Neurodegenerative diseases

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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

Common diseases

Amyloidoses:

  • Alzheimer disease (Abeta).

'Pure' tauopathies:

Synucleinopathies:[2]

TDP-43 proteinopathies:

FUS proteinopathies:

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

Prionopathies:

  • Creutzfeldt-Jakob disease (PrP).

Table

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

Disease Mutated 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 FUS (FTLD-FUS) 		FUS cortex, medulla, hippocampus, and motor cells of the spinal cord dementia, cases classified as FTLD-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.
  • 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):

FUSopathies (FTLD-FUS)

  • Clinical manifestations depend on the distribution of the pathologic alterations in the CNS
  • Currently 3 disorders among the FTLD-FUS subgroup.
  • In contrast to ALS-FUS, no genetic alterations of FUS have been reported to date for cases within the FTLD-FUS group.

DDx (also FUS+ve):

  • Spinocerebellar Ataxia (SCA)
  • Huntington Disease (SD)

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).
  • TAF15+ve
  • alpha-Internexin+ve.

Neuronal Intermediate Filament Inclusion Disease

  • AKA: NIFID.
  • Hyaline conglomerates (brightly eosinophilic branching fibrillar structures embedded in a round, well-delineated, glassy vacuole).
  • FUS+ve (heterogenous).
  • 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.
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