Difference between revisions of "Neurodegenerative diseases"

From Libre Pathology
Jump to navigation Jump to search
Line 151: Line 151:
Look for:
Look for:
*Lewy bodies (seen in Parkinson's d., Dementia with Lewy bodies) = round cytoplasmic eosinophilic body +/- pale halo.
*Lewy bodies (seen in Parkinson's d., Dementia with Lewy bodies) = 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 MSA.
*Glial cytoplasmatic inclusions (Papp-Lantos bodies) seen in MSA.


Revision as of 16:49, 5 April 2019

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:

Synucleinopathies:[2]

TDP-43 proteinopathies:

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).

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 PrPres (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)[3] [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 d., Dementia with Lewy bodies) = 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 MSA.

Tau

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

TDP-43

  • May accumulate due to a progranulin mutation.

Microscopic

Ubiquitin

  • Marks proteins for recycling.

Microscopic

  • p62; poli-ubiquitin-binding protein p62.[4]

Look for:

  • Lewy bodies. (???)

Clinical perspective

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:[8]

  • 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

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.[17]
  • Seen in conjunction with vascular amyloid deposition; see cerebral amyloid angiopathy.
  • Evidence of possible iatrogenic transmission by cadaver-sourced growth hormone batches.[18][19]



Genetics

Genes associated with Alzheimer disease:[20]

  • Amyloid precursor protein (APP).
    • On chromosome 21 - may explain why Trisomy 21 (Down syndrome) increases the risk of Alzheimer disease.[21]
  • Presenilin 1 (PSEN1).[22]
  • Presenilin 2 (PSEN2).[23]
  • Apolipoprotein E (APOE)[24] - 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):[25]

  • 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:

  1. Neurofibrillary tangles.
  2. 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).[30]
    • Images: senile plaques (utah.edu)[31] senile plaques - beta-APP - high mag. (WC).
  3. Neuron loss.
  4. +/-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 [32]

  • (A) assessment of amyloid b deposits
  • (B) staging of neurofibrillary tangles
  • (C) scoring of neuritic plaques
(A) abeta plaques (Thal phase)[33] (B) Neurofibrillary tangles (Braak stage) [34] (C) neuritic plaques (CERAD) [35]
(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:[36]

  • Misfolded cell-surface protein called PrPSC.
    • This is derived from the protein PrPC encoded by the PRNP gene.

Includes:

  • Creutzfeldt-Jakob disease (CJD).
  • Sporadic fatal insomnia (sFI).[36]
  • Fatal familial insomnia (FFI).[37][38]
  • Gestmann-Straussler-Scheinker syndrome (GSS) - due to PRNP gene mutations.[39]

IHC

PrPC:[37]

  • 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.[40]

Microscopic

Features:

  • Spongy appearance (cytoplasmic vacuolization[41]).

Note:

  • 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)

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:

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:[43]

  • Tremor.
  • Rigidity.
  • Akinesia.
  • Postural instability.

Genetics:[44]

  • LRRK2 gene[45] - autosomal dominant.
  • PARK2 gene (parkin)[46] - autosomal recessive.

Gross

Features:[47]

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

Notes:

Microscopic

Features:[47]

  • 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

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).[48]
    • Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.[49][50]
    • 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. [51]

Tauopathies

More than 20 different degenerative disorders can be classified as tauopathies.[52] FTLD-tau is an umbrella term used for tauopathies including PSP, CBD, PiD and GGT. [53]


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.[54]
    • 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.[55]
  • 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.[56]

Clinical:

  • Impaired control of gaze, esp. difficulty looking up and down (supranuclear palsy).[57]
  • Parkinsonism.[11]

Microscopic

Features:[1][56][58]

  • 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.[59][60]

Images:

Pick disease

General

  • Dementia.

Gross

  • Frontal and temporal lobe atrophy.[61]
    • May be called "walnut brain"[62] - as it resembles a walnut.

Microscopic

Features:[61]

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

Image(s):

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):[64]
    • 11-34 CAG repeat = normal.[65]
    • >42 CAG repeat = Huntington disease.

Clinical:[66]

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

Gross

  • Severe caudate atrophy.[67]
    • Prominent frontal horns of the lateral ventricles.[68]

Note:

  • A normal caudate bulges into the ventricle.

Images:

Microscopic

Features:[66]

  • 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.[69]
    • There are several subtypes of FTLD with TDP-43.

Gross

  • Frontal and temporal lobe atrophy.

Image:

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.[70][71]
  • 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).[72]

Microscopic

Features:[70][73]

  • 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.[74]
  • TDP-43 proteinopathy in motor neurons (90% of all sporadic ALS cases).
  • C9orf72 expansion cases: p62+ve, TDP-43-ve inclusions in the dentate gyrus, neocortex, and cerebellum.[76]
    • FUS-mutant cases show FUS+ve, p62+ve (few) and TDP-43-ve inclusions.[77]

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:[79]

  • Axonal spheroids.
  • Iron deposition.

Images:

Stains

  • Prussian blue +ve.

See also

References

  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.
  2. ↑ Uversky, VN. (Oct 2008). "Alpha-synuclein misfolding and neurodegenerative diseases.". Curr Protein Pept Sci 9 (5): 507-40. PMID 18855701.
  3. ↑ MUN. 15 November 2010.
  4. ↑ 4.0 4.1 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/.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ URL: http://dictionary.reference.com/browse/skein. Accessed on: 20 November 2010.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 11.0 11.1 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ Korczyn, AD. (Apr 2015). "Vascular parkinsonism-characteristics, pathogenesis and treatment.". Nat Rev Neurol. doi:10.1038/nrneurol.2015.61. PMID 25917706.
  15. ↑ 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.
  16. ↑ Chauhan, NB. (2014). "Chronic neurodegenerative consequences of traumatic brain injury.". Restor Neurol Neurosci 32 (2): 337-65. doi:10.3233/RNN-130354. PMID 24398724.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 104311
  23. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 600759
  24. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 107741
  25. ↑ Braak H, Braak E, Bohl J (1993). "Staging of Alzheimer-related cortical destruction". Eur. Neurol. 33 (6): 403–8. PMID 8307060.
  26. ↑ 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.
  27. ↑ Braak, H.; Braak, E. (1991). "Neuropathological stageing of Alzheimer-related changes.". Acta Neuropathol 82 (4): 239-59. PMID 1759558.
  28. ↑ URL: http://www.pakmed.net/academic/age/alz/alz030.htm. Accessed on: 12 November 2010.
  29. ↑ URL: http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm. Accessed on: 13 November 2010.
  30. ↑ 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.
  31. ↑ URL: http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html. Accessed on: 5 December 2010.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ Braak, H.; Braak, E. (1991). "Neuropathological stageing of Alzheimer-related changes.". Acta Neuropathol 82 (4): 239-59. PMID 1759558.
  35. ↑ 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.
  36. ↑ 36.0 36.1 Watts JC, Balachandran A, Westaway D (March 2006). "The expanding universe of prion diseases". PLoS Pathog. 2 (3): e26. doi:10.1371/journal.ppat.0020026. PMC 1434791. PMID 16609731. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1434791/.
  37. ↑ 37.0 37.1 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. 672. ISBN 978-1416054542.
  38. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 600072
  39. ↑ 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. 671. ISBN 978-1416054542.
  40. ↑ Burton, Julian L.; Rutty, Guy N. (2010). The Hospital Autopsy A Manual of Fundamental Autopsy Practice (3rd ed.). Oxford University Press. pp. 83. ISBN 978-0340965146.
  41. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0I002-PQ01-M.htm. Accessed on: 19 October 2010.
  42. ↑ Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 419 Q4. ISBN 978-1416025887.
  43. ↑ URL: http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519. Accessed on: 30 March 2011.
  44. ↑ 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. 677. ISBN 978-1416054542.
  45. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 609007
  46. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 602544
  47. ↑ 47.0 47.1 Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1319. ISBN 978-1416031215.
  48. ↑ Wenning, GK.; Stefanova, N.; Jellinger, KA.; Poewe, W.; Schlossmacher, MG. (Sep 2008). "Multiple system atrophy: a primary oligodendrogliopathy.". Ann Neurol 64 (3): 239-46. doi:10.1002/ana.21465. PMID 18825660.
  49. ↑ MUN. 16 November 2010.
  50. ↑ "Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy". Neuropathol. Appl. Neurobiol. 33 (6): 615–20. 2007. doi:10.1111/j.1365-2990.2007.00907.x. PMID 17990994.
  51. ↑ Pimenta, PF.; da Silva, RP.; Sacks, DL.; da Silva, PP. (Apr 1989). "Cell surface nanoanatomy of Leishmania major as revealed by fracture-flip. A surface meshwork of 44 nm fusiform filaments identifies infective developmental stage promastigotes.". Eur J Cell Biol 48 (2): 180-90. PMID 2743996.
  52. ↑ Williams, DR. (Oct 2006). "Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau.". Intern Med J 36 (10): 652-60. doi:10.1111/j.1445-5994.2006.01153.x. PMID 16958643.
  53. ↑ Forrest, SL.; Kril, JJ.; Stevens, CH.; Kwok, JB.; Hallupp, M.; Kim, WS.; Huang, Y.; McGinley, CV. et al. (Feb 2018). "Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies.". Brain 141 (2): 521-534. doi:10.1093/brain/awx328. PMID 29253099.
  54. ↑ Dickson, DW.; Bergeron, C.; Chin, SS.; Duyckaerts, C.; Horoupian, D.; Ikeda, K.; Jellinger, K.; Lantos, PL. et al. (Nov 2002). "Office of Rare Diseases neuropathologic criteria for corticobasal degeneration.". J Neuropathol Exp Neurol 61 (11): 935-46. PMID 12430710.
  55. ↑ Ahmed, Z.; Bigio, EH.; Budka, H.; Dickson, DW.; Ferrer, I.; Ghetti, B.; Giaccone, G.; Hatanpaa, KJ. et al. (Oct 2013). "Globular glial tauopathies (GGT): consensus recommendations.". Acta Neuropathol 126 (4): 537-544. doi:10.1007/s00401-013-1171-0. PMID 23995422.
  56. ↑ 56.0 56.1 URL: http://emedicine.medscape.com/article/1151430-overview. Accessed on: 11 November 2010.
  57. ↑ Levy, R. (Jun 2011). "[Progressive supranuclear palsy: what's new?].". Geriatr Psychol Neuropsychiatr Vieil 9 (2): 191-201. doi:10.1684/pnv.2011.0271. PMID 21690028.
  58. ↑ Williams DR, Lees AJ (March 2009). "Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges". Lancet Neurol 8 (3): 270–9. doi:10.1016/S1474-4422(09)70042-0. PMID 19233037.
  59. ↑ URL: http://neuropathologyblog.blogspot.com/2008/03/grumose-degeneration-in-cerebellar.html. Accessed on: 4 December 2010.
  60. ↑ Yamanouchi H, Yokoo H, Yuhara Y, et al. (March 2002). "An autopsy case of ornithine transcarbamylase deficiency". Brain Dev. 24 (2): 91–4. PMID 11891099.
  61. ↑ 61.0 61.1 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. 676. ISBN 978-1416054542.
  62. ↑ URL: http://medical-dictionary.thefreedictionary.com/Walnut+Brain. Accessed on: 14 March 2012.
  63. ↑ Grossman, M. (Feb 2010). "Primary progressive aphasia: clinicopathological correlations.". Nat Rev Neurol 6 (2): 88-97. doi:10.1038/nrneurol.2009.216. PMID 20139998.
  64. ↑ Kumar P, Kalonia H, Kumar A (2010). "Huntington's disease: pathogenesis to animal models". Pharmacol Rep 62 (1): 1–14. PMID 20360611.
  65. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 613004
  66. ↑ 66.0 66.1 Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 415 Q44. ISBN 978-1416025887.
  67. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm. Accessed on: 29 October 2010.
  68. ↑ URL: http://path.upmc.edu/cases/case117/gross.html. Accessed on: 3 January 2012.
  69. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 105400
  70. ↑ 70.0 70.1 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. 679. ISBN 978-1416054542.
  71. ↑ Guerrero, EN.; Wang, H.; Mitra, J.; Hegde, PM.; Stowell, SE.; Liachko, NF.; Kraemer, BC.; Garruto, RM. et al. "TDP-43/FUS in motor neuron disease: Complexity and challenges.". Prog Neurobiol 145-146: 78-97. doi:10.1016/j.pneurobio.2016.09.004. PMID 27693252.
  72. ↑ Chernoff, N.; Hill, DJ.; Diggs, DL.; Faison, BD.; Francis, BM.; Lang, JR.; Larue, MM.; Le, TT. et al. (2017). "A critical review of the postulated role of the non-essential amino acid, β-N-methylamino-L-alanine, in neurodegenerative disease in humans.". J Toxicol Environ Health B Crit Rev 20 (4): 1-47. doi:10.1080/10937404.2017.1297592. PMID 28598725.
  73. ↑ Saberi, S.; Stauffer, JE.; Schulte, DJ.; Ravits, J. (Nov 2015). "Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants.". Neurol Clin 33 (4): 855-76. doi:10.1016/j.ncl.2015.07.012. PMID 26515626.
  74. ↑ Leigh, PN.; Anderton, BH.; Dodson, A.; Gallo, JM.; Swash, M.; Power, DM. (Nov 1988). "Ubiquitin deposits in anterior horn cells in motor neurone disease.". Neurosci Lett 93 (2-3): 197-203. PMID 2853844.
  75. ↑ Nakamura, S.; Wate, R.; Kaneko, S.; Ito, H.; Oki, M.; Tsuge, A.; Nagashima, M.; Asayama, S. et al. (Feb 2014). "An autopsy case of sporadic amyotrophic lateral sclerosis associated with the I113T SOD1 mutation.". Neuropathology 34 (1): 58-63. doi:10.1111/neup.12049. PMID 23773010.
  76. ↑ Al-Sarraj, S.; King, A.; Troakes, C.; Smith, B.; Maekawa, S.; Bodi, I.; Rogelj, B.; Al-Chalabi, A. et al. (Dec 2011). "p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS.". Acta Neuropathol 122 (6): 691-702. doi:10.1007/s00401-011-0911-2. PMID 22101323.
  77. ↑ Vance, C.; Rogelj, B.; Hortobágyi, T.; De Vos, KJ.; Nishimura, AL.; Sreedharan, J.; Hu, X.; Smith, B. et al. (Feb 2009). "Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.". Science 323 (5918): 1208-1211. doi:10.1126/science.1165942. PMID 19251628.
  78. ↑ URL: http://pathology.mc.duke.edu/neuropath/CNSlecture4/CNSlecture4.htm. Accessed on: 30 August 2011.
  79. ↑ URL: http://path.upmc.edu/cases/case207/dx.html. Accessed on: 11 January 2012.
Retrieved from "https://librepathology.org/w/index.php?title=Neurodegenerative_diseases&oldid=50044"