (Oct 2019). "Calling α-synuclein a prion is scientifically justifiable.". Acta Neuropathol 138 (4): 505-508. doi:10.1007/s00401-019-02058-0. PMID 31407029.
↑ MUN. 15 November 2010.
↑ ^5.0 ^5.1 Seelaar H, Klijnsma KY, de Koning I, et al. (May 2010). "Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration". J. Neurol. 257 (5): 747–53. doi:10.1007/s00415-009-5404-z. PMC 2864899. PMID 19946779. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864899/.
↑ Kumaran R, Kingsbury A, Coulter I, et al. (October 2007). "DJ-1 (PARK7) is associated with 3R and 4R tau neuronal and glial inclusions in neurodegenerative disorders". Neurobiol. Dis. 28 (1): 122–32. doi:10.1016/j.nbd.2007.07.012. PMID 17719794.
↑ Geser F, Brandmeir NJ, Kwong LK, et al. (May 2008). "Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis". Arch. Neurol. 65 (5): 636–41. doi:10.1001/archneur.65.5.636. PMID 18474740.
↑ URL: http://dictionary.reference.com/browse/skein. Accessed on: 20 November 2010.
↑ Gelpi, E.. "Clinical Neuropathology teaching case 3-2015: female or male brain? Anti-ubiquitin visualizes Barr bodies in hippocampal granule cells which allows the determination of gender in human brains.". Clin Neuropathol 34 (3): 115-6. PMID 25909954.
↑ Kovacs, GG.; Risser, D.. "Clinical Neuropathology image 6-2014: Corpora amylacea replacing cornu ammonis (CACA).". Clin Neuropathol 33 (6): 378-9. PMID 25343241.
↑ Coppola, G.; Chinnathambi, S.; Lee, JJ.; Dombroski, BA.; Baker, MC.; Soto-Ortolaza, AI.; Lee, SE.; Klein, E. et al. (Aug 2012). "Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases.". Hum Mol Genet 21 (15): 3500-12. doi:10.1093/hmg/dds161. PMID 22556362.
↑ Shiau, Carolyn; Toren, Andrew (2006). Toronto Notes 2006: Comprehensive Medical Reference (Review for MCCQE 1 and USMLE Step 2) (22nd edition (2006) ed.). Toronto Notes for Medical Students, Inc.. pp. PS19. ISBN 978-0968592861.
↑ Tuite, PJ.; Krawczewski, K. (Apr 2007). "Parkinsonism: a review-of-systems approach to diagnosis.". Semin Neurol 27 (2): 113-22. doi:10.1055/s-2007-971174. PMID 17390256.
↑ Ahmed, Z.; Asi, YT.; Sailer, A.; Lees, AJ.; Houlden, H.; Revesz, T.; Holton, JL. (Nov 2011). "Review: The neuropathology, pathophysiology and genetics of multiple system atrophy.". Neuropathol Appl Neurobiol. doi:10.1111/j.1365-2990.2011.01234.x. PMID 22074330.
↑ ^15.0 ^15.1 Bertram, K.; Williams, DR. (Apr 2012). "Visual hallucinations in the differential diagnosis of parkinsonism.". J Neurol Neurosurg Psychiatry 83 (4): 448-52. doi:10.1136/jnnp-2011-300980. PMID 22228724.
↑ Mahmoud, F.; Tampi, RR. (Oct 2011). "Valproic Acid-Induced Parkinsonism in the Elderly: A Comprehensive Review of the Literature.". Am J Geriatr Pharmacother. doi:10.1016/j.amjopharm.2011.09.002. PMID 21993183.
↑ Gerlach, M.; Riederer, P.; Przuntek, H.; Youdim, MB. (Dec 1991). "MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease.". Eur J Pharmacol 208 (4): 273-86. PMID 1815982.
↑ Korczyn, AD. (Apr 2015). "Vascular parkinsonism-characteristics, pathogenesis and treatment.". Nat Rev Neurol. doi:10.1038/nrneurol.2015.61. PMID 25917706.
↑ Vilensky, JA.; Gilman, S.; McCall, S. (Jul 2010). "A historical analysis of the relationship between encephalitis lethargica and postencephalitic parkinsonism: a complex rather than a direct relationship.". Mov Disord 25 (9): 1116-23. doi:10.1002/mds.22908. PMID 20629120.
↑ Chauhan, NB. (2014). "Chronic neurodegenerative consequences of traumatic brain injury.". Restor Neurol Neurosci 32 (2): 337-65. doi:10.3233/RNN-130354. PMID 24398724.
↑ Nelson, PT.; Alafuzoff, I.; Bigio, EH.; Bouras, C.; Braak, H.; Cairns, NJ.; Castellani, RJ.; Crain, BJ. et al. (May 2012). "Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature.". J Neuropathol Exp Neurol 71 (5): 362-81. doi:10.1097/NEN.0b013e31825018f7. PMID 22487856.
↑ Duyckaerts, C.; Sazdovitch, V.; Ando, K.; Seilhean, D.; Privat, N.; Yilmaz, Z.; Peckeu, L.; Amar, E. et al. (Feb 2018). "Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology.". Acta Neuropathol 135 (2): 201-212. doi:10.1007/s00401-017-1791-x. PMID 29209767.
↑ Jaunmuktane, Z.; Mead, S.; Ellis, M.; Wadsworth, JD.; Nicoll, AJ.; Kenny, J.; Launchbury, F.; Linehan, J. et al. (Sep 2015). "Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy.". Nature 525 (7568): 247-50. doi:10.1038/nature15369. PMID 26354483.
↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 674-5. ISBN 978-1416054542.
↑ Nieuwenhuis-Mark, RE.. "Diagnosing Alzheimer's dementia in Down syndrome: problems and possible solutions.". Res Dev Disabil 30 (5): 827-38. doi:10.1016/j.ridd.2009.01.010. PMID 19269132.
↑ Online 'Mendelian Inheritance in Man' (OMIM) 104311
↑ Online 'Mendelian Inheritance in Man' (OMIM) 600759
↑ Online 'Mendelian Inheritance in Man' (OMIM) 107741
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↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1317. ISBN 978-1416031215.
↑ Braak, H.; Braak, E. (1991). "Neuropathological stageing of Alzheimer-related changes.". Acta Neuropathol 82 (4): 239-59. PMID 1759558.
↑ URL: http://www.pakmed.net/academic/age/alz/alz030.htm. Accessed on: 12 November 2010.
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↑ Montine, TJ.; Phelps, CH.; Beach, TG.; Bigio, EH.; Cairns, NJ.; Dickson, DW.; Duyckaerts, C.; Frosch, MP. et al. (Jan 2012). "National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach.". Acta Neuropathol 123 (1): 1-11. doi:10.1007/s00401-011-0910-3. PMID 22101365.
↑ Thal, DR.; Rüb, U.; Orantes, M.; Braak, H. (Jun 2002). "Phases of A beta-deposition in the human brain and its relevance for the development of AD.". Neurology 58 (12): 1791-800. PMID 12084879.
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↑ Mirra, SS.; Heyman, A.; McKeel, D.; Sumi, SM.; Crain, BJ.; Brownlee, LM.; Vogel, FS.; Hughes, JP. et al. (Apr 1991). "The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease.". Neurology 41 (4): 479-86. PMID 2011243.
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↑ Online 'Mendelian Inheritance in Man' (OMIM) 600072
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[pmid19918325-1] 1.0 ^1.1 ^1.2 ^1.3 Dickson DW (2009). "Neuropathology of non-Alzheimer degenerative disorders". Int J Clin Exp Pathol 3 (1): 1–23. PMC 2776269. PMID 19918325. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776269/?tool=pubmed.

[pmid18855701-2] Uversky, VN. (Oct 2008). "Alpha-synuclein misfolding and neurodegenerative diseases.". Curr Protein Pept Sci 9 (5): 507-40. PMID 18855701.

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[7] Geser F, Brandmeir NJ, Kwong LK, et al. (May 2008). "Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis". Arch. Neurol. 65 (5): 636–41. doi:10.1001/archneur.65.5.636. PMID 18474740.

[8] URL: http://dictionary.reference.com/browse/skein. Accessed on: 20 November 2010.

[9] Gelpi, E.. "Clinical Neuropathology teaching case 3-2015: female or male brain? Anti-ubiquitin visualizes Barr bodies in hippocampal granule cells which allows the determination of gender in human brains.". Clin Neuropathol 34 (3): 115-6. PMID 25909954.

[10] Kovacs, GG.; Risser, D.. "Clinical Neuropathology image 6-2014: Corpora amylacea replacing cornu ammonis (CACA).". Clin Neuropathol 33 (6): 378-9. PMID 25343241.

[11] Coppola, G.; Chinnathambi, S.; Lee, JJ.; Dombroski, BA.; Baker, MC.; Soto-Ortolaza, AI.; Lee, SE.; Klein, E. et al. (Aug 2012). "Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases.". Hum Mol Genet 21 (15): 3500-12. doi:10.1093/hmg/dds161. PMID 22556362.

[Ref_TN2006_PS19-12] Shiau, Carolyn; Toren, Andrew (2006). Toronto Notes 2006: Comprehensive Medical Reference (Review for MCCQE 1 and USMLE Step 2) (22nd edition (2006) ed.). Toronto Notes for Medical Students, Inc.. pp. PS19. ISBN 978-0968592861.

[pmid17390256-13] Tuite, PJ.; Krawczewski, K. (Apr 2007). "Parkinsonism: a review-of-systems approach to diagnosis.". Semin Neurol 27 (2): 113-22. doi:10.1055/s-2007-971174. PMID 17390256.

[pmid22074330-14] Ahmed, Z.; Asi, YT.; Sailer, A.; Lees, AJ.; Houlden, H.; Revesz, T.; Holton, JL. (Nov 2011). "Review: The neuropathology, pathophysiology and genetics of multiple system atrophy.". Neuropathol Appl Neurobiol. doi:10.1111/j.1365-2990.2011.01234.x. PMID 22074330.

[pmid22228724-15] 15.0 ^15.1 Bertram, K.; Williams, DR. (Apr 2012). "Visual hallucinations in the differential diagnosis of parkinsonism.". J Neurol Neurosurg Psychiatry 83 (4): 448-52. doi:10.1136/jnnp-2011-300980. PMID 22228724.

[pmid21993183-16] Mahmoud, F.; Tampi, RR. (Oct 2011). "Valproic Acid-Induced Parkinsonism in the Elderly: A Comprehensive Review of the Literature.". Am J Geriatr Pharmacother. doi:10.1016/j.amjopharm.2011.09.002. PMID 21993183.

[pmid1815982-17] Gerlach, M.; Riederer, P.; Przuntek, H.; Youdim, MB. (Dec 1991). "MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease.". Eur J Pharmacol 208 (4): 273-86. PMID 1815982.

[pmid25917706-18] Korczyn, AD. (Apr 2015). "Vascular parkinsonism-characteristics, pathogenesis and treatment.". Nat Rev Neurol. doi:10.1038/nrneurol.2015.61. PMID 25917706.

[pmid20629120-19] Vilensky, JA.; Gilman, S.; McCall, S. (Jul 2010). "A historical analysis of the relationship between encephalitis lethargica and postencephalitic parkinsonism: a complex rather than a direct relationship.". Mov Disord 25 (9): 1116-23. doi:10.1002/mds.22908. PMID 20629120.

[pmid24398724-20] Chauhan, NB. (2014). "Chronic neurodegenerative consequences of traumatic brain injury.". Restor Neurol Neurosci 32 (2): 337-65. doi:10.3233/RNN-130354. PMID 24398724.

