Difference between revisions of "Neurodegenerative diseases"

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{{familytree  | | | | | | | A01 | | | | | | | | A01=Neurodegenerative<br>disorders}}
{{familytree  | | | | | | | A01 | | | | | | | | A01=Neurodegenerative<br>disorders}}
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{{familytree  | B01 | | B02 | | B03 | | B04 | |B01=Amyloidoses|B02=Tauopathies|B03=α-synucleinopathies|B04=TDP-43}}
{{familytree  | B01 | | B02 | | B03 | | B04 | | B05 || B01=Amyloidoses|B02=Tauopathies|B03=α-synucleinopathies|B04=TDP-43|B05=FUS/EWS/TAF15}}
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[[Amyloid]]oses:
[[Amyloid]]oses:
*Alzheimer disease (Abeta).
*Alzheimer disease (Abeta).
*Creutzfeldt-Jakob disease (PrP).


Taupathies:
'Pure' tauopathies:
*Progressive supranuclear palsy.
*[[Progressive supranuclear palsy]].
*Pick's disease.
*[[Pick's disease]].
*Corticobasal degeneration.
*FTDP-17.
*[[Dementia pugilistica]].


Synucleinopathies:<ref name=pmid18855701>{{Cite journal  | last1 = Uversky | first1 = VN. | title = Alpha-synuclein misfolding and neurodegenerative diseases. | journal = Curr Protein Pept Sci | volume = 9 | issue = 5 | pages = 507-40 | month = Oct | year = 2008 | doi =  | PMID = 18855701 }}</ref>
Synucleinopathies:<ref name=pmid18855701>{{Cite journal  | last1 = Uversky | first1 = VN. | title = Alpha-synuclein misfolding and neurodegenerative diseases. | journal = Curr Protein Pept Sci | volume = 9 | issue = 5 | pages = 507-40 | month = Oct | year = 2008 | doi =  | PMID = 18855701 }}</ref>
*Parkinson disease.
*[[Parkinson disease]].
*Dementia with [[Lewy bodies]].
*Dementia with [[Lewy bodies]].
*Multiple system atrophy.
*[[Multiple system atrophy]].


TDP-43 proteinopathies:
TDP-43 proteinopathies:
*Amyotrophic alteral sclerosis.
*[[Amyotrophic lateral sclerosis]].
*Frontotemporal lobar degeneration with ubiquitinated inclusions.
*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.<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====
====Table====
Disease/pathology/clinical correlation based on ''Dickson'':<ref name=pmid19918325>{{cite journal |author=Dickson DW |title=Neuropathology of non-Alzheimer degenerative disorders |journal=Int J Clin Exp Pathol |volume=3 |issue=1 |pages=1–23 |year=2009 |pmid=19918325 |pmc=2776269 |doi= |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776269/?tool=pubmed}}</ref>
Disease/pathology/clinical correlation based on ''Dickson'':<ref name=pmid19918325>{{cite journal |author=Dickson DW |title=Neuropathology of non-Alzheimer degenerative disorders |journal=Int J Clin Exp Pathol |volume=3 |issue=1 |pages=1–23 |year=2009 |pmid=19918325 |pmc=2776269 |doi= |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776269/?tool=pubmed}}</ref>
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
| '''Disease'''
! Disease
| '''Mutated protein'''
! Deposited protein
| '''Distribution'''
! Distribution
| '''Clinical'''
! Clinical
| '''Histology'''
! Histology
| '''Image'''
! Image
|-
|-
| [[Alzheimer disease]]
| [[Alzheimer disease]]
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| cortical & basal ganglia
| cortical & basal ganglia
| dementia (rapid progression), <br>movement disorder  
| dementia (rapid progression), <br>movement disorder  
| cytoplasmic vacuolization
| cytoplasmic vacuolization, PrP+ve plaques, Kuru plaques (MV2 variant)
| [http://en.wikipedia.org/wiki/File:SpongiformChangeCJD.jpg]
| [http://en.wikipedia.org/wiki/File:SpongiformChangeCJD.jpg]
|-
| [[Progressive supranuclear palsy]]
| tau 4R
| basal ganglia, brainstem
| parkinsonism
| globose neurofibrillary tangles <br>in neurons, coiled bodies <br>in oligodendrocytes
| Image?
|-
| [[Pick disease]]
| tau 3R
| corticolimbic
| dementia + focal <br>cortical syndrome
| Pick body ???
| Image?
|-
|-
| [[Parkinson disease]]
| [[Parkinson disease]]
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| brainstem
| brainstem
| parkinsonism  
| parkinsonism  
| Lewy bodies
| Lewy bodies in substantia nigra and locus coeruleus
| [http://firstaidteam.com/usmlerximages/v/USMLERxLewy+bodies.gif.html]
| [http://firstaidteam.com/usmlerximages/v/USMLERxLewy+bodies.gif.html] [https://de.wikipedia.org/wiki/Datei:LewyBodies_small.JPG]
|-
|-
| Dementia with <br>Lewy bodies
| [[Dementia with Lewy bodies|Dementia with <br>Lewy bodies]]
| alpha-synuclein
| alpha-synuclein
| corticolimbic, brainstem
| corticolimbic, brainstem
| dementia + parkinsonism
| dementia + parkinsonism
| Lewy bodies
| Lewy bodies brainstem and cortical, tangles
| [http://firstaidteam.com/usmlerximages/v/USMLERxLewy+bodies.gif.html]
| [http://firstaidteam.com/usmlerximages/v/USMLERxLewy+bodies.gif.html] [https://commons.wikimedia.org/wiki/File:DLB_frontal_lewy_bodies_HE.jpg]
|-
|-
| [[Multiple system atrophy]]
| [[Multiple system atrophy]]
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| basal ganglia, brainstem, cerebellum
| basal ganglia, brainstem, cerebellum
| parkinsonism, ataxia  
| parkinsonism, ataxia  
| cytoplasmic inclusion in oligodendrocytes<ref>MUN. 15 November 2010.</ref>
| Papp-Lantos inclusions (cytoplasmic deposits in oligodendrocytes)<ref>MUN. 15 November 2010.</ref>
| Image
| [https://commons.wikimedia.org/wiki/File:MSA_Gallays_Papp_Lantos_inclusions.jpg]
|-
|-
| [[Amyotrophic lateral sclerosis|Amyotrophic lateral <br>sclerosis (ALS)]]
| [[Amyotrophic lateral sclerosis|Amyotrophic lateral <br>sclerosis (ALS)]]
| TDP-43
| [[TDP-43]]
| motor neurons
| motor neurons
| spasticity, weakness
| spasticity, weakness
| histology?
| motor neuron loss, TDP-43+ve, TAF15-ve, EWS-ve inclusions in motor neurons
| Image
| [https://commons.wikimedia.org/wiki/File:Als_inclusions.png]
|-  
|-  
| Frontotemporal lobar <br>degeneration (FTLD) with <br>ubiquitinated inclusions
| Frontotemporal lobar <br>degeneration with TDP-43 (FTLD-TDP)
| TDP-43
| [[TDP-43]]
| cortex, basal ganglia
| cortex, basal ganglia
| dementia, focal cortical syndromes
| dementia, focal cortical syndromes
| histology?
| histology depends on (type 1-4), ubiquitin and [[TDP-43]]+ve, tau and FUS-ve
| Image?
| [https://commons.wikimedia.org/wiki/File:FTLD_TSP43_hippocampus.jpg]
|-
| Frontotemporal lobar <br>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
| [http://brain.oxfordjournals.org/content/brain/134/9/2595/F1.medium.gif]
|-
|-
| [[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 <br>in neurons, tufted astrocytes, coiled bodies <br>in oligodendrocytes
| [https://commons.wikimedia.org/wiki/File:PSP_Tau_tufted_astrocyte.jpg]
|-
| [[Pick disease]] (FTLD-tau)
| tau 3R
| corticolimbic
| dementia + focal <br>cortical syndrome
| Intraneuronal argyrophilic inclusions (Pick body)
| [http://frontalcortex.com/gallery/pics/gliageek_PBtau.jpg]
|-
| Corticobasal degeneration (CBD) (FTLD-tau)
| tau 4R
| cortical, basal ganglia
| dementia + movement disorder (Parkinson-plus syndrome)
| ballooned neurons, astrocytic plaques, pretangles in basal nucleus
| [http://webeye.ophth.uiowa.edu/eyeforum/cases-i/case155/4-Progressive-Supranuclear-Palsy-histology.jpg]
|-
| Argryophilic grain disease (AGD) (FTLD-tau)
| tau 4R
| medial temporal lobe, limbic structures
| late-onset amnestic syndrome
| Argyrophilic grains (also found unspecific in elederly)
| [http://de.wikipedia.org/wiki/Silberkornkrankheit#/media/File:AGD_gallays.jpg]
|- <!--
|- <!--
| Disease
| Disease
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===Alpha-synuclein===
===Alpha-synuclein===
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 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===
===Tau===
*AT8 = stains phosphorylated tau.<ref name=pmid19946779>{{cite journal |author=Seelaar H, Klijnsma KY, de Koning I, ''et al.'' |title=Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration |journal=J. Neurol. |volume=257 |issue=5 |pages=747–53 |year=2010 |month=May |pmid=19946779 |pmc=2864899 |doi=10.1007/s00415-009-5404-z |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864899/}}</ref>
*AT8 = stains phosphorylated tau.<ref name=pmid19946779>{{cite journal |author=Seelaar H, Klijnsma KY, de Koning I, ''et al.'' |title=Frequency of ubiquitin and FUS-positive, [[TDP-43]]-negative frontotemporal lobar degeneration |journal=J. Neurol. |volume=257 |issue=5 |pages=747–53 |year=2010 |month=May |pmid=19946779 |pmc=2864899 |doi=10.1007/s00415-009-5404-z |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864899/}}</ref>
**''AT'' = anti-tau.
**''AT'' = anti-tau.
**Stains tau 4R and tau 3R.<ref>{{cite journal |author=Kumaran R, Kingsbury A, Coulter I, ''et al.'' |title=DJ-1 (PARK7) is associated with 3R and 4R tau neuronal and glial inclusions in neurodegenerative disorders |journal=Neurobiol. Dis. |volume=28 |issue=1 |pages=122–32 |year=2007 |month=October |pmid=17719794 |doi=10.1016/j.nbd.2007.07.012 |url=}}</ref>
**Stains tau 4R and tau 3R.<ref>{{cite journal |author=Kumaran R, Kingsbury A, Coulter I, ''et al.'' |title=DJ-1 (PARK7) is associated with 3R and 4R tau neuronal and glial inclusions in neurodegenerative disorders |journal=Neurobiol. Dis. |volume=28 |issue=1 |pages=122–32 |year=2007 |month=October |pmid=17719794 |doi=10.1016/j.nbd.2007.07.012 |url=}}</ref>
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===Ubiquitin===
===Ubiquitin===
*Marks proteins for recycling.
*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>


