Incidence and extent of TDP-43 accumulation in aging human brain

Uchino, Akira; Takao, Masaki; Hatsuta, Hiroyuki; Sumikura, Hiroyuki; Nakano, Yuta; Nogami, Akane; Saito, Yuko; Arai, Tomio; Nishiyama, Kazutoshi; Murayama, Shigeo

doi:10.1186/s40478-015-0215-1

Cited by 120 publications

(141 citation statements)

References 30 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…A recent published abstract also suggested high prevalence of TDP-43 proteinopathy in cognitive healthy older Japanese cohort (60). However, no other ethnical groups were included in this study for comparison.…”

Section: Discussionmentioning

confidence: 97%

Higher Prevalence of TDP‐43 Proteinopathy in Cognitively Normal Asians: A Clinicopathological Study on a Multiethnic Sample

et al. 2015

View full text Add to dashboard Cite

Transactive response DNA binding-protein 43 (TDP-43) proteinopathy is the major hallmark of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. It is also present in a subset of Alzheimer’s disease cases. Recently, few reports showed TDP-43 changes in cognitively normal elderly. In Caucasians, TDP-43 proteinopathy independently correlate with cognitive decline. However, it is challenging to establish direct links between cognitive and/or neuropsychiatric symptoms and protein inclusions in neurodegenerative diseases because individual cognitive reserves modify the threshold for clinical disease expression. Cognitive reserve is influenced by demographic, environmental and genetic factors. We investigated the relationships between demographic, clinical, and neuropathological variables and TDP-43 proteinopathy in a large multiethnic sample of cognitively normal elderly. TDP-43 proteinopathy were identified in 10.5%, independently associated with older age (p = 0.03) and Asian ethnicity (p = 0.002). Asians showed a higher prevalence of TDP-43 proteinopathy than Caucasians, even after adjustment for sex, age, Braak stage, and schooling (odds ratio = 3.50, confidence interval 1.41–8.69, p = 0.007). These findings suggested Asians older adults may be protected from the clinical manifestation of brain TDP-43 proteinopathy. Future studies are needed to identify possible race-related protective factors against clinical expression of TDP-43 proteinopathies.

show abstract

Section: Discussionmentioning

confidence: 97%

Higher Prevalence of TDP‐43 Proteinopathy in Cognitively Normal Asians: A Clinicopathological Study on a Multiethnic Sample

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Hence, we conclude that it is reasonable to use the inferior olive to classify a case as stage 5 as long as there is involvement of stage 4 regions but to ignore the inferior olive if stage 4 is skipped. Ignoring the inferior olive when stage 4 is skipped is not unreasonable given that it is rarely involved in stages 1–3, as well as the fact that published data shows the inferior olive to have TDP-43 immunoreactivity in about 10% of brains from normal control patients[40]. …”

Section: Discussionmentioning

confidence: 99%

Updated TDP-43 in Alzheimer’s disease staging scheme

et al. 2016

View full text Add to dashboard Cite

In this study we update the TDP-43 in Alzheimer’s disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimer’s disease, in 14 different brain regions (eight previously described plus six newly reported) and use conditional probability to model the spread of TDP-43 across the 14 brain regions. We show that in addition to the eight original regions we previously reported (amygdala, entorhinal cortex, subiculum, dentate gyrus of the hippocampus, occipitotemporal cortex, inferior temporal cortex, middle frontal cortex and basal ganglia (putamen/globus pallidum)), that TDP-43 is also deposited in the insular cortex, ventral striatum, basal forebrain, substantia nigra, midbrain tectum, and the inferior olive of the medulla oblongata, in Alzheimer’s disease. The conditional probability analysis produced six significantly different stages (P< 0.01), and suggest that TDP-43 deposition begins in the amygdala (stage 1), then moves to entorhinal cortex and subiculum (stage 2), then to the dentate gyrus of the hippocampus and occipitotemporal cortex (stage 3), then insular cortex, ventral striatum, basal forebrain and inferior temporal cortex (stage 4), then substantia nigra, inferior olive and midbrain tectum (stage 5), and finally to basal ganglia and middle frontal cortex (stage 6). This updated staging scheme is superior to our previous staging scheme, classifying 100 % of the cases (versus 94% in the old scheme), based on criteria provided, and better accounts for Alzheimer’s disease clinical and imaging features, such as Mini-Mental Status Examination score and hippocampal volume. We discuss the relevance of the updated staging scheme, as well as its impact on the prion-like hypothesis of protein spread in neurodegenerative disease. We also address the issue of whether frontotemporal lobar degeneration with TDP-43 could be the primary pathology in stage 6.

show abstract

“…[5][6][7][8][9][10][11][12] Indeed, the high frequency of neuropathologic comorbidity in older persons with dementia has become widely appreciated around the globe. [13][14][15][16][17][18][19][20][21] In 2013, the first 22 brain autopsies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were reported. 22 All had been diagnosed during life with AD dementia or AD-type mild cognitive impairment.…”

Section: Methodsmentioning

confidence: 99%

Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies

et al. 2016

View full text Add to dashboard Cite

Objective: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels. Methods:The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined.Results: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy.Conclusions: Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life. A 1997 Nun Study (NS) report demonstrated a powerful effect on cognitive function of comorbid brain infarcts and Alzheimer disease (AD) neuropathologic changes, reporting an odds ratio (OR) of 20.7 for dementia in participants with both high levels of AD neuropathologic changes and cerebral infarcts.1 A 2002 report of 285 autopsied participants in the Honolulu-Asia Aging Study (HAAS) provided a comprehensive description of 4 major neuropathologic abnormalities, each robustly associated with late-life cognitive impairment: AD neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis (HS), and microinfarcts.2 Subsequent HAAS analyses demonstrated that generalized brain atrophy may occur independently, as a fifth common abnormality associated with cognitive impairment.3,4 Extensive analyses using autopsy and clinical data have further documented both the multiplicity of neuropathologic abnormalities associated with late-life dementia and the complex relationships between them. [5][6][7][8][9][10][11][12] Indeed, the high frequency of neuropathologic comorbidity in older persons with dementia has become widely appreciated around the globe. [13][14][15][16][17][18][19][20][21] In 2013, the first 22 brain autopsies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were reported. 22 All had been diagnosed during life with AD dementia or AD-type mild cogniti...

show abstract

Incidence and extent of TDP-43 accumulation in aging human brain

Cited by 120 publications

References 30 publications

Higher Prevalence of TDP‐43 Proteinopathy in Cognitively Normal Asians: A Clinicopathological Study on a Multiethnic Sample

Higher Prevalence of TDP‐43 Proteinopathy in Cognitively Normal Asians: A Clinicopathological Study on a Multiethnic Sample

Updated TDP-43 in Alzheimer’s disease staging scheme

Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies

Contact Info

Product

Resources

About