Difference between revisions of "Neurodegenerative diseases"

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Neurodegenerative diseases (view source)

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{{familytree  | | | | | | | A01 | | | | | | | | A01=Neurodegenerative<br>disorders}}
{{familytree  | | | | | | | A01 | | | | | | | | A01=Neurodegenerative<br>disorders}}
{{familytree  | |,|-|-|-|v|-|^|-|v|-|-|-|v|-|-|-|.| | |}}
{{familytree  | |,|-|-|-|v|-|^|-|v|-|-|-|v|-|-|-|.| | |}}
{{familytree  | B01 | | B02 | | B03 | | B04 | | B05 || B01=Amyloidoses|B02=Tauopathies|B03=α-synucleinopathies|B04=TDP-43|B05=FUS}}
{{familytree  | B01 | | B02 | | B03 | | B04 | | B05 || B01=Amyloidoses|B02=Tauopathies|B03=α-synucleinopathies|B04=TDP-43|B05=FUS/EWS/TAF15}}
{{familytree/end}}
{{familytree/end}}


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TDP-43 proteinopathies:
TDP-43 proteinopathies:
*[[Amyotrophic lateral sclerosis]].
*[[Amyotrophic lateral sclerosis]].
*Frontotemporal lobar degeneration.
*Frontotemporal lobar degeneration with TDP-43 (FTLD-TDP).


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


Prionopathies:
Prionopathies:
*Creutzfeldt-Jakob disease (PrP).
*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====
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{| 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
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|-
|-
| [[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
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|-  
|-  
| Frontotemporal lobar <br>degeneration with TDP-43 (FTLD-TDP)
| 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 depends on (type 1-4), ubiquitin and TDP-43+ve, tau and FUS-ve  
| histology depends on (type 1-4), ubiquitin and [[TDP-43]]+ve, tau and FUS-ve  
| [https://commons.wikimedia.org/wiki/File:FTLD_TSP43_hippocampus.jpg]
| [https://commons.wikimedia.org/wiki/File:FTLD_TSP43_hippocampus.jpg]
|-
|-
| Frontotemporal lobar <br>degeneration with FUS (FTLD-FUS)
| Frontotemporal lobar <br>degeneration with FET (FTLD-FET)
| FUS
| FUS/EWS/TAF15
| cortex, medulla, hippocampus, and motor cells of the spinal cord
| cortex, medulla, hippocampus, and motor cells of the spinal cord
| dementia, cases classified as FTLD-U, NIFID and BIBD
| dementia, cases classified as aFTLD-U, NIFID and BIBD
| FUS+ve, TAF15+ve, EWS+ve cytoplasmic & intranuclear inclusions, neuritic threads  
| FUS+ve, TAF15+ve, EWS+ve cytoplasmic & intranuclear inclusions, neuritic threads  
| [http://brain.oxfordjournals.org/content/brain/134/9/2595/F1.medium.gif]
| [http://brain.oxfordjournals.org/content/brain/134/9/2595/F1.medium.gif]
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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.
*Glial cytoplasmatic inclusions (Papp-Lantos bodies) seen in MSA.
*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 disease|Alzheimer's]] dementia - most common.
*[[Alzheimer's disease|Alzheimer's]] dementia - most common.
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*Diagnosis is clinical & pathologic.
*Diagnosis is clinical & pathologic.
**Pathologic finding alone are not diagnostic.
**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.<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====
====Genetics====
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*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:
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*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>
*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>


====Images====
===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>
<gallery>
Image:SpongiformChangeCJD.jpg | CJD. (WC/DRdoubleB)
Image:SpongiformChangeCJD.jpg | CJD. (WC/DRdoubleB)
Image:VCJD_Tonsil.jpg | vCJD - prion protein immunostain. (WC/Sbrandner)
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>
</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)].
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*Neuronal loss and gliosis (absent in minimal-change MSA).
*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>  
*Alpha-synuclein-rich glial and neuronal cytoplasmic inclusions in white matter (finding at autopsy).<ref name=pmid18825660>{{Cite journal  | last1 = Wenning | first1 = GK. | last2 = Stefanova | first2 = N. | last3 = Jellinger | first3 = KA. | last4 = Poewe | first4 = W. | last5 = Schlossmacher | first5 = MG. | title = Multiple system atrophy: a primary oligodendrogliopathy. | journal = Ann Neurol | volume = 64 | issue = 3 | pages = 239-46 | month = Sep | year = 2008 | doi = 10.1002/ana.21465 | PMID = 18825660 }}</ref>  
**Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.<ref>MUN. 16 November 2010.</ref><ref>{{cite journal |vauthors=Trojanowski JQ, Revesz T |title=Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy |journal=Neuropathol. Appl. Neurobiol. |volume=33 |issue=6 |pages=615–20 |year=2007 |pmid=17990994 |doi=10.1111/j.1365-2990.2007.00907.x |url=}}</ref>
**Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.<ref>MUN. 16 November 2010.</ref><ref>{{cite journal |authors=Trojanowski JQ, Revesz T |title=Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy |journal=Neuropathol. Appl. Neurobiol. |volume=33 |issue=6 |pages=615–20 |year=2007 |pmid=17990994 |doi=10.1111/j.1365-2990.2007.00907.x |url=}}</ref>
**Inclusions usu. abundant in basal ganglia, substantia nigra, pontine nuclei, medulla and cerebellum.
**Inclusions usu. abundant in basal ganglia, substantia nigra, pontine nuclei, medulla and cerebellum.
*Pons and Putamen:
*Pons and Putamen:
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=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''.
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*[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>


=FUSopathies (FTLD-FUS)=
=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
* Clinical manifestations depend on the distribution of the pathologic alterations in the CNS
* Currently 3 disorders among the FTLD-FUS subgroup.
* 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.
* 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):
DDx (also FUS+ve):
*Spinocerebellar Ataxia (SCA)
*Spinocerebellar Ataxia (SCA)
*Huntington Disease (SD)
*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==
==Basophilic inclusion body disease==
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* Intraneuronal cytoplasmic basophilic inclusion bodies.
* Intraneuronal cytoplasmic basophilic inclusion bodies.
* FUS+ve (universally).
* FUS+ve (universally).
* TAF15+ve
* EWS+ve.
* TAF15+ve.
* alpha-Internexin+ve.
* alpha-Internexin+ve.


==Neuronal Intermediate Filament Inclusion Disease==
==Neuronal Intermediate Filament Inclusion Disease==
* AKA: NIFID.
* AKA: NIFID.
* Hyaline conglomerates (brightly eosinophilic branching fibrillar structures embedded in a round, well-delineated, glassy vacuole).  
* Sporadic early‐onset frontotemporal dementia, motor neuron disease, extrapyramidal motor symptoms.
* FUS+ve (heterogenous).
* 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.
* Ubiquitin +/-ve.
* NF +ve (some subunits).
* NF +ve (some subunits).
Line 636: Line 752:
==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:
Line 655: Line 784:
*[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)].
*[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==
Michael
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