Cognitive impairment in progressive supranuclear palsy is associated with tau burden

Koga, Shunsuke; Parks, Adam; Kasanuki, Koji; Sanchez‐Contreras, Monica; Baker, Matthew; Josephs, Keith A.; Ahlskog, J. Eric; Uitti, Ryan J.; Graff‐Radford, Neill R.; Gerpen, Jay A. van; Wszołek, Zbigniew K.; Rademakers, Rosa; Dickson, Dennis W.

doi:10.1002/mds.27198

Cited by 49 publications

(21 citation statements)

References 44 publications

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“…The dementia and frontal symptoms, the most common features in PSP-F, were associated with earlier death [26,31]. A recently published study found cognitive impairment in PSP, especially executive dysfunction, was associated with severity of PSP-related tau pathology in autopsy-confirmed PSP patients, which might explain the association with poorer prognosis [32]. After excluding PSP-F and PSP-FOG, we found that a trend for the association of PSP-P with a longer survival.…”

Section: Discussionmentioning

confidence: 97%

Midbrain/pons area ratio and clinical features predict the prognosis of progressive Supranuclear palsy

Cui

Ling

et al. 2020

BMC Neurol

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Background: Progressive supranuclear palsy (PSP) is a rare movement disorder with poor prognosis. This retrospective study aimed to characterize the natural history of PSP and to find predictors of shorter survival and faster decline of activity of daily living. Method: All patients recruited fulfilled the movement disorder society (MDS) clinical diagnostic criteria for PSP (MDS-PSP criteria) for probable and possible PSP with median 12 years. Data were obtained including age, sex, date of onset, age at onset (AAO), symptoms reported at first visit and follow-up, date of death and date of institutionalization. Magnetic resonance imaging was collected at the first visit. Endpoints were death and institutionalization. Kaplan-Meier method and Cox proportional hazard model were used to explore factors associated with early death and institutionalization. Results: Fifty-nine patients fulfilling MDS-PSP criteria were enrolled in our study. Nineteen patients (32.2%) had died and 31 patients (52.5%) were institutionalized by the end of the follow-up. Predictors associated with poorer survival were late-onset PSP and decreased M/P area ratio. Predictors associated with earlier institutionalization were older AAO and decreased M/P area ratio. Conclusion: Older AAO and decreased M/P area ratio were predictors for earlier dearth and institutionalization in PSP. The neuroimaging biomarker M/P area ratio was a predictor for prognosis in PSP.

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Section: Discussionmentioning

confidence: 97%

Midbrain/pons area ratio and clinical features predict the prognosis of progressive Supranuclear palsy

Cui

Ling

et al. 2020

BMC Neurol

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“…Immunohistochemistry for phospho-tau (CP13, mouse monoclonal, 1:1000, from Dr. Peter Davies, Feinstein Institute, North Shore Hospital, NY) was performed using a DAKO Autostainer (Universal Staining System, Carpinteria, CA) to establish the neuropathological diagnosis of CBD [10]. The severity of tau pathology, including NFTs, pretangles, coiled bodies, astrocytic plaques, and threads was graded semi-quantitatively on a four-point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) by an experienced neuropathologist (DWD) in 21 brain regions: inferior temporal gyrus, superior frontal gyrus, motor cortex, caudate, globus pallidus, basal nucleus, hypothalamus, ventral thalamus, subthalamic nucleus, thalamic fasciculus, red nucleus, substantia nigra, oculomotor complex, midbrain tectum/superior colliculus, locus coeruleus, pontine tegmentum, pontine base, medullary tegmentum, inferior olivary nucleus, dentate nucleus, and cerebellar white matter [28]. The regional tau burden was defined as the sum of scores for all lesion types in each brain region (range: 0–12) [28].…”

Section: Methodsmentioning

confidence: 99%

“…To quantify the tau burden, digital image analysis was performed in select brain regions [28]. CP13-stained sections of the pons, medulla, and cerebellar hemisphere were scanned on the ScanScopeXT.…”

Section: Methodsmentioning

confidence: 99%

“…For genotyping, genomic DNA was extracted from the cerebellum of frozen brain tissue using standard procedures. Genotyping for GRN (SNP rs5848 C/T SNPs, T minor allele), TMEM106B (rs3173615 C/G SNPs, G minor allele), MAPT H1/H2 (SNP rs1052553 A/G, A = H1, G = H2), and APOE alleles (SNP rs429358 C/T and rs7412 C/T) was assessed with TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA) as previously reported [29,28,50,27]. Genotype calls were obtained with QuantStudio™ Real-Time PCR Software (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

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Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype

et al. 2018

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Corticobasal degeneration (CBD) is a clinically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to elucidate whether transactive response DNA-binding protein of 43 kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43. In cases with TDP-43 pathology, additional brain regions (i.e., precentral, cingulate, and superior frontal gyri, hippocampus, medulla, and cerebellum) were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP-43 pathology, and clinicopathologic and genetic features were compared between the clusters. TDP-43 pathology was observed in 45% of CBD cases, most frequently in midbrain tegmentum (80% of TDP-43-positive cases), followed by subthalamic nucleus (69%). TDP-43-positive CBD was divided into TDP-limited (52%) and TDP-severe (48%) by hierarchical clustering analysis. TDP-severe patients were more likely to have been diagnosed clinically as PSP compared to TDP-limited and TDP-negative patients (80 vs 32 vs 30%, P < 0.001). The presence of downward gaze palsy was the strongest factor for the antemortem diagnosis of PSP, and severe TDP-43 pathology in the midbrain tectum was strongly associated with downward gaze palsy. In addition, tau burden in the olivopontocerebellar system was significantly greater in TDP-positive than TDP-negative CBD. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP-severe than in TDP-negative and TDP-limited CBD (65 vs 89 vs 91%, P < 0.001). The homozygous minor allele frequencies in GRN rs5848 and TMEM106B rs3173615 were not significantly different between the three groups. In conclusion, the present study indicates that CBD with severe TDP-43 pathology is a distinct clinicopathologic subtype of CBD, characterized by PSP-like clinical presentations, severe tau pathology in the olivopontocerebellar system, and low frequency of MAPT H1 haplotype.

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“…As in AD, there is evidence for tau oligomers driving neurodegeneration in PSP . Furthermore, the burden of tau pathology is positively associated with the degree of cognitive impairment in PSP cases . Pick's disease is a rare form of dementia originally characterized by Arnold Pick in the late 1800s.…”

Section: The Role Of Tau In Ad and Ftld‐taumentioning

confidence: 99%

Tau tubulin kinases in proteinopathy

et al. 2019

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A number of neurodegenerative diseases are characterized by deposition of abnormally phosphorylated tau or TDP‐43 in disease‐affected neurons. These diseases include Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. No disease‐modifying therapeutics is available to treat these disorders, and we have a limited understanding of the cellular and molecular factors integral to disease initiation or progression. Phosphorylated tau and TDP‐43 are important markers of pathology in dementia disorders and directly contribute to tau‐ and TDP‐43‐related neurotoxicity and neurodegeneration. Here, we review the scope of tau and TDP‐43 phosphorylation in neurodegenerative disease and discuss recent work demonstrating the kinases TTBK1 and TTBK2 phosphorylate both tau and TDP‐43, promoting neurodegeneration.

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Cognitive impairment in progressive supranuclear palsy is associated with tau burden

Cited by 49 publications

References 44 publications

Midbrain/pons area ratio and clinical features predict the prognosis of progressive Supranuclear palsy

Midbrain/pons area ratio and clinical features predict the prognosis of progressive Supranuclear palsy

Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype

Tau tubulin kinases in proteinopathy

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