[21] Nelson, PT.; Alafuzoff, I.; Bigio, EH.; Bouras, C.; Braak, H.; Cairns, NJ.; Castellani, RJ.; Crain, BJ. et al. (May 2012). "Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature.". J Neuropathol Exp Neurol 71 (5): 362-81. doi:10.1097/NEN.0b013e31825018f7. PMID 22487856.

[22] Duyckaerts, C.; Sazdovitch, V.; Ando, K.; Seilhean, D.; Privat, N.; Yilmaz, Z.; Peckeu, L.; Amar, E. et al. (Feb 2018). "Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology.". Acta Neuropathol 135 (2): 201-212. doi:10.1007/s00401-017-1791-x. PMID 29209767.

[23] Jaunmuktane, Z.; Mead, S.; Ellis, M.; Wadsworth, JD.; Nicoll, AJ.; Kenny, J.; Launchbury, F.; Linehan, J. et al. (Sep 2015). "Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy.". Nature 525 (7568): 247-50. doi:10.1038/nature15369. PMID 26354483.

[24] Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 674-5. ISBN 978-1416054542.

[pmid19269132-25] Nieuwenhuis-Mark, RE.. "Diagnosing Alzheimer's dementia in Down syndrome: problems and possible solutions.". Res Dev Disabil 30 (5): 827-38. doi:10.1016/j.ridd.2009.01.010. PMID 19269132.

[omim104311-26] Online 'Mendelian Inheritance in Man' (OMIM) 104311

[omim600759-27] Online 'Mendelian Inheritance in Man' (OMIM) 600759

[omim107741-28] Online 'Mendelian Inheritance in Man' (OMIM) 107741

[pmid8307060-29] Braak H, Braak E, Bohl J (1993). "Staging of Alzheimer-related cortical destruction". Eur. Neurol. 33 (6): 403–8. PMID 8307060.

[30] Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1317. ISBN 978-1416031215.

[31] Braak, H.; Braak, E. (1991). "Neuropathological stageing of Alzheimer-related changes.". Acta Neuropathol 82 (4): 239-59. PMID 1759558.

[pakmednet-32] URL: http://www.pakmed.net/academic/age/alz/alz030.htm. Accessed on: 12 November 2010.

[alexbert-33] URL: http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm. Accessed on: 13 November 2010.

[34] Mirra, SS.; Heyman, A.; McKeel, D.; Sumi, SM.; Crain, BJ.; Brownlee, LM.; Vogel, FS.; Hughes, JP. et al. (Apr 1991). "The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease.". Neurology 41 (4): 479-86. PMID 2011243.

[35] URL: http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html. Accessed on: 5 December 2010.

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@@ Line 43: / Line 43: @@
 Prionopathies:
 *Creutzfeldt-Jakob disease (PrP).
+'''Note:''' Some people consider α-synuclein as a prion-like protein.<ref>{{Cite journal  | last1 = Watts | first1 = JC. | title = Calling α-synuclein a prion is scientifically justifiable. | journal = Acta Neuropathol | volume = 138 | issue = 4 | pages = 505-508 | month = Oct | year = 2019 | doi = 10.1007/s00401-019-02058-0 | PMID = 31407029 }}</ref>
 ====Table====
@@ Line 172: / Line 174: @@
 ===Ubiquitin===
 *Marks proteins for recycling.
+*Stains Barr bodies in hippocampal granule cells<ref> {{Cite journal  | last1 = Gelpi | first1 = E. | title = Clinical Neuropathology teaching case 3-2015: female or male brain? Anti-ubiquitin visualizes Barr bodies in hippocampal granule cells which allows the determination of gender in human brains. | journal = Clin Neuropathol | volume = 34 | issue = 3 | pages = 115-6 | month =  | year =  | doi =  | PMID = 25909954 }}</ref>
+===p62===
 *p62; poli-ubiquitin-binding protein p62.<ref name=pmid19946779/>
 ===Microscopic===
 Look for:
-*Lewy bodies.
+* Lewy bodies and extracellular pigment in neuromelanin-containing nuclei (SN, LC, DVN) -> PD.
+* Spongiform vacuolation in the neuropil (seen in Prion disease and FTLD-TDP).
+* Neurofibrillar tangles (pyramidal layer of dentate gyrus).
+* Granulovacuolar degeneration (granules within cytoplasmic vacuoles, mainly in the hippocampal pyramidal neurons, seen in AD).
+* Cores of amyloid plaqyes.
+* Cotton wool plaques (seen in familiar AD).
+* Pick cells (balloned neurons in frontal cortex).
+* Pick bodies (granular layer of dentate gyrus).
+* Extensive astrogliosis (striatonigral degeneration, hepatic encephalopathy).
 * Corpora amylacea in the cornu ammonis may be increased in neurodegenerative diseases. <ref>{{Cite journal  | last1 = Kovacs | first1 = GG. | last2 = Risser | first2 = D. | title = Clinical Neuropathology image 6-2014: Corpora amylacea replacing cornu ammonis (CACA). | journal = Clin Neuropathol | volume = 33 | issue = 6 | pages = 378-9 | month =  | year =  | doi =  | PMID = 25343241 }}</ref>
+<gallery>
+File:213-09-11-Congo Red Lewy body.tif|Lewy body
+File:Amyloid plaques alzheimer disease HE stain.jpg|Cotton wool plaques
+File:Neurofibrillary tangles in the Hippocampus of an old person with Alzheimer-related pathology, HE 3.JPG|Neurofibrillary tangles
+File:SpongiformChangeCJD.jpg | Spongiform vacuolation
+</gallery>
 =Clinical perspective=
+*Correlations between clinical signs and molecular can be poor.
+**Example: The MAPT A152T gene mutation may cause clinical symptoms matching AD, [[Neurodegenerative diseases#Corticobasal degeneration|CBD]], [[Neurodegenerative diseases#Progressive supranuclear palys|PSP]] and  [[Neurodegenerative diseases#Lewy body disease|LBD]].<ref>{{Cite journal  | last1 = Coppola | first1 = G. | last2 = Chinnathambi | first2 = S. | last3 = Lee | first3 = JJ. | last4 = Dombroski | first4 = BA. | last5 = Baker | first5 = MC. | last6 = Soto-Ortolaza | first6 = AI. | last7 = Lee | first7 = SE. | last8 = Klein | first8 = E. | last9 = Huang | first9 = AY. | title = Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases. | journal = Hum Mol Genet | volume = 21 | issue = 15 | pages = 3500-12 | month = Aug | year = 2012 | doi = 10.1093/hmg/dds161 | PMID = 22556362 }}</ref>