====Microscopic====
===p62===
*p62; poli-ubiquitin-binding protein p62.<ref name=pmid19946779/>
*p62; poli-ubiquitin-binding protein p62.<ref name=pmid19946779/>


===Microscopic===
Look for:
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=
=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===
===Dementia general (mostly useless) DDx===
*Alzheimer's dementia - most common.
*[[Alzheimer's disease|Alzheimer's]] dementia - most common.
*Vascular.
*Vascular.
**Multi-infarct dementia.
**Multi-infarct dementia.
*Parkinson's associated dementia.
*Parkinson's associated dementia.
*Lewy body dementia.
*Lewy body dementia.
*Alcohol-related dementia.
*[[Alcohol]]-related dementia.
*Fronto-temporal dementia (Pick disease).
*Fronto-temporal dementia (Pick disease).
*Multisystem atrophy.
*Multisystem atrophy.


====Mnemonic====
====Mnemonic====
Dementia mnemonic ''VITAMIN D VEST'':<ref>TN06 PS19</ref>
Dementia mnemonic ''VITAMIN D VEST'':<ref name=Ref_TN2006_PS19>{{Ref TN2006| PS19}}</ref>
*Vitamin deficiency (B12, folate, thiamine).
*Vitamin deficiency (B12, folate, thiamine).
*Infection (HIV).
*Infection (HIV).
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===Parkinsonism causes===
===Parkinsonism causes===
*Parkinson's disease <ref name=pmid17390256>{{Cite journal  | last1 = Tuite | first1 = PJ. | last2 = Krawczewski | first2 = K. | title = Parkinsonism: a review-of-systems approach to diagnosis. | journal = Semin Neurol | volume = 27 | issue = 2 | pages = 113-22 | month = Apr | year = 2007 | doi = 10.1055/s-2007-971174 | PMID = 17390256 }}</ref>
*Parkinson's disease <ref name=pmid17390256>{{Cite journal  | last1 = Tuite | first1 = PJ. | last2 = Krawczewski | first2 = K. | title = Parkinsonism: a review-of-systems approach to diagnosis. | journal = Semin Neurol | volume = 27 | issue = 2 | pages = 113-22 | month = Apr | year = 2007 | doi = 10.1055/s-2007-971174 | PMID = 17390256 }}</ref>
*[[Multiple system atrophy]].<ref name=pmid22074330>{{Cite journal  | last1 = Ahmed | first1 = Z. | last2 = Asi | first2 = YT. | last3 = Sailer | first3 = A. | last4 = Lees | first4 = AJ. | last5 = Houlden | first5 = H. | last6 = Revesz | first6 = T. | last7 = Holton | first7 = JL. | title = Review: The neuropathology, pathophysiology and genetics of multiple system atrophy. | journal = Neuropathol Appl Neurobiol | volume =  | issue =  | pages =  | month = Nov | year = 2011 | doi = 10.1111/j.1365-2990.2011.01234.x | PMID = 22074330 }}</ref>
*[[Dementia with Lewy bodies]].
*Dementia with Lewy bodies.
*[[Multiple system atrophy]] (MSA).<ref name=pmid22074330>{{Cite journal  | last1 = Ahmed | first1 = Z. | last2 = Asi | first2 = YT. | last3 = Sailer | first3 = A. | last4 = Lees | first4 = AJ. | last5 = Houlden | first5 = H. | last6 = Revesz | first6 = T. | last7 = Holton | first7 = JL. | title = Review: The neuropathology, pathophysiology and genetics of multiple system atrophy. | journal = Neuropathol Appl Neurobiol | volume =  | issue =  | pages =  | month = Nov | year = 2011 | doi = 10.1111/j.1365-2990.2011.01234.x | PMID = 22074330 }}</ref>
*Drug induced (valproic acid).<ref name=pmid21993183>{{Cite journal  | last1 = Mahmoud | first1 = F. | last2 = Tampi | first2 = RR. | title = Valproic Acid-Induced Parkinsonism in the Elderly: A Comprehensive Review of the Literature. | journal = Am J Geriatr Pharmacother | volume =  | issue =  | pages =  | month = Oct | year = 2011 | doi = 10.1016/j.amjopharm.2011.09.002 | PMID = 21993183 }}</ref>
*[[Progressive supranuclear palsy]] (PSP).<ref name=pmid22228724>{{Cite journal  | last1 = Bertram | first1 = K. | last2 = Williams | first2 = DR. | title = Visual hallucinations in the differential diagnosis of parkinsonism. | journal = J Neurol Neurosurg Psychiatry | volume = 83 | issue = 4 | pages = 448-52 | month = Apr | year = 2012 | doi = 10.1136/jnnp-2011-300980 | PMID = 22228724 }}</ref>
*Drug induced (valproic acid, MPTP).<ref name=pmid21993183>{{Cite journal  | last1 = Mahmoud | first1 = F. | last2 = Tampi | first2 = RR. | title = Valproic Acid-Induced Parkinsonism in the Elderly: A Comprehensive Review of the Literature. | journal = Am J Geriatr Pharmacother | volume =  | issue =  | pages =  | month = Oct | year = 2011 | doi = 10.1016/j.amjopharm.2011.09.002 | PMID = 21993183 }}</ref><ref name=pmid1815982> {{Cite journal  | last1 = Gerlach | first1 = M. | last2 = Riederer | first2 = P. | last3 = Przuntek | first3 = H. | last4 = Youdim | first4 = MB. | title = MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease. | journal = Eur J Pharmacol | volume = 208 | issue = 4 | pages = 273-86 | month = Dec | year = 1991 | doi =  | PMID = 1815982 }}</ref>
* Vascular. <ref name=pmid25917706>{{Cite journal  | last1 = Korczyn | first1 = AD. | title = Vascular parkinsonism-characteristics, pathogenesis and treatment. | journal = Nat Rev Neurol | volume =  | issue =  | pages =  | month = Apr | year = 2015 | doi = 10.1038/nrneurol.2015.61 | PMID = 25917706 }}</ref>
* Postencephalitic. <ref name=pmid20629120>{{Cite journal  | last1 = Vilensky | first1 = JA. | last2 = Gilman | first2 = S. | last3 = McCall | first3 = S. | title = A historical analysis of the relationship between encephalitis lethargica and postencephalitic parkinsonism: a complex rather than a direct relationship. | journal = Mov Disord | volume = 25 | issue = 9 | pages = 1116-23 | month = Jul | year = 2010 | doi = 10.1002/mds.22908 | PMID = 20629120 }}</ref>
* Tramuatic (Dementia pugilistica).<ref name=pmid24398724>{{Cite journal  | last1 = Chauhan | first1 = NB. | title = Chronic neurodegenerative consequences of traumatic brain injury. | journal = Restor Neurol Neurosci | volume = 32 | issue = 2 | pages = 337-65 | month =  | year = 2014 | doi = 10.3233/RNN-130354 | PMID = 24398724 }}</ref>


=Amyloidoses=
=Amyloidoses=
==Alzheimer disease==
==Alzheimer disease==
===General===
===General===
*Onset: episodic memory loss.
*Onset: episodic memory loss.  
*Diagnosis is clinical & pathologic.
*Diagnosis is clinical & pathologic.
**Pathologic finding alone are not diagnostic.
**Pathologic finding alone are not diagnostic.
*[[Trisomy 21]] (Down syndrome) - increases risk.<ref>{{Cite journal  | last1 = Nieuwenhuis-Mark | first1 = RE. | title = Diagnosing Alzheimer's dementia in Down syndrome: problems and possible solutions. | journal = Res Dev Disabil | volume = 30 | issue = 5 | pages = 827-38 | month = | year = | doi = 10.1016/j.ridd.2009.01.010 | PMID = 19269132 }}
**Onset, rate of progression and the development of pathology are highly variable.
</ref>
*Defined by:
**Pathological accumulation of amyloid β () into extracellular plaques.
**Abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs).
**Clinicopathological correlation better for NFT than for Aβ.<ref>{{Cite journal  | last1 = Nelson | first1 = PT. | last2 = Alafuzoff | first2 = I. | last3 = Bigio | first3 = EH. | last4 = Bouras | first4 = C. | last5 = Braak | first5 = H. | last6 = Cairns | first6 = NJ. | last7 = Castellani | first7 = RJ. | last8 = Crain | first8 = BJ. | last9 = Davies | first9 = P. | title = Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. | journal = J Neuropathol Exp Neurol | volume = 71 | issue = 5 | pages = 362-81 | month = May | year = 2012 | doi = 10.1097/NEN.0b013e31825018f7 | PMID = 22487856 }}</ref>
*Seen in conjunction with vascular amyloid deposition; see ''[[cerebral amyloid angiopathy]]''.
*Seen in conjunction with vascular amyloid deposition; see ''[[cerebral amyloid angiopathy]]''.
*Evidence of possible iatrogenic transmission by cadaver-sourced growth hormone batches.<ref>{{Cite journal  | last1 = Duyckaerts | first1 = C. | last2 = Sazdovitch | first2 = V. | last3 = Ando | first3 = K. | last4 = Seilhean | first4 = D. | last5 = Privat | first5 = N. | last6 = Yilmaz | first6 = Z. | last7 = Peckeu | first7 = L. | last8 = Amar | first8 = E. | last9 = Comoy | first9 = E. | title = 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. | journal = Acta Neuropathol | volume = 135 | issue = 2 | pages = 201-212 | month = Feb | year = 2018 | doi = 10.1007/s00401-017-1791-x | PMID = 29209767 }}</ref><ref>{{Cite journal  | last1 = Jaunmuktane | first1 = Z. | last2 = Mead | first2 = S. | last3 = Ellis | first3 = M. | last4 = Wadsworth | first4 = JD. | last5 = Nicoll | first5 = AJ. | last6 = Kenny | first6 = J. | last7 = Launchbury | first7 = F. | last8 = Linehan | first8 = J. | last9 = Richard-Loendt | first9 = A. | title = Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. | journal = Nature | volume = 525 | issue = 7568 | pages = 247-50 | month = Sep | year = 2015 | doi = 10.1038/nature15369 | PMID = 26354483 }}</ref>
====Genetics====
Genes associated with Alzheimer disease:<ref>{{Ref PCPBoD8|674-5}}</ref>
*Amyloid precursor protein (APP).
**On chromosome 21 - may explain why [[Trisomy 21]] (Down syndrome) increases the risk of Alzheimer disease.<ref name=pmid19269132>{{Cite journal  | last1 = Nieuwenhuis-Mark | first1 = RE. | title = Diagnosing Alzheimer's dementia in Down syndrome: problems and possible solutions. | journal = Res Dev Disabil | volume = 30 | issue = 5 | pages = 827-38 | month =  | year =  | doi = 10.1016/j.ridd.2009.01.010 | PMID = 19269132 }}</ref>
*Presenilin 1 (PSEN1).<ref name=omim104311>{{OMIM|104311}}</ref>
*Presenilin 2 (PSEN2).<ref name=omim600759>{{OMIM|600759}}</ref>
*Apolipoprotein E (APOE)<ref name=omim107741>{{OMIM|107741}}</ref> - specifically the ''epsilon-4'' allele.
===Gross===
===Gross===
Features:
Features:
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**Stage III-IV: inferior aspect of brain.
**Stage III-IV: inferior aspect of brain.
**Stage V-VI: limbic system.
**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====
<gallery>
Image:Alzheimers_brain.jpg | Alzheimer's brain. ([[WC]]/NIH)
Image:AD versus CO.jpg | Alzheimer's brain macroscopy (top) vs control (bottom). (WC/Hersenbank)
File:Alois Alzheimer 002.jpg | Alois Alzheimer provided a first description of the pathology. (NLM)
</gallery>


