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While significant investments have been made in imaging acquisition and biomarker methods, progressing from brain MRI to PET scans and developing higher sensitivity imaging tracers and serum markers, the primary methods for documenting clinical manifestations of AD, using neuropsychological tests to detect a cognitive impairment, have gone largely unnoticed outside of the neuropsychological professional community. Over time, while different list learning and story memory tasks have been developed and used, remarkably, the AD research world continues to primarily rely on the delayed recall score from memory tasks. [...]while detecting pathological emergence of AD has evolved, the persistent reliance on the same behavioral measure for an early signal of memory impairment has meant not keeping up with the biomarker community in finding memory markers that are or might be better than those that are 75+ years old. The process score profile consistent with early AD has been characterized as having slowed learning across trials of a word-list memory task (i.e. a flattened learning slope), increased susceptibility to interference, and a greater frequency of nontarget word intrusion errors, particularly on cued recall trials that pull for intrusions that are semantically related to the target words (Delis et al., 1991; Loewenstein et al., 2004; Salmon and Bondi, 2009). Most of the older adult research that involves biomarkers has been conducted on predominately non-Hispanic white participants. [...]the fact that 53% of the sample in this study was Spanish-speaking is a relative strength.

Objectives: Although subjective cognitive complaints (SCC) are an integral component of the diagnostic criteria for mild cognitive impairment (MCI), previous findings indicate they may not accurately reflect cognitive ability. Within the Alzheimer’s Disease Neuroimaging Initiative, we investigated longitudinal change in the discrepancy between self- and informant-reported SCC across empirically derived subtypes of MCI and normal control (NC) participants. Methods: Data were obtained for 353 MCI participants and 122 “robust” NC participants. Participants were classified into three subtypes at baseline via cluster analysis: amnestic MCI, mixed MCI, and cluster-derived normal (CDN), a presumptive false-positive group who performed within normal limits on neuropsychological testing. SCC at baseline and two annual follow-up visits were assessed via the Everyday Cognition Questionnaire (ECog), and discrepancy scores between self- and informant-report were calculated. Analysis of change was conducted using analysis of covariance. Results: The amnestic and mixed MCI subtypes demonstrated increasing ECