Knopman, David S.

AbstractChronic pain is highly prevalent in older adults and is associated with poor functional outcomes. Furthermore, opioid analgesics are commonly utilized for the treatment of pain in older adults despite well-described adverse effects. Importantly, both chronic pain and opioid analgesics have been linked with impairments in cognitive function, though data are limited. In this manuscript we summarize the evidence and critical knowledge gaps regarding the relationships between pain, opioid analgesics, and cognition in older adults. Furthermore, we provide a conceptual framework to guide future research in the development, implementation, and evaluation of strategies to optimize analgesic outcomes in older adults while minimizing deleterious effects on cognition.

Background: The hippocampus and temporal lobe are atrophic in typical amnestic Alzheimer’s disease (tAD) and are used as imaging biomarkers in treatment trials. However, a better understanding of how temporal structures differ across atypical AD phenotypes and relate to cognition is needed. Objective: Our goal was to compare temporal lobe regions between tAD and two atypical AD phenotypes (logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA)), and assess cognitive associations. Methods: We age and gender-matched 77 tAD participants to 50 LPA and 27 PCA participants, all of which were amyloid-positive. We used linear mixed-effects models to compare FreeSurfer-derived hippocampal volumes and cortical thickness of entorhinal, inferior and middle temporal, and fusiform gyri, and to assess relationships between imaging and memory, naming, and visuospatial function across and within AD phenotype. Results: Hippocampal volume and entorhinal thickness were smaller bilaterally in tAD than LPA and PCA. PCA showed greater right inferior temporal and bilateral fusiform thinning and LPA showed greater left middle and inferior temporal and left fusiform thinning. Atypical AD phenotypes differed with greater right hemisphere thinning in PCA and greater left hemisphere thinning in LPA. Verbal and visual memory related most strongly to hippocampal volume; naming related to left temporal thickness; and visuospatial related to bilateral fusiform thickness. Fewer associations remained when examined within AD group. Conclusion: Atypical AD phenotypes are associated with greater thinning of lateral temporal structures, with relative sparing of medial temporal lobe, compared to tAD. These findings may have implications for future clinical trials in AD.

Background: Olfactory identification (OI) impairment appears early in the course of Alzheimer’s disease dementia (AD), prior to detectable cognitive impairment. However, the neuroanatomical correlates of impaired OI in cognitively normal older adults (CN) and persons with mild cognitive impairment (MCI) are not fully understood. Objective: We examined the neuroanatomic correlates of OI impairment in older adults from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: Our sample included 1,600 older adults without dementia who completed clinical assessment and structural brain imaging from 2011 to 2013. We characterized OI impairment using the 12-item Sniffin’ Sticks odor identification test (score ≤6). We used voxel-based morphometry (VBM) and region of interest (ROI) analyses to examine the neuroanatomic correlates of impaired OI in CN and MCI, after adjusting for potential confounders. Analyses were also separately stratified by race and sex. Results: In CN, OI impairment was associated with smaller amygdala gray matter (GM) volume ( p < 0.05). In MCI, OI impairment was associated with smaller GM volumes of the olfactory cortex, amygdala, entorhinal cortex, hippocampus, and insula (ps < 0.05). Differential associations were observed by sex in MCI; OI impairment was associated with lower insular GM volumes among men but not among women (p-interaction = 0.04). There were no meaningful interactions by race. Conclusion: The brain regions associated with OI impairment in individuals without dementia are specifically those regions known to be the primary targets of AD pathogenic processes. These findings highlight the potential utility of olfactory assessment in the identification and stratification of older adults at risk for AD.

Abstract Introduction The aim of this study was to develop a conditional normative model for Rey's Auditory Verbal Learning Test (AVLT) that accounts for practice effects. Methods In our normative sample, robust conditional norms were derived from 1001 cognitively unimpaired (CU) adults ages 50 to 89 who completed the AVLT up to eight times. Linear mixed‐effects models adjusted for baseline performance, prior test exposures, time, demographics, and interaction terms. In our preliminary validation, mean performance on conditional and typical normative scores across two to four completed follow‐up tests in preclinical Alzheimer's disease participants at baseline with positive amyloid and tau positron emission ( n = 27 CU amyloid [A]+tau[T]+) was compared to biomarker negative individuals ( n = 269 CU A–T–). Results AVLT performance using typical norms did not differ across A+T+ and A–T– groups. Conditional norms z‐scores were lower in the A+T+ relative to the A–T– group for 30‐minute recall ( P = .033) and sum of trials ( P = .030). Discussion Conditional normative methods that account for practice effects show promise for identifying longitudinal cognitive decline.