===Microscopic===
===Microscopic===
Line 207: Line 302:
#*Consists of ''tau''.
#*Consists of ''tau''.
#*Location: hippocampus, cerebral cortex, hypothalamus.
#*Location: hippocampus, cerebral cortex, hypothalamus.
#*Dementia severity correlates better with NF tangles number than senile plaque number.<ref>{{Ref PBoD8|1317}}</ref>
#*Six-tiered scoring method to assess tangle load <ref>{{Cite journal  | last1 = Braak | first1 = H. | last2 = Braak | first2 = E. | title = Neuropathological stageing of Alzheimer-related changes. | journal = Acta Neuropathol | volume = 82 | issue = 4 | pages = 239-59 | month =  | year = 1991 | doi =  | PMID = 1759558 }}</ref>
#*Images: [http://www.pakmed.net/academic/age/alz/plaques_tanglesBorder.jpg tangles - schematic (pakmed.net)]<ref name=pakmednet>URL: [http://www.pakmed.net/academic/age/alz/alz030.htm http://www.pakmed.net/academic/age/alz/alz030.htm]. Accessed on: 12 November 2010.</ref>, [http://faculty.washington.edu/alexbert/MEDEX/Fall/adtangle.jpg tangle (washington.edu)].<ref name=alexbert>URL: [http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm]. Accessed on: 13 November 2010.</ref>
#*Images: [http://www.pakmed.net/academic/age/alz/plaques_tanglesBorder.jpg tangles - schematic (pakmed.net)]<ref name=pakmednet>URL: [http://www.pakmed.net/academic/age/alz/alz030.htm http://www.pakmed.net/academic/age/alz/alz030.htm]. Accessed on: 12 November 2010.</ref>, [http://faculty.washington.edu/alexbert/MEDEX/Fall/adtangle.jpg tangle (washington.edu)].<ref name=alexbert>URL: [http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm]. Accessed on: 13 November 2010.</ref>
#*Dementia severity correlates better with NF tangles number than senile plaque number.<ref>{{Ref PBoD8|1317}}</ref>
#Senile plaques ([[AKA]] neuritic plaques).
#Senile plaques ([[AKA]] neuritic plaques).
#*Consists of two components:
#*Consists of two components:
Line 215: Line 311:
#*#Neurites - swollen axons.
#*#Neurites - swollen axons.
#*Considered to be more specific for Alzheimer's than NF tangles.
#*Considered to be more specific for Alzheimer's than NF tangles.
#*There is a staging system for plaques I (mild), II (moderate), III (severe).
#**How to remember: '''s'''enile '''p'''laques = '''sp'''ecific.
#*There is a CERAD staging system for senile plaque load: 0 (none), I (mild), II (moderate), III (severe).<ref>{{Cite journal  | last1 = Mirra | first1 = SS. | last2 = Heyman | first2 = A. | last3 = McKeel | first3 = D. | last4 = Sumi | first4 = SM. | last5 = Crain | first5 = BJ. | last6 = Brownlee | first6 = LM. | last7 = Vogel | first7 = FS. | last8 = Hughes | first8 = JP. | last9 = van Belle | first9 = G. | title = The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. | journal = Neurology | volume = 41 | issue = 4 | pages = 479-86 | month = Apr | year = 1991 | doi =  | PMID = 2011243 }}</ref>
#*Images: [http://library.med.utah.edu/WebPath/jpeg5/CNS091.jpg senile plaques (utah.edu)]<ref>URL: [http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html]. Accessed on: 5 December 2010.</ref> [http://commons.wikimedia.org/wiki/File:Cerebral_amyloid_angiopathy_-2a-_amyloid_beta_-_high_mag.jpg senile plaques - beta-APP - high mag. (WC)].
#*Images: [http://library.med.utah.edu/WebPath/jpeg5/CNS091.jpg senile plaques (utah.edu)]<ref>URL: [http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html]. Accessed on: 5 December 2010.</ref> [http://commons.wikimedia.org/wiki/File:Cerebral_amyloid_angiopathy_-2a-_amyloid_beta_-_high_mag.jpg senile plaques - beta-APP - high mag. (WC)].
#Neuron loss.
#+/-[[Cerebral amyloid angiopathy]].
====Images====
<gallery>
Image:Neuritic plaque HE stain.jpg | Neuritic plaques with amyloid core in HE. (WC/jensflorian)
Image:Alzheimer neuritic plaque gallyas stain.jpg | Neuritic plaques in Gallays silver impregnation. (WC/jensflorian)
Image:Alzheimer dementia (3) presenile onset.jpg | Neuritic plaques with amyloid core in Bodian stain. (WC/KGH)
Image:Cerebral amyloid angiopathy -2a- amyloid beta - high mag.jpg | Plaques with Abeta IHC. (WC/Nephron)
Image:Neurofibrillary tangles in the Hippocampus of an old person with Alzheimer-related pathology, HE 3.JPG | Neurofibrillary tangles in HE. (WC/Patho)
File:Neurofibrillary tangles in the Hippocampus of an old person with Alzheimer-related pathology, immunohistochemistry for tau protein.JPG | Tau IHC highlighting tangles. (WC/Patho)
File:Neurofibrillary tangles in the Hippocampus of an old person with Alzheimer-related pathology, Gallyas silver stain.JPG | Tangles in Gallays silver impregnation.(WC/Patho)
File:Hirano bodies in the Hippocampus in an old person with Alzheimer-related pathology, HE 2.JPG | HE stain with ghost tangles and Hirano bodies in AD. (WC/Patho)
File:Granulovacuolar degeneration.JPG | HE stain with granulovaculolar degeneration in AD. (WC/Patho)
</gallery>
===Classification===
NIA/AA Guidelines: "ABC" scoring method <ref>{{Cite journal  | last1 = Montine | first1 = TJ. | last2 = Phelps | first2 = CH. | last3 = Beach | first3 = TG. | last4 = Bigio | first4 = EH. | last5 = Cairns | first5 = NJ. | last6 = Dickson | first6 = DW. | last7 = Duyckaerts | first7 = C. | last8 = Frosch | first8 = MP. | last9 = Masliah | first9 = E. | title = National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. | journal = Acta Neuropathol | volume = 123 | issue = 1 | pages = 1-11 | month = Jan | year = 2012 | doi = 10.1007/s00401-011-0910-3 | PMID = 22101365 }}</ref>
* (A) assessment of amyloid b deposits
* (B) staging of neurofibrillary tangles
* (C) scoring of neuritic plaques
{| class="wikitable"
|-
! (A) abeta plaques (Thal phase)<ref>{{Cite journal  | last1 = Thal | first1 = DR. | last2 = Rüb | first2 = U. | last3 = Orantes | first3 = M. | last4 = Braak | first4 = H. | title = Phases of A beta-deposition in the human brain and its relevance for the development of AD. | journal = Neurology | volume = 58 | issue = 12 | pages = 1791-800 | month = Jun | year = 2002 | doi =  | PMID = 12084879 }}</ref>
! (B) Neurofibrillary tangles (Braak stage) <ref>{{Cite journal  | last1 = Braak | first1 = H. | last2 = Braak | first2 = E. | title = Neuropathological stageing of Alzheimer-related changes. | journal = Acta Neuropathol | volume = 82 | issue = 4 | pages = 239-59 | month =  | year = 1991 | doi =  | PMID = 1759558 }}</ref>
! (C) neuritic plaques (CERAD) <ref>{{Cite journal  | last1 = Mirra | first1 = SS. | last2 = Heyman | first2 = A. | last3 = McKeel | first3 = D. | last4 = Sumi | first4 = SM. | last5 = Crain | first5 = BJ. | last6 = Brownlee | first6 = LM. | last7 = Vogel | first7 = FS. | last8 = Hughes | first8 = JP. | last9 = van Belle | first9 = G. | title = The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. | journal = Neurology | volume = 41 | issue = 4 | pages = 479-86 | month = Apr | year = 1991 | doi =  | PMID = 2011243 }}</ref>
|-
| (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:
Notes:
*Abeta amyloid:
*Abeta amyloid:
Line 231: Line 377:
*Misfolded cell-surface protein called PrP<sup>SC</sup>.
*Misfolded cell-surface protein called PrP<sup>SC</sup>.
**This is derived from the protein ''PrP<sup>C</sup>'' encoded by the ''PRNP'' gene.  
**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:
Includes:
*Creutzfeldt-Jakob disease (CJD).
*Creutzfeldt-Jakob disease (CJD).
*Sporadic fatal insomnia (sFI).<ref name=pmid16609731>{{cite journal |author=Watts JC, Balachandran A, Westaway D |title=The expanding universe of prion diseases |journal=PLoS Pathog. |volume=2 |issue=3 |pages=e26 |year=2006 |month=March |pmid=16609731 |pmc=1434791 |doi=10.1371/journal.ppat.0020026 |url=}}</ref>
*Sporadic fatal insomnia (sFI).<ref name=pmid16609731>{{cite journal |author=Watts JC, Balachandran A, Westaway D |title=The expanding universe of prion diseases |journal=PLoS Pathog. |volume=2 |issue=3 |pages=e26 |year=2006 |month=March |pmid=16609731 |pmc=1434791 |doi=10.1371/journal.ppat.0020026 |url=}}</ref>
*Fatal familial insomnia (FFI).<ref name=Ref_PCPBoD8_672>{{Ref PCPBoD8|672}}</ref>
*Fatal familial insomnia (FFI).<ref name=Ref_PCPBoD8_672>{{Ref PCPBoD8|672}}</ref><ref name=omim600072>{{OMIM|600072}}</ref>
*Gestmann-Straussler-Scheinker syndrome (GSS) - due to PRNP gene mutations.<ref name=Ref_PCPBoD8_671>{{Ref PCPBoD8|671}}</ref>
*Gestmann-Straussler-Scheinker syndrome (GSS) - due to PRNP gene mutations.<ref name=Ref_PCPBoD8_671>{{Ref PCPBoD8|671}}</ref>


Line 264: Line 412:
*Spongy appearance (cytoplasmic vacuolization<ref>URL: [http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0I002-PQ01-M.htm http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0I002-PQ01-M.htm]. Accessed on: 19 October 2010.</ref>).
*Spongy appearance (cytoplasmic vacuolization<ref>URL: [http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0I002-PQ01-M.htm http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0I002-PQ01-M.htm]. Accessed on: 19 October 2010.</ref>).


