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{{familytree/start}} | {{familytree/start}} | ||
{{familytree | | | | | | | A01 | | | | | | | | A01=Neurodegenerative<br>disorders}} | {{familytree | | | | | | | A01 | | | | | | | | A01=Neurodegenerative<br>disorders}} | ||
{{familytree | |,|-|-|-|v|-|^|-|v|-|-|-|.| | |}} | {{familytree | |,|-|-|-|v|-|^|-|v|-|-|-|v|-|-|-|.| | |}} | ||
{{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}} | ||
{{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). | ||
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: | 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==== | ||
Line 47: | Line 50: | ||
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto" | {| class="wikitable sortable" style="margin-left:auto;margin-right:auto" | ||
! Disease | ! Disease | ||
! | ! Deposited protein | ||
! Distribution | ! Distribution | ||
! Clinical | ! Clinical | ||
Line 64: | Line 67: | ||
| 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] | ||
|- | |- | ||
| [[Parkinson disease]] | | [[Parkinson disease]] | ||
Line 85: | Line 74: | ||
| 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 Lewy bodies|Dementia with <br>Lewy bodies]] | | [[Dementia with Lewy bodies|Dementia with <br>Lewy bodies]] | ||
Line 92: | Line 81: | ||
| 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]] | ||
Line 99: | Line 88: | ||
| basal ganglia, brainstem, cerebellum | | basal ganglia, brainstem, cerebellum | ||
| parkinsonism, ataxia | | parkinsonism, ataxia | ||
| cytoplasmic | | Papp-Lantos inclusions (cytoplasmic deposits in oligodendrocytes)<ref>MUN. 15 November 2010.</ref> | ||
| | | [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 | ||
| | | motor neuron loss, TDP-43+ve, TAF15-ve, EWS-ve inclusions in motor neurons | ||
| | | [https://commons.wikimedia.org/wiki/File:Als_inclusions.png] | ||
|- | |- | ||
| Frontotemporal lobar <br>degeneration (FTLD) | | 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 | ||
| | | [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 | ||
Line 127: | Line 152: | ||
===Alpha-synuclein=== | ===Alpha-synuclein=== | ||
Look for: | Look for: | ||
*Lewy bodies (seen in Parkinson's | *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> | ||
Line 146: | Line 174: | ||
===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> | |||
=== | |||
===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. | ||
Line 185: | Line 234: | ||
===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> | ||
*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> | *[[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> | ||
*[[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> | *[[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).<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> | *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= | ||
Line 196: | Line 248: | ||
*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==== | ||
Line 218: | Line 280: | ||
**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==== | ====Images==== | ||
<gallery> | <gallery> | ||
Image:Alzheimers_brain.jpg | Alzheimer's brain. ([[WC]]/NIH) | 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> | </gallery> | ||
Line 229: | 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> | ||
#Senile plaques ([[AKA]] neuritic plaques). | #Senile plaques ([[AKA]] neuritic plaques). | ||
#*Consists of two components: | #*Consists of two components: | ||
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#*Considered to be more specific for Alzheimer's than NF tangles. | #*Considered to be more specific for Alzheimer's than NF tangles. | ||
#**How to remember: '''s'''enile '''p'''laques = '''sp'''ecific. | #**How to remember: '''s'''enile '''p'''laques = '''sp'''ecific. | ||
#*There is a staging system for | #*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. | #Neuron loss. | ||
#+/-[[Cerebral amyloid angiopathy]]. | #+/-[[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: | ||
Line 257: | 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: | ||
Line 293: | Line 415: | ||
*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> | ||
==== | ===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)]. | ||
=Alpha-synucleinopathies= | =Alpha-synucleinopathies= | ||
Without clincial information [[Parkinson's disease]] and [[Dementia with Lewy bodies]] cannot separated in histology. | |||
==Dementia with Lewy bodies== | ==Dementia with Lewy bodies== | ||
Line 313: | Line 444: | ||
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== | ||
Line 349: | 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- | *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''. | ||
Line 406: | 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= | ||
Line 466: | Line 752: | ||
==Amyotrophic lateral sclerosis== | ==Amyotrophic lateral sclerosis== | ||
*Abbreviated ''ALS''. | *Abbreviated ''ALS''. | ||
===General=== | ===General=== | ||
*[[AKA]] Lou Gehrig's disease. | *[[AKA]] Lou Gehrig's disease. | ||
*Characterized by motor neuron death. | *Characterized by motor neuron death. | ||
*May be familial and associated with ''SOD1'' | *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 485: | 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== |
edits