Difference between revisions of "Neurodegenerative diseases"

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 {{familytree  | | | | | | | A01 | | | | | | | | A01=Neurodegenerative<br>disorders}}
 {{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}}
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 *Frontotemporal lobar degeneration with TDP-43 (FTLD-TDP).
-FUS proteinopathies:
+FET proteinopathies:
 *Basophilic inclusion body disease (BIBD).
 *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:
 *Creutzfeldt-Jakob disease (PrP).
+'''Note:''' Some people consider α-synuclein as a prion-like protein.<ref>{{Cite journal  | last1 = Watts | first1 = JC. | title = Calling α-synuclein a prion is scientifically justifiable. | journal = Acta Neuropathol | volume = 138 | issue = 4 | pages = 505-508 | month = Oct | year = 2019 | doi = 10.1007/s00401-019-02058-0 | PMID = 31407029 }}</ref>
 ====Table====
@@ Line 48: / Line 50: @@
 {| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
 ! Disease
-! Mutated protein
+! Deposited protein
 ! Distribution
 ! Clinical
@@ Line 103: / Line 105: @@
 | [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
-| 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
 | [http://brain.oxfordjournals.org/content/brain/134/9/2595/F1.medium.gif]
@@ Line 150: / Line 152: @@
 ===Alpha-synuclein===
 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===
@@ Line 170: / Line 174: @@
 ===Ubiquitin===
 *Marks proteins for recycling.
+*Stains Barr bodies in hippocampal granule cells<ref> {{Cite journal  | last1 = Gelpi | first1 = E. | title = Clinical Neuropathology teaching case 3-2015: female or male brain? Anti-ubiquitin visualizes Barr bodies in hippocampal granule cells which allows the determination of gender in human brains. | journal = Clin Neuropathol | volume = 34 | issue = 3 | pages = 115-6 | month =  | year =  | doi =  | PMID = 25909954 }}</ref>
-====Microscopic====
+===p62===
 *p62; poli-ubiquitin-binding protein p62.<ref name=pmid19946779/>
+===Microscopic===
 Look for:
-*Lewy bodies. (???)
+* Lewy bodies and extracellular pigment in neuromelanin-containing nuclei (SN, LC, DVN) -> PD.
+* Spongiform vacuolation in the neuropil (seen in Prion disease and FTLD-TDP).
+* Neurofibrillar tangles (pyramidal layer of dentate gyrus).
+* Granulovacuolar degeneration (granules within cytoplasmic vacuoles, mainly in the hippocampal pyramidal neurons, seen in AD).
+* Cores of amyloid plaqyes.
+* Cotton wool plaques (seen in familiar AD).
+* Pick cells (balloned neurons in frontal cortex).
+* Pick bodies (granular layer of dentate gyrus).
+* Extensive astrogliosis (striatonigral degeneration, hepatic encephalopathy).
+* Corpora amylacea in the cornu ammonis may be increased in neurodegenerative diseases. <ref>{{Cite journal  | last1 = Kovacs | first1 = GG. | last2 = Risser | first2 = D. | title = Clinical Neuropathology image 6-2014: Corpora amylacea replacing cornu ammonis (CACA). | journal = Clin Neuropathol | volume = 33 | issue = 6 | pages = 378-9 | month =  | year =  | doi =  | PMID = 25343241 }}</ref>
+<gallery>
+File:213-09-11-Congo Red Lewy body.tif|Lewy body
+File:Amyloid plaques alzheimer disease HE stain.jpg|Cotton wool plaques
+File:Neurofibrillary tangles in the Hippocampus of an old person with Alzheimer-related pathology, HE 3.JPG|Neurofibrillary tangles
+File:SpongiformChangeCJD.jpg | Spongiform vacuolation
+</gallery>
 =Clinical perspective=
+*Correlations between clinical signs and molecular can be poor.
+**Example: The MAPT A152T gene mutation may cause clinical symptoms matching AD, [[Neurodegenerative diseases#Corticobasal degeneration|CBD]], [[Neurodegenerative diseases#Progressive supranuclear palys|PSP]] and  [[Neurodegenerative diseases#Lewy body disease|LBD]].<ref>{{Cite journal  | last1 = Coppola | first1 = G. | last2 = Chinnathambi | first2 = S. | last3 = Lee | first3 = JJ. | last4 = Dombroski | first4 = BA. | last5 = Baker | first5 = MC. | last6 = Soto-Ortolaza | first6 = AI. | last7 = Lee | first7 = SE. | last8 = Klein | first8 = E. | last9 = Huang | first9 = AY. | title = Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases. | journal = Hum Mol Genet | volume = 21 | issue = 15 | pages = 3500-12 | month = Aug | year = 2012 | doi = 10.1093/hmg/dds161 | PMID = 22556362 }}</ref>