Images:  
Note:
*[http://commons.wikimedia.org/wiki/File:SpongiformChangeCJD.jpg CJD (WC)].
*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>
*[http://commons.wikimedia.org/wiki/File:VCJD_Tonsil.jpg vCJD - IHC (WC)].
 
===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>
Image:SpongiformChangeCJD.jpg | CJD. (WC/DRdoubleB)
File:Variant Creutzfeldt-Jakob disease (vCJD), H&E.jpg|Spongiform changes in CJD. (CDC/ Teresa Hammett)
File:Variant CJD HE.jpg | Florid plaques in vCJD. (WC/Sbrandner)
File:Cdc cjd2.jpg | Florid plaques in vCJD - low mag. (WC/CDC.gov)
Image:VCJD_Tonsil.jpg | vCJD - prion protein immunostain tonsil. (WC/Sbrandner)
File:CJD PRP cortex.jpg | sCJD - prion protein immunostain cortex. (WC/jensflorian)
File:CJD PRP cerebellum.jpg | sCJD - prion protein immunostain cerebellum. (WC/jensflorian)
</gallery>
*[http://path.upmc.edu/cases/case86.html CJD - several cases (upmc.edu)].
*[http://path.upmc.edu/cases/case86.html CJD - several cases (upmc.edu)].


=Alpha-synucleinopathies=
=Alpha-synucleinopathies=
Includes the Lewy body diseases [[Parkinson's disease]] and [[Dementia with Lewy bodies]].
Without clincial information [[Parkinson's disease]] and [[Dementia with Lewy bodies]] cannot separated in histology.


==Dementia with Lewy bodies==
==Dementia with Lewy bodies==
Line 281: Line 443:
===Microscopic===
===Microscopic===
Features:
Features:
*Lewy bodies.
*[[Lewy bodies]].
*Lewy neurites.
Note: Cortical Lewy bodies are easily missed in HE.  


===IHC===
===IHC===
*Alpha-synuclein +ve.
*Alpha-synuclein +ve.
===Images===
<gallery>
File:DLB frontal lewy bodies HE.jpg | Lewy bodies in frontal cortex of DLB. (WC/jensflorian)
File:A synuclein cortex DLB.jpg | Alpha-synculein IHC showing cortical Lewy bodies. (WC/jensflorian)
File:Lewy neurites alpha synuclein.jpg | Alpha-synculein IHC showing Lewy Neurites in DLB. (WC/jensflorian)
</gallery>


==Parkinson disease==
==Parkinson disease==
===General===
===General===
*Common.
*Common - often sporadic.
*May be genetic.


Clinical ''TRAP'':<ref>URL: [http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519 http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519]. Accessed on: 30 March 2011.</ref>
Clinical ''TRAP'':<ref>URL: [http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519 http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519]. Accessed on: 30 March 2011.</ref>
Line 295: Line 467:
*Akinesia.
*Akinesia.
*Postural instability.
*Postural instability.
Genetics:<ref name=Ref_PCPBoD8_677>{{Ref PCPBoD8|677}}</ref>
*LRRK2 gene<ref name=omim609007>{{OMIM|609007}}</ref> - autosomal dominant.
*PARK2 gene (parkin)<ref name=omim602544>{{OMIM|602544}}</ref> - autosomal recessive.


===Gross===
===Gross===
Line 313: Line 489:
**Eosinophilic cytoplasmic inclusion with "dense" (darker) core and pale (surrounding) halo.
**Eosinophilic cytoplasmic inclusion with "dense" (darker) core and pale (surrounding) halo.
***Consist of filaments composed of alpha-synuclein.
***Consist of filaments composed of alpha-synuclein.
*Lewy neurites - alpha-synuclein positive processes.


===IHC===
===IHC===
*Alpha-synuclein +ve.
*Alpha-synuclein +ve.
===Images===
<gallery>
File:Journal.pone.0008247.g001.png | Schematic progression of PD (PLOSone/Jubault et al.).
File:Histological sample of Substantia nigra in Parkinson's disease.jpg | Lewy body (HE, left) and Lewy neurite (aSyn IHC, right).
File:Lewy Body alphaSynuclein.jpg | Alpha-synculein positive Lewy body (WC/Marvin101).
File:Lewy bodies (alpha synuclein inclusions).jpg | Lewy body and Lewy neurites (WC/Suraj Rajan).
</gallery>
===Molecular===
*Hereditary forms in less than 10% of the cases
**Involved genes are consecutively labeled PARK1, PARK2....


==Multiple system atrophy==
==Multiple system atrophy==
Multiple system atrophy is a neurodegenerative disease of the parkinsonism-plus disorder group.
===General===
===General===
Clinical findings variable:
Clinical findings variable:
*Parkinsonism (stiatonigral degeneration).
*Parkinsonism (stiatonigral degeneration, MSA-P).
*Ataxia (olivo-panto-cerebellar degeneration).
*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:
* [[Spinocerebellar ataxia]].
* [[Parkinson disease]].
* Motor-neuron disease.
* [[Lewy-Body disease]].
 
===Macroscopy===
* Cerebral (mild) & cerebellar atrophy.
* greenish [[putamen]].
* Discoloration [[Substantia nigra]] and [[Locus coeruleus]]


===Microscopic===
===Microscopic===
Features:
Features:
*Alpha-synuclein-rich glial cytoplasmic inclusions (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 cerebral, subcortical white matter, cerebellar.
**Inclusions in oligodendrocytes.<ref>MUN. 16 November 2010.</ref>
*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 |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:
** Nuclear inclusions (sparse in most cases).
** Neuropil threads (alpha-synuclein).
*Loss of myelinated fibers from external capsule, striatum and pallidum.


===Images===
<gallery>
File:Msa_macroscopy_putamen_discoloration.jpg | Gray-brown discoloration in putamen of a striatonigral-type MSA (WC/jensflorian).
File:MSA Gallays Papp Lantos inclusions.jpg | Gallays silver stain showing MSA-typic inclusions (WC/jensflorian).
File:MSA aSynuclein.jpg | a-synuclein IHC showing Glial and neuronal cytoplasmic inclusion in the pons of a MSA case (WC/jensflorian).
</gallery>
===Molecular===
* No known alpha-synuclein mutation.
* Genetic variants of SNCA gene assoicated with MSA. <ref name=PMID2743996>{{Cite journal  | last1 = Pimenta | first1 = PF. | last2 = da Silva | first2 = RP. | last3 = Sacks | first3 = DL. | last4 = da Silva | first4 = PP. | title = Cell surface nanoanatomy of Leishmania major as revealed by fracture-flip. A surface meshwork of 44 nm fusiform filaments identifies infective developmental stage promastigotes. | journal = Eur J Cell Biol | volume = 48 | issue = 2 | pages = 180-90 | month = Apr | year = 1989 | doi =  | PMID = 2743996 }}</ref>