Background: Brain accumulation of amyloid-β is a hallmark event in Alzheimer’s disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia. Objective: To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population. Methods: We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained. Results: Known AD risk variants in APOE, PICALM, CR1, and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA ( p = 1.51×10 –50 ) and ADNI ( p = 3.21×10 –64 ). However, in both cohorts the non- APOE variants uniquely contributed only modestly (MCSA = 2.1%, ADNI = 4.4%) to explaining variation in amyloid PET levels. Conclusion: Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity.

AbstractBackground and purposeAutoimmune encephalitis (AE) is a potentially treatable cause of rapidly progressive dementia that may mimic Creutzfeldt–Jakob disease (CJD). Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers may discriminate CJD from AD, but utility in discriminating CJD and AE is unclear. This study compared AD CSF biomarkers in CJD and AE.MethodsPatients with probable or definite CJD and probable or definite AE who underwent Roche Elecsys AD CSF biomarker testing at Mayo Clinic from March 2020 through April 2021 were included. Total‐tau, phosphorylated181 tau and amyloid‐β42 levels were compared.ResultsOf 11 CJD cases, four were autopsy proven; the rest had positive real‐time quaking‐induced conversion testing. Disease‐associated autoantibodies were detected in 8/15 cases of AE: leucine‐rich glioma‐inactivated 1 and neuronal intermediate filaments (two cases each), and N‐methyl‐d‐aspartate receptor, contactin‐associated protein‐like 2, dipeptidyl‐peptidase‐like protein 6 and immunoglobulin‐like cell adhesion molecule IgLON family member 5. Total‐tau provided excellent discrimination between CJD and AE in a univariate model (odds ratio 1.46 per 100 pg/ml, 95% confidence interval 1.17–2.11, p < 0.05, c = 0.93). Total‐tau was elevated in 91% of CJD cases (median > 1300, range 236–>1300 pg/ml), of which 55% were above the limit of assay measurement (>1300 pg/ml). Total‐tau was elevated in 20% of AE cases (median 158, range 80–>1300 pg/ml).ConclusionTotal‐tau was greater in CJD than AE. Given that amyloid‐β42 and phosphorylated181 tau were comparable, the ratio differences were probably driven by elevated total‐tau in CJD. This study supports the role for AD biomarker testing in patients with rapidly progressive dementia.

Objective Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid β (Aβ) deposition and neurodegeneration. Whether vascular and Alzheimer disease‐associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood. Methods Participants in the Atherosclerosis Risk in Communities–Positron Emission Tomography study were followed from 1987–1989 (45–64 years old) through 2016–2017 (74–94 years old), with repeat cognitive assessment and dementia adjudication. In 2011–2013, dementia‐free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aβ) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aβ standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models. Results In 298 individuals, 36 developed dementia (median follow‐up = 4.9 years). Midlife hypertension and Aβ each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16–5.67; Aβ SUVR [per standard deviation (SD)]: HR = 2.57, 95% CI = 1.72–3.84), but did not interact significantly, whereas late life diabetes (HR = 2.50, 95% CI = 1.18–5.28) and Aβ independently predicted dementia risk. WMHs (per SD: HR = 1.51, 95% CI = 1.03–2.20) and Aβ SUVR (HR = 2.52, 95% CI = 1.83–3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aβ and MVRFs (HR = 2.18, 95% CI = 1.18–4.01). Interpretation Midlife hypertension and late life Aβ are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607–619

AbstractIntroductionWe investigated the association of the area deprivation index (ADI) with cognitive decline, mild cognitive impairment (MCI), and dementia in older adults (≥50 years old). ADI is a neighborhood socioeconomic disadvantage measure assessed at the census block group level.MethodsThe study included 4699 participants, initially without dementia, with available ADI values for 2015 and at least one study visit in 2008 through 2018. Using logistic regression and Cox proportional hazards models with age as the time scale, we assessed the odds for MCI and the risk for dementia, respectively.ResultsIn cognitively unimpaired (CU) adults at baseline, the risk for progression to dementia increased for every decile increase in the ADI state ranking (hazard ratio = 1.06, 95% confidence interval (1.01–1.11), P = .01). Higher ADI values were associated with subtly faster cognitive decline.DiscussionIn older CU adults, higher baseline neighborhood socioeconomic deprivation levels were associated with progression to dementia and slightly faster cognitive decline.Highlights The study used area deprivation index, a composite freely available neighborhood deprivation measure. Higher levels of neighborhood deprivation were associated with greater mild cognitive impairment odds. Higher neighborhood deprivation levels were associated with higher dementia risk.