 ===Dementia general (mostly useless) DDx===
 *[[Alzheimer's disease|Alzheimer's]] dementia - most common.
@@ Line 355: / Line 377: @@
 *Misfolded cell-surface protein called PrP<sup>SC</sup>.
 **This is derived from the protein ''PrP<sup>C</sup>'' encoded by the ''PRNP'' gene.
+*Different genetics strains are associated with varying clinical phenotype.<ref>{{Cite journal  | last1 = Monari | first1 = L. | last2 = Chen | first2 = SG. | last3 = Brown | first3 = P. | last4 = Parchi | first4 = P. | last5 = Petersen | first5 = RB. | last6 = Mikol | first6 = J. | last7 = Gray | first7 = F. | last8 = Cortelli | first8 = P. | last9 = Montagna | first9 = P. | title = Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism. | journal = Proc Natl Acad Sci U S A | volume = 91 | issue = 7 | pages = 2839-42 | month = Mar | year = 1994 | doi = 10.1073/pnas.91.7.2839 | PMID = 7908444 }}</ref>
 Includes:
@@ Line 390: / Line 414: @@
 Note:
 *Spongiform changes may be seen in [[ALS]], [[Alzheimer's disease]] and Lewy body disease (e.g. [[Parkinson disease]]); however, the changes are only in the upper cortex and not diffuse.<ref>{{Ref APBR|419 Q4}}</ref>
+===Molecular===
+*The CJD phenotype is associated with a PRNP D178N mutation and valine polymorphism at codon 129 (D178N-129V).
+** Note: A Met129 polymorphism will cause Fatal familiar insomnia in the setting of the same PRNP D178N mutation. <ref>{{Cite journal  | last1 = Goldfarb | first1 = LG. | last2 = Petersen | first2 = RB. | last3 = Tabaton | first3 = M. | last4 = Brown | first4 = P. | last5 = LeBlanc | first5 = AC. | last6 = Montagna | first6 = P. | last7 = Cortelli | first7 = P. | last8 = Julien | first8 = J. | last9 = Vital | first9 = C. | title = Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. | journal = Science | volume = 258 | issue = 5083 | pages = 806-8 | month = Oct | year = 1992 | doi = 10.1126/science.1439789 | PMID = 1439789 }}</ref>
 <gallery>
@@ Line 505: / Line 534: @@
 *Neuronal loss and gliosis (absent in minimal-change MSA).
 *Alpha-synuclein-rich glial and neuronal cytoplasmic inclusions in white matter (finding at autopsy).<ref name=pmid18825660>{{Cite journal  | last1 = Wenning | first1 = GK. | last2 = Stefanova | first2 = N. | last3 = Jellinger | first3 = KA. | last4 = Poewe | first4 = W. | last5 = Schlossmacher | first5 = MG. | title = Multiple system atrophy: a primary oligodendrogliopathy. | journal = Ann Neurol | volume = 64 | issue = 3 | pages = 239-46 | month = Sep | year = 2008 | doi = 10.1002/ana.21465 | PMID = 18825660 }}</ref>
-**Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.<ref>MUN. 16 November 2010.</ref><ref>{{cite journal |vauthors=Trojanowski JQ, Revesz T |title=Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy |journal=Neuropathol. Appl. Neurobiol. |volume=33 |issue=6 |pages=615–20 |year=2007 |pmid=17990994 |doi=10.1111/j.1365-2990.2007.00907.x |url=}}</ref>
+**Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.<ref>MUN. 16 November 2010.</ref><ref>{{cite journal |authors=Trojanowski JQ, Revesz T |title=Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy |journal=Neuropathol. Appl. Neurobiol. |volume=33 |issue=6 |pages=615–20 |year=2007 |pmid=17990994 |doi=10.1111/j.1365-2990.2007.00907.x |url=}}</ref>
 **Inclusions usu. abundant in basal ganglia, substantia nigra, pontine nuclei, medulla and cerebellum.
 *Pons and Putamen:

Difference between revisions of "Neurodegenerative diseases"

Latest revision as of 20:32, 24 May 2020

Overview

Common diseases

Table

Immunohistochemistry

Alpha-synuclein

Tau

TDP-43

Microscopic

Ubiquitin

p62

Microscopic

Clinical perspective

Dementia general (mostly useless) DDx

Mnemonic

Functional anatomy of dementia

Parkinsonism causes

Amyloidoses

Alzheimer disease

General

Genetics

Gross

Images

Microscopic

Images

Classification

Prion diseases

General

IHC

Creutzfeldt-Jakob disease

General

Variant Creutzfeldt-Jakob disease

General

Microscopic

Molecular

Alpha-synucleinopathies

Dementia with Lewy bodies

General

Microscopic

IHC

Images

Parkinson disease

General

Gross

Microscopic

IHC

Images

Molecular

Multiple system atrophy

General

Macroscopy

Microscopic

Images

Molecular

Tauopathies

Argyrophilic grain disease

Corticobasal degeneration

Globular glial tauopathies

Microscopic

Progressive supranuclear palsy

General

Microscopic

Pick disease

General

Gross

Microscopic

TDP Proteinopathies

FTLD-TDP

FTLD-FET

Atypical FTLD‐U

Basophilic inclusion body disease

Neuronal Intermediate Filament Inclusion Disease

Other

Chronic traumatic encephalopathy

Huntington disease

General

Gross

Microscopic

Binswanger disease