=Tauopathies=
=Tauopathies=
More than 20 different degenerative disorders can be classified as tauopathies.<ref>{{Cite journal  | last1 = Williams | first1 = DR. | title = Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. | journal = Intern Med J | volume = 36 | issue = 10 | pages = 652-60 | month = Oct | year = 2006 | doi = 10.1111/j.1445-5994.2006.01153.x | PMID = 16958643 }}</ref> '''FTLD-tau''' is an umbrella term used for tauopathies including PSP, CBD, PiD and GGT. <ref>{{Cite journal  | last1 = Forrest | first1 = SL. | last2 = Kril | first2 = JJ. | last3 = Stevens | first3 = CH. | last4 = Kwok | first4 = JB. | last5 = Hallupp | first5 = M. | last6 = Kim | first6 = WS. | last7 = Huang | first7 = Y. | last8 = McGinley | first8 = CV. | last9 = Werka | first9 = H. | title = Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. | journal = Brain | volume = 141 | issue = 2 | pages = 521-534 | month = Feb | year = 2018 | doi = 10.1093/brain/awx328 | PMID = 29253099 }}</ref>
==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.<ref>{{Cite journal  | last1 = Dickson | first1 = DW. | last2 = Bergeron | first2 = C. | last3 = Chin | first3 = SS. | last4 = Duyckaerts | first4 = C. | last5 = Horoupian | first5 = D. | last6 = Ikeda | first6 = K. | last7 = Jellinger | first7 = K. | last8 = Lantos | first8 = PL. | last9 = Lippa | first9 = CF. | title = Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. | journal = J Neuropathol Exp Neurol | volume = 61 | issue = 11 | pages = 935-46 | month = Nov | year = 2002 | doi =  | PMID = 12430710 }}</ref>
**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.<ref>{{Cite journal  | last1 = Ahmed | first1 = Z. | last2 = Bigio | first2 = EH. | last3 = Budka | first3 = H. | last4 = Dickson | first4 = DW. | last5 = Ferrer | first5 = I. | last6 = Ghetti | first6 = B. | last7 = Giaccone | first7 = G. | last8 = Hatanpaa | first8 = KJ. | last9 = Holton | first9 = JL. | title = Globular glial tauopathies (GGT): consensus recommendations. | journal = Acta Neuropathol | volume = 126 | issue = 4 | pages = 537-544 | month = Oct | year = 2013 | doi = 10.1007/s00401-013-1171-0 | PMID = 23995422 }}</ref>
*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==
==Progressive supranuclear palsy==
*Commonly abbreviated ''PSP''.
*Commonly abbreviated ''PSP''.
*[[AKA]] ''Steele-Richardson-Olszewski syndrome''.
===General===
===General===
*[[AKA]] ''Steele-Richardson-Olszewski syndrome''.
*Diagnosis - clinical.<ref name=psp_emedicine>URL: [http://emedicine.medscape.com/article/1151430-overview http://emedicine.medscape.com/article/1151430-overview]. Accessed on: 11 November 2010.</ref>
*Diagnosis: clinical.<ref name=psp_emedicine>URL: [http://emedicine.medscape.com/article/1151430-overview http://emedicine.medscape.com/article/1151430-overview]. Accessed on: 11 November 2010.</ref>
 
Clinical:
*Impaired control of gaze, esp. difficulty looking up and down (supranuclear palsy).<ref name=pmid21690028>{{Cite journal  | last1 = Levy | first1 = R. | title = [Progressive supranuclear palsy: what's new?]. | journal = Geriatr Psychol Neuropsychiatr Vieil | volume = 9 | issue = 2 | pages = 191-201 | month = Jun | year = 2011 | doi = 10.1684/pnv.2011.0271 | PMID = 21690028 }}</ref>
*Parkinsonism.<ref name=pmid22228724>{{Cite journal  | last1 = Bertram | first1 = K. | last2 = Williams | first2 = DR. | title = Visual hallucinations in the differential diagnosis of parkinsonism. | journal = J Neurol Neurosurg Psychiatry | volume = 83 | issue = 4 | pages = 448-52 | month = Apr | year = 2012 | doi = 10.1136/jnnp-2011-300980 | PMID = 22228724 }}</ref>


===Microscopic===
===Microscopic===
Line 347: Line 605:
*Grumose degeneration of the cerebellar dentate nucleus.
*Grumose degeneration of the cerebellar dentate nucleus.
**Granular eosinophilic material adjacent to nuclei; once thought to be pathognomonic for PSP.<ref>URL: [http://neuropathologyblog.blogspot.com/2008/03/grumose-degeneration-in-cerebellar.html http://neuropathologyblog.blogspot.com/2008/03/grumose-degeneration-in-cerebellar.html]. Accessed on: 4 December 2010.</ref><ref>{{cite journal |author=Yamanouchi H, Yokoo H, Yuhara Y, ''et al.'' |title=An autopsy case of ornithine transcarbamylase deficiency |journal=Brain Dev. |volume=24 |issue=2 |pages=91–4 |year=2002 |month=March |pmid=11891099 |doi= |url=}}</ref>
**Granular eosinophilic material adjacent to nuclei; once thought to be pathognomonic for PSP.<ref>URL: [http://neuropathologyblog.blogspot.com/2008/03/grumose-degeneration-in-cerebellar.html http://neuropathologyblog.blogspot.com/2008/03/grumose-degeneration-in-cerebellar.html]. Accessed on: 4 December 2010.</ref><ref>{{cite journal |author=Yamanouchi H, Yokoo H, Yuhara Y, ''et al.'' |title=An autopsy case of ornithine transcarbamylase deficiency |journal=Brain Dev. |volume=24 |issue=2 |pages=91–4 |year=2002 |month=March |pmid=11891099 |doi= |url=}}</ref>
Images:
*[http://path.upmc.edu/cases/case238/micro.html PSP - several images (upmc.edu)].


==Pick disease==
==Pick disease==
Line 354: Line 615:
===Gross===
===Gross===
*Frontal and temporal lobe atrophy.<ref name=Ref_PCPBoD8_676>{{Ref PCPBoD8|676}}</ref>
*Frontal and temporal lobe atrophy.<ref name=Ref_PCPBoD8_676>{{Ref PCPBoD8|676}}</ref>
**May be called "walnut brain"<ref>URL: [http://medical-dictionary.thefreedictionary.com/Walnut+Brain http://medical-dictionary.thefreedictionary.com/Walnut+Brain]. Accessed on: 14 March 2012.</ref> - as it resembles a walnut.


===Microscopic===
===Microscopic===
Line 362: Line 624:
Image(s):
Image(s):
*[http://www.nature.com/nrneurol/journal/v6/n2/fig_tab/nrneurol.2009.216_F1.html Pick body (nature.com)].<ref name=pmid20139998>{{Cite journal  | last1 = Grossman | first1 = M. | title = Primary progressive aphasia: clinicopathological correlations. | journal = Nat Rev Neurol | volume = 6 | issue = 2 | pages = 88-97 | month = Feb | year = 2010 | doi = 10.1038/nrneurol.2009.216 | PMID = 20139998 }}</ref>
*[http://www.nature.com/nrneurol/journal/v6/n2/fig_tab/nrneurol.2009.216_F1.html Pick body (nature.com)].<ref name=pmid20139998>{{Cite journal  | last1 = Grossman | first1 = M. | title = Primary progressive aphasia: clinicopathological correlations. | journal = Nat Rev Neurol | volume = 6 | issue = 2 | pages = 88-97 | month = Feb | year = 2010 | doi = 10.1038/nrneurol.2009.216 | PMID = 20139998 }}</ref>
=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=
=Other=
==Chronic traumatic encephalopathy==
==Chronic traumatic encephalopathy==
*Abbreviated ''CTE''.
*Abbreviated ''CTE''.
===General===
{{Main|Chronic traumatic encephalopathy}}
*Due to head trauma - usu. repeated.
**Seen in ''American football'' and ''boxing''.
***The in the context of boxing it is known as ''dementia pugilistica''; ''pugil'' is ''boxer'' in Latin.<ref>URL: [http://dictionary.reference.com/browse/pugilism http://dictionary.reference.com/browse/pugilism]. Accessed on: 21 November 2011.</ref>
*May be associated with motor neuron disease.<ref name=pmid22050943>{{Cite journal  | last1 = Daneshvar | first1 = DH. | last2 = Riley | first2 = DO. | last3 = Nowinski | first3 = CJ. | last4 = McKee | first4 = AC. | last5 = Stern | first5 = RA. | last6 = Cantu | first6 = RC. | title = Long-term consequences: effects on normal development profile after concussion. | journal = Phys Med Rehabil Clin N Am | volume = 22 | issue = 4 | pages = 683-700 | month = Nov | year = 2011 | doi = 10.1016/j.pmr.2011.08.009 | PMID = 22050943 }}</ref>
 
===Microscopic===
Features:<ref name=pmid22035690>{{Cite journal  | last1 = Stern | first1 = RA. | last2 = Riley | first2 = DO. | last3 = Daneshvar | first3 = DH. | last4 = Nowinski | first4 = CJ. | last5 = Cantu | first5 = RC. | last6 = McKee | first6 = AC. | title = Long-term Consequences of Repetitive Brain Trauma: Chronic Traumatic Encephalopathy. | journal = PM R | volume = 3 | issue = 10 Suppl 2 | pages = S460-7 | month = Oct | year = 2011 | doi = 10.1016/j.pmrj.2011.08.008 | PMID = 22035690 }}</ref>
*Wall-to-wall neurofibrillary tangles.
**Common in olfactory bulb, mammillary bodies, hippocampus.
**Usually perivascular.
**Often superficial (unlike [[Alzheimer disease]]) and at the deep aspect of sulci.
 
