%0 Journal Article %J J Alzheimers Dis %D 2023 %T Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer's Disease and Lewy Body Dementia in the Oldest Old: A Case Series. %A Leiby, Anne-Marie C %A Scambray, Kiana A %A Nguyen, Hannah L %A Basith, Farheen %A Fakhraee, Shahrzad %A Melikyan, Zarui A %A Bukhari, Syed A %A Montine, Thomas J %A Corrada, Maria M %A Kawas, Claudia H %A Sajjadi, S Ahmad %K Aged %K Aged, 80 and over %K Alzheimer Disease %K DNA-Binding Proteins %K Humans %K Lewy Body Disease %K Syncope %K Tauopathies %K TDP-43 Proteinopathies %X

BACKGROUND: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals.

OBJECTIVE: Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART).

METHODS: In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART.

RESULTS: Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups.

CONCLUSIONS: Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

%B J Alzheimers Dis %V 96 %P 113-124 %8 2023 %G eng %N 1 %R 10.3233/JAD-230238 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer's Disease Pathology. %A Ryman, Sephira G %A Yutsis, Maya %A Tian, Lu %A Henderson, Victor W %A Montine, Thomas J %A Salmon, David P %A Galasko, Douglas %A Poston, Kathleen L %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cognitive Dysfunction %K Female %K Humans %K Lewy Body Disease %K Male %X

BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology.

OBJECTIVE: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD.

METHODS: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer's Coordinating Center's Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical).

RESULTS: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage.

CONCLUSION: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.

%B J Alzheimers Dis %V 80 %P 1243-1256 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646154?dopt=Abstract %R 10.3233/JAD-201187 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations between Use of Specific Analgesics and Concentrations of Amyloid-β 42 or Phospho-Tau in Regions of Human Cerebral Cortex. %A Flanagan, Margaret E %A Larson, Eric B %A Walker, Rod L %A Keene, C Dirk %A Postupna, Nadia %A Cholerton, Brenna %A Sonnen, Joshua A %A Dublin, Sascha %A Crane, Paul K %A Montine, Thomas J %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Analgesics %K Analgesics, Opioid %K Anti-Inflammatory Agents, Non-Steroidal %K Autopsy %K Cerebral Cortex %K Female %K Humans %K Logistic Models %K Male %K Peptide Fragments %K Prospective Studies %K tau Proteins %X

Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimer's disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex.

%B J Alzheimers Dis %V 61 %P 653-662 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226863?dopt=Abstract %R 10.3233/JAD-170414 %0 Journal Article %J Alzheimers Dement %D 2012 %T National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. %A Hyman, Bradley T %A Phelps, Creighton H %A Beach, Thomas G %A Bigio, Eileen H %A Cairns, Nigel J %A Carrillo, Maria C %A Dickson, Dennis W %A Duyckaerts, Charles %A Frosch, Matthew P %A Masliah, Eliezer %A Mirra, Suzanne S %A Nelson, Peter T %A Schneider, Julie A %A Thal, Dietmar Rudolf %A Thies, Bill %A Trojanowski, John Q %A Vinters, Harry V %A Montine, Thomas J %K Alzheimer Disease %K Brain %K Consensus Development Conferences, NIH as Topic %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

%B Alzheimers Dement %V 8 %P 1-13 %8 2012 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22265587?dopt=Abstract %R 10.1016/j.jalz.2011.10.007 %0 Journal Article %J Alzheimers Dement %D 2011 %T Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. %A Sperling, Reisa A %A Aisen, Paul S %A Beckett, Laurel A %A Bennett, David A %A Craft, Suzanne %A Fagan, Anne M %A Iwatsubo, Takeshi %A Jack, Clifford R %A Kaye, Jeffrey %A Montine, Thomas J %A Park, Denise C %A Reiman, Eric M %A Rowe, Christopher C %A Siemers, Eric %A Stern, Yaakov %A Yaffe, Kristine %A Carrillo, Maria C %A Thies, Bill %A Morrison-Bogorad, Marcelle %A Wagster, Molly V %A Phelps, Creighton H %K Alzheimer Disease %K Biomarkers %K Cognition Disorders %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K United States %X

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

%B Alzheimers Dement %V 7 %P 280-92 %8 2011 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21514248?dopt=Abstract %R 10.1016/j.jalz.2011.03.003