 ===Dementia general (mostly useless) DDx===
 *[[Alzheimer's disease|Alzheimer's]] dementia - most common.
@@ Line 352: / Line 377: @@
 *Misfolded cell-surface protein called PrP<sup>SC</sup>.
 **This is derived from the protein ''PrP<sup>C</sup>'' encoded by the ''PRNP'' gene.
+*Different genetics strains are associated with varying clinical phenotype.<ref>{{Cite journal  | last1 = Monari | first1 = L. | last2 = Chen | first2 = SG. | last3 = Brown | first3 = P. | last4 = Parchi | first4 = P. | last5 = Petersen | first5 = RB. | last6 = Mikol | first6 = J. | last7 = Gray | first7 = F. | last8 = Cortelli | first8 = P. | last9 = Montagna | first9 = P. | title = Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism. | journal = Proc Natl Acad Sci U S A | volume = 91 | issue = 7 | pages = 2839-42 | month = Mar | year = 1994 | doi = 10.1073/pnas.91.7.2839 | PMID = 7908444 }}</ref>
 Includes:
@@ Line 387: / Line 414: @@
 Note:
 *Spongiform changes may be seen in [[ALS]], [[Alzheimer's disease]] and Lewy body disease (e.g. [[Parkinson disease]]); however, the changes are only in the upper cortex and not diffuse.<ref>{{Ref APBR|419 Q4}}</ref>
+===Molecular===
+*The CJD phenotype is associated with a PRNP D178N mutation and valine polymorphism at codon 129 (D178N-129V).
+** Note: A Met129 polymorphism will cause Fatal familiar insomnia in the setting of the same PRNP D178N mutation. <ref>{{Cite journal  | last1 = Goldfarb | first1 = LG. | last2 = Petersen | first2 = RB. | last3 = Tabaton | first3 = M. | last4 = Brown | first4 = P. | last5 = LeBlanc | first5 = AC. | last6 = Montagna | first6 = P. | last7 = Cortelli | first7 = P. | last8 = Julien | first8 = J. | last9 = Vital | first9 = C. | title = Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. | journal = Science | volume = 258 | issue = 5083 | pages = 806-8 | month = Oct | year = 1992 | doi = 10.1126/science.1439789 | PMID = 1439789 }}</ref>
 <gallery>
@@ Line 502: / Line 534: @@
 *Neuronal loss and gliosis (absent in minimal-change MSA).
 *Alpha-synuclein-rich glial and neuronal cytoplasmic inclusions in white matter (finding at autopsy).<ref name=pmid18825660>{{Cite journal  | last1 = Wenning | first1 = GK. | last2 = Stefanova | first2 = N. | last3 = Jellinger | first3 = KA. | last4 = Poewe | first4 = W. | last5 = Schlossmacher | first5 = MG. | title = Multiple system atrophy: a primary oligodendrogliopathy. | journal = Ann Neurol | volume = 64 | issue = 3 | pages = 239-46 | month = Sep | year = 2008 | doi = 10.1002/ana.21465 | PMID = 18825660 }}</ref>
-**Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.<ref>MUN. 16 November 2010.</ref><ref>{{cite journal |vauthors=Trojanowski JQ, Revesz T |title=Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy |journal=Neuropathol. Appl. Neurobiol. |volume=33 |issue=6 |pages=615–20 |year=2007 |pmid=17990994 |doi=10.1111/j.1365-2990.2007.00907.x |url=}}</ref>
+**Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.<ref>MUN. 16 November 2010.</ref><ref>{{cite journal |authors=Trojanowski JQ, Revesz T |title=Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy |journal=Neuropathol. Appl. Neurobiol. |volume=33 |issue=6 |pages=615–20 |year=2007 |pmid=17990994 |doi=10.1111/j.1365-2990.2007.00907.x |url=}}</ref>
 **Inclusions usu. abundant in basal ganglia, substantia nigra, pontine nuclei, medulla and cerebellum.
 *Pons and Putamen:
@@ Line 593: / Line 625: @@
 *[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
-* 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.
+* 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==
@@ Line 608: / Line 675: @@
 * Intraneuronal cytoplasmic basophilic inclusion bodies.
 * FUS+ve (universally).
-* TAF15+ve
+* EWS+ve.
+* TAF15+ve.
 * alpha-Internexin+ve.
 ==Neuronal Intermediate Filament Inclusion Disease==
 * AKA: NIFID.
-* Hyaline conglomerates (brightly eosinophilic branching fibrillar structures embedded in a round, well-delineated, glassy vacuole).
+* 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.
 * NF +ve (some subunits).

Difference between revisions of "Neurodegenerative diseases"

Neurodegenerative diseases (view source)

Revision as of 20:32, 24 May 2020

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