===IHC===
*Increased TDP-43 staining.
 
Note:
*ALS associated with trauma brain injuries.<ref>{{Cite journal  | last1 = Costanza | first1 = A. | last2 = Weber | first2 = K. | last3 = Gandy | first3 = S. | last4 = Bouras | first4 = C. | last5 = Hof | first5 = PR. | last6 = Giannakopoulos | first6 = P. | last7 = Canuto | first7 = A. | title = Review: Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates. | journal = Neuropathol Appl Neurobiol | volume = 37 | issue = 6 | pages = 570-84 | month = Oct | year = 2011 | doi = 10.1111/j.1365-2990.2011.01186.x | PMID = 21696410 }}</ref>


==Huntington disease==
==Huntington disease==
===General===
===General===
*Autosomal dominant inheritance.
*Autosomal dominant inheritance.
*Mutation: unstable CAG repeat.<ref name=pmid20360611>{{cite journal |author=Kumar P, Kalonia H, Kumar A |title=Huntington's disease: pathogenesis to animal models |journal=Pharmacol Rep |volume=62 |issue=1 |pages=1–14 |year=2010 |pmid=20360611 |doi= |url=}}</ref>
*Mutation in ''Huntington gene'' (HTT):<ref name=pmid20360611>{{cite journal |author=Kumar P, Kalonia H, Kumar A |title=Huntington's disease: pathogenesis to animal models |journal=Pharmacol Rep |volume=62 |issue=1 |pages=1–14 |year=2010 |pmid=20360611 |doi= |url=}}</ref>
**11-34 CAG repeat = normal.<ref name=omim613004>{{OMIM|613004}}</ref>
**>42 CAG repeat = Huntington disease.
 
Clinical:<ref name=Ref_APBR415>{{Ref APBR|415 Q44}}</ref>
*Early onset dementia.
*Involuntary movements (chorea) - both arms and legs.
*Behaviour changes, e.g. grimacing.
*Speech changes.


===Gross===
===Gross===
*Severe caudate atrophy.<ref>URL: [http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm]. Accessed on: 29 October 2010.</ref>
*Severe caudate atrophy.<ref>URL: [http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm]. Accessed on: 29 October 2010.</ref>
**Prominent frontal horns of the lateral ventricles.<ref>URL: [http://path.upmc.edu/cases/case117/gross.html http://path.upmc.edu/cases/case117/gross.html]. Accessed on: 3 January 2012.</ref>
**Prominent frontal horns of the lateral ventricles.<ref>URL: [http://path.upmc.edu/cases/case117/gross.html http://path.upmc.edu/cases/case117/gross.html]. Accessed on: 3 January 2012.</ref>
Note:
*A normal caudate bulges into the ventricle.


Images:  
Images:  
*[http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm Huntington's disease (ouhsc.edu)].
*[http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm Huntington's disease (ouhsc.edu)].
*[http://path.upmc.edu/cases/case117/gross.html Prominent frontal horns of the lateral ventricles (upmc.edu)].
*[http://path.upmc.edu/cases/case117/gross.html Prominent frontal horns of the lateral ventricles (upmc.edu)].
===Microscopic===
Features:<ref name=Ref_APBR415>{{Ref APBR|415 Q44}}</ref>
*Neuron loss.
*Gliosis.


==Binswanger disease==
==Binswanger disease==
Line 407: Line 736:
Features:
Features:
*Subcortical lesions that replace the myelin consisting of macrophages.
*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.<ref>{{OMIM|105400}}</ref>
**There are several subtypes of FTLD with TDP-43.
===Gross===
*Frontal and temporal lobe atrophy.
Image:
*[http://commons.wikimedia.org/wiki/File:Frontotemporal_degeneration.png FTLD (WC)].


==Amyotrophic lateral sclerosis==
==Amyotrophic lateral sclerosis==
*Abbreviated ''ALS''.
*Abbreviated ''ALS''.
===General===
===General===
*[[AKA]] Lou Gehrig's disease.
*[[AKA]] Lou Gehrig's disease.
*TDP-43 proteinopathy.
*Characterized by motor neuron death.
*Characterized by motor neuron death.
*May be familial and associated with ''SOD1'' gene.<ref name=Ref_PCPBoD8_679>{{Ref PCPBoD8|679}}</ref>
*May be familial and associated with ''C9orf72 expansion'', or ''SOD1'', ''FUS'' and ''TARDBP'' mutations.<ref name=Ref_PCPBoD8_679>{{Ref PCPBoD8|679}}</ref><ref>{{Cite journal  | last1 = Guerrero | first1 = EN. | last2 = Wang | first2 = H. | last3 = Mitra | first3 = J. | last4 = Hegde | first4 = PM. | last5 = Stowell | first5 = SE. | last6 = Liachko | first6 = NF. | last7 = Kraemer | first7 = BC. | last8 = Garruto | first8 = RM. | last9 = Rao | first9 = KS. | title = TDP-43/FUS in motor neuron disease: Complexity and challenges. | journal = Prog Neurobiol | volume = 145-146 | issue =  | pages = 78-97 | month =  | year =  | doi = 10.1016/j.pneurobio.2016.09.004 | PMID = 27693252 }}</ref>
*Pathological protein aggregates cause dysfunction of RNA-binding proteins.


Clinical:
===Clinical===
*Weakness.
*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).<ref>{{Cite journal  | last1 = Chernoff | first1 = N. | last2 = Hill | first2 = DJ. | last3 = Diggs | first3 = DL. | last4 = Faison | first4 = BD. | last5 = Francis | first5 = BM. | last6 = Lang | first6 = JR. | last7 = Larue | first7 = MM. | last8 = Le | first8 = TT. | last9 = Loftin | first9 = KA. | title = A critical review of the postulated role of the non-essential amino acid, β-N-methylamino-L-alanine, in neurodegenerative disease in humans. | journal = J Toxicol Environ Health B Crit Rev | volume = 20 | issue = 4 | pages = 1-47 | month =  | year = 2017 | doi = 10.1080/10937404.2017.1297592 | PMID = 28598725 }}</ref>


===Microscopic===
===Microscopic===
Features:<ref name=Ref_PCPBoD8_679>{{Ref PCPBoD8|679}}</ref>
Features:<ref name=Ref_PCPBoD8_679>{{Ref PCPBoD8|679}}</ref><ref>{{Cite journal  | last1 = Saberi | first1 = S. | last2 = Stauffer | first2 = JE. | last3 = Schulte | first3 = DJ. | last4 = Ravits | first4 = J. | title = Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants. | journal = Neurol Clin | volume = 33 | issue = 4 | pages = 855-76 | month = Nov | year = 2015 | doi = 10.1016/j.ncl.2015.07.012 | PMID = 26515626 }}</ref>
*Motor neurons with ''Bunina bodies''.
*Loss of the giant cells of Betz.
*Motor neurons with eosinophilic inclusions (''Bunina bodies'').
**PAS positive cytoplasmic inclusions.
**PAS positive cytoplasmic inclusions.
*Motor neuron loss + reactive gliosis + neurogenic muscular atrophy.
*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.<ref>{{Cite journal  | last1 = Leigh | first1 = PN. | last2 = Anderton | first2 = BH. | last3 = Dodson | first3 = A. | last4 = Gallo | first4 = JM. | last5 = Swash | first5 = M. | last6 = Power | first6 = DM. | title = Ubiquitin deposits in anterior horn cells in motor neurone disease. | journal = Neurosci Lett | volume = 93 | issue = 2-3 | pages = 197-203 | month = Nov | year = 1988 | doi =  | PMID = 2853844 }}</ref>
*[[TDP-43]] proteinopathy in motor neurons (90% of all sporadic ALS cases).
**SOD1-mutant cases are [[TDP-43]]-ve.<ref>{{Cite journal  | last1 = Nakamura | first1 = S. | last2 = Wate | first2 = R. | last3 = Kaneko | first3 = S. | last4 = Ito | first4 = H. | last5 = Oki | first5 = M. | last6 = Tsuge | first6 = A. | last7 = Nagashima | first7 = M. | last8 = Asayama | first8 = S. | last9 = Fujita | first9 = K. | title = An autopsy case of sporadic amyotrophic lateral sclerosis associated with the I113T SOD1 mutation. | journal = Neuropathology | volume = 34 | issue = 1 | pages = 58-63 | month = Feb | year = 2014 | doi = 10.1111/neup.12049 | PMID = 23773010 }}</ref>
*C9orf72 expansion cases: p62+ve, [[TDP-43]]-ve inclusions in the dentate gyrus, neocortex, and cerebellum.<ref>{{Cite journal  | last1 = Al-Sarraj | first1 = S. | last2 = King | first2 = A. | last3 = Troakes | first3 = C. | last4 = Smith | first4 = B. | last5 = Maekawa | first5 = S. | last6 = Bodi | first6 = I. | last7 = Rogelj | first7 = B. | last8 = Al-Chalabi | first8 = A. | last9 = Hortobágyi | first9 = T. | title = 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. | journal = Acta Neuropathol | volume = 122 | issue = 6 | pages = 691-702 | month = Dec | year = 2011 | doi = 10.1007/s00401-011-0911-2 | PMID = 22101323 }}</ref>
**FUS-mutant cases show FUS+ve, p62+ve (few) and [[TDP-43]]-ve inclusions.<ref>{{Cite journal  | last1 = Vance | first1 = C. | last2 = Rogelj | first2 = B. | last3 = Hortobágyi | first3 = T. | last4 = De Vos | first4 = KJ. | last5 = Nishimura | first5 = AL. | last6 = Sreedharan | first6 = J. | last7 = Hu | first7 = X. | last8 = Smith | first8 = B. | last9 = Ruddy | first9 = D. | title = Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. | journal = Science | volume = 323 | issue = 5918 | pages = 1208-1211 | month = Feb | year = 2009 | doi = 10.1126/science.1165942 | PMID = 19251628 }}</ref>


