Petersen, Ronald C.

AbstractThe poor generalizability of clinical research data due to the enrollment of highly educated, non‐Latinx White participants hampers the development of therapies for Alzheimer's disease (AD). Black and Latinx older adults have a greater risk for dementia, yet it is unclear how health‐care disparities and sociocultural factors influence potential AD therapies and prognosis. Low enrollment of under‐represented populations may be attributable to several factors including greater exclusion due to higher rates of comorbidities, lower access to AD clinics, and the legacy of unethical treatment in medical research. This perspective outlines solutions tested in the Brain Health Registry (BHR) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), including culturally‐informed digital research methods, community‐engaged research strategies, leadership from under‐represented communities, and the reduction of exclusion criteria based on comorbidities. Our successes demonstrate that it is possible to increase the inclusion and engagement of under‐represented populations into US‐based clinical studies, thereby increasing the generalizability of their results.

AbstractBackgroundGlobular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non‐globular glial 4‐repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD).MethodsFor this case–control study the Mayo Clinic brain banks were queried for all cases with an autopsy‐confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR‐parkinsonism index, midbrain volume, and white matter hyperintensities.18F‐Fluorodeoxyglucose‐, 11C Pittsburg compound‐, and 18F‐flortaucipir‐positron emission tomography scans were reviewed.ResultsTwelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p = 0.02) with median age at death 76.5 years (range: 55–87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p = 0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson‐plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR‐parkinsonism index, and larger midbrain volumes.ConclusionsFemale sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

AbstractIntroductionThe Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50‐60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022.MethodsADNI4 will recruit URPs using community‐engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50‐60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in‐clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials.Results and DiscussionADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators.

Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. Results: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95–106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19–0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39–163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17–0.78]; p < 0.01) and lower Braak stage (p = 0.01). Conclusion: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

Abstract The aim of this cross‐sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or magnetic resonance imaging (MRI) markers of neurodegeneration associated with Alzheimer's disease. We included women with prior history of breast cancer or no prior history of any cancer at enrollment in the Mayo Clinic Study of Aging (MCSA). This information was abstracted using the Rochester Epidemiology Project medical‐linkage system. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), and MRI markers. Among 2840 women aged 50 and older in the MCSA, 151 had a history of breast cancer, and 42 (28%) of these had a history of tamoxifen treatment. A total of 2235 women had no prior history of any cancer, and 76 (3%) of these had a history of raloxifene use. No significant associations between tamoxifen use and cognition, or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders. Similarly, raloxifene use was not significantly associated with cognition, or odds of MCI in women without a history of cancer after adjusting for confounders. We did not find significant associations between the use of either SERM and MRI markers. Use of tamoxifen or raloxifene was not significantly associated with cognition in postmenopausal women.

ObjectiveThis study was undertaken to assess cross‐sectional and longitudinal [18F]‐flortaucipir positron emission tomography (PET) uptake in pathologically confirmed frontotemporal lobar degeneration (FTLD) and to compare FTLD to cases with high and low levels of Alzheimer disease (AD) neuropathologic changes (ADNC).MethodsOne hundred forty‐three participants who had completed at least one flortaucipir PET and had autopsy‐confirmed FTLD (n = 52) or high (n = 58) or low ADNC (n = 33) based on Braak neurofibrillary tangle stages 0–IV versus V–VI were included. Flortaucipir standard uptake value ratios (SUVRs) were calculated for 9 regions of interest (ROIs): an FTLD meta‐ROI, midbrain, globus pallidum, an AD meta‐ROI, entorhinal, inferior temporal, orbitofrontal, precentral, and medial parietal. Linear mixed effects models were used to compare mean baseline SUVRs and annual rate of change in SUVR by group. Sensitivity and specificity to distinguish FTLD from high and low ADNC were calculated.ResultsBaseline uptake in the FTLD meta‐ROI, midbrain, and globus pallidus was greater in FTLD than high and low ADNC. No region showed a greater rate of flortaucipir accumulation in FTLD. Baseline uptake in the AD‐related regions and orbitofrontal and precentral cortices was greater in high ADNC, and all showed greater rates of accumulation compared to FTLD. Baseline differences were superior to longitudinal rates in differentiating FTLD from high and low ADNC. A simple baseline metric of midbrain/inferior temporal ratio of flortaucipir uptake provided good to excellent differentiation between FTLD and high and low ADNC (sensitivities/specificities = 94%/95% and 71%/70%).InterpretationThere are cross‐sectional and longitudinal differences in flortaucipir uptake between FTLD and high and low ADNC. However, optimum differentiation between FTLD and ADNC was achieved with baseline uptake rather than longitudinal rates. ANN NEUROL 2022;92:1016–1029

Abstract Introduction Alzheimer's disease (AD) biomarkers are increasingly more reliable in predicting neuropathology. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, we sought to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) are recognized. Methods We queried the Florida Autopsied Multi‐Ethnic (FLAME) cohort for cases ranging from Braak stages I through VI, excluding non‐AD neuropathologies and tauopathies. Thioflavin‐S staining was compared to immunohistochemical measures of phosphorylated threonine (pT) 181, pT205, pT217, and pT231 in two hippocampal subsectors across n = 24 cases. Results Each phosphorylated tau site immunohistochemically labeled early neurofibrillary tangle maturity levels compared to advanced levels recognized by thioflavin‐S. Hippocampal burden generally increased with each Braak stage. Discussion These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during early neurofibrillary tangle maturity levels and may explain why these fluid biomarker measures are observed before symptom onset. Highlights Immunohistochemical evaluation of four phosphorylated tau fluid biomarker sites. Earlier neurofibrillary tangle maturity levels recognized by phosphorylated tau in proline‐rich region. Advanced tangle pathology is elevated in the subiculum compared to the cornu ammonis 1 of the hippocampus. Novel semi‐quantitative frequency to calculate tangle maturity frequency.