Images:
Images:
*[http://jsp.umin.ac.jp/corepictures2007/18/o02/index.html Bunina body (umin.ac.jp)].
*[http://jsp.umin.ac.jp/corepictures2007/18/o02/index.html Bunina body (umin.ac.jp)].
*[http://pathology.mc.duke.edu/neuropath/CNSlecture4/alsbunina.jpg Bunina body (duke.edu)].<ref>URL: [http://pathology.mc.duke.edu/neuropath/CNSlecture4/CNSlecture4.htm http://pathology.mc.duke.edu/neuropath/CNSlecture4/CNSlecture4.htm]. Accessed on: 30 August 2011.</ref>
*[http://pathology.mc.duke.edu/neuropath/CNSlecture4/alsbunina.jpg Bunina body (duke.edu)].<ref>URL: [http://pathology.mc.duke.edu/neuropath/CNSlecture4/CNSlecture4.htm http://pathology.mc.duke.edu/neuropath/CNSlecture4/CNSlecture4.htm]. Accessed on: 30 August 2011.</ref>
*[http://path.upmc.edu/cases/case291.html ALS - several images (upmc.edu)].
<gallery>
File:ALS-TDP-HE.jpg | Motor neuron loss in ALS-TDP. (WC)
File:ALS-TDP-43_IHC.jpg | pTDP-43 positive inclusions in neurons. (WC)
</gallery>
DDx:
*Spinal muscular atrophy.
*Primary Lateral Sclerosis.
*Hereditary Spastic Paraparesis (HSP).


==Hallervorden-Spatz disease==
==Hallervorden-Spatz disease==

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:

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).

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 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)[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

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]

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

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

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).[34]
    • Images: senile plaques (utah.edu)[35] senile plaques - beta-APP - high mag. (WC).
  3. Neuron loss.
  4. +/-Cerebral amyloid angiopathy.

Images

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 PrPSC.
    • This is derived from the protein PrPC 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

PrPC:[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:

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]


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

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:

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

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).[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

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:

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):

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.

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:

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).
  • 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:

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:

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. 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.
  4. MUN. 15 November 2010.
  5. 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/.
  6. 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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  18. Korczyn, AD. (Apr 2015). "Vascular parkinsonism-characteristics, pathogenesis and treatment.". Nat Rev Neurol. doi:10.1038/nrneurol.2015.61. PMID 25917706.
  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.
  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.
  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.
  26. Online 'Mendelian Inheritance in Man' (OMIM) 104311
  27. Online 'Mendelian Inheritance in Man' (OMIM) 600759
  28. Online 'Mendelian Inheritance in Man' (OMIM) 107741
  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.
  32. URL: http://www.pakmed.net/academic/age/alz/alz030.htm. Accessed on: 12 November 2010.
  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.
  36. 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.
  37. 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.
  38. Braak, H.; Braak, E. (1991). "Neuropathological stageing of Alzheimer-related changes.". Acta Neuropathol 82 (4): 239-59. PMID 1759558.
  39. 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.
  40. 40.0 40.1 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/.
  41. Monari, L.; Chen, SG.; Brown, P.; Parchi, P.; Petersen, RB.; Mikol, J.; Gray, F.; Cortelli, P. et al. (Mar 1994). "Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism.". Proc Natl Acad Sci U S A 91 (7): 2839-42. doi:10.1073/pnas.91.7.2839. PMID 7908444.
  42. 42.0 42.1 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.
  43. Online 'Mendelian Inheritance in Man' (OMIM) 600072
  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. 671. ISBN 978-1416054542.
  45. 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.
  46. URL: http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0I002-PQ01-M.htm. Accessed on: 19 October 2010.
  47. Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 419 Q4. ISBN 978-1416025887.
  48. Goldfarb, LG.; Petersen, RB.; Tabaton, M.; Brown, P.; LeBlanc, AC.; Montagna, P.; Cortelli, P.; Julien, J. et al. (Oct 1992). "Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism.". Science 258 (5083): 806-8. doi:10.1126/science.1439789. PMID 1439789.
  49. URL: http://www.nysslha.org/i4a/pages/index.cfm?pageid=3519. Accessed on: 30 March 2011.
  50. 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.
  51. Online 'Mendelian Inheritance in Man' (OMIM) 609007
  52. Online 'Mendelian Inheritance in Man' (OMIM) 602544
  53. 53.0 53.1 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.
  54. 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.
  55. MUN. 16 November 2010.
  56. Trojanowski JQ, Revesz T (2007). "Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy". Neuropathol. Appl. Neurobiol. 33 (6): 615–20. doi:10.1111/j.1365-2990.2007.00907.x. PMID 17990994.
  57. 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.
  58. 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.
  59. 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.
  60. 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.
  61. 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.
  62. 62.0 62.1 URL: http://emedicine.medscape.com/article/1151430-overview. Accessed on: 11 November 2010.
  63. 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.
  64. 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.
  65. URL: http://neuropathologyblog.blogspot.com/2008/03/grumose-degeneration-in-cerebellar.html. Accessed on: 4 December 2010.
  66. 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.
  67. 67.0 67.1 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.
  68. URL: http://medical-dictionary.thefreedictionary.com/Walnut+Brain. Accessed on: 14 March 2012.
  69. Grossman, M. (Feb 2010). "Primary progressive aphasia: clinicopathological correlations.". Nat Rev Neurol 6 (2): 88-97. doi:10.1038/nrneurol.2009.216. PMID 20139998.
  70. Kumar P, Kalonia H, Kumar A (2010). "Huntington's disease: pathogenesis to animal models". Pharmacol Rep 62 (1): 1–14. PMID 20360611.
  71. Online 'Mendelian Inheritance in Man' (OMIM) 613004
  72. 72.0 72.1 Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 415 Q44. ISBN 978-1416025887.
  73. URL: http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q07-Ans.htm. Accessed on: 29 October 2010.
  74. URL: http://path.upmc.edu/cases/case117/gross.html. Accessed on: 3 January 2012.
  75. Online 'Mendelian Inheritance in Man' (OMIM) 105400
  76. 76.0 76.1 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.
  77. 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.
  78. 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.
  79. 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.
  80. 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.
  81. 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.
  82. 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.
  83. 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.
  84. URL: http://pathology.mc.duke.edu/neuropath/CNSlecture4/CNSlecture4.htm. Accessed on: 30 August 2011.
  85. URL: http://path.upmc.edu/cases/case207/dx.html. Accessed on: 11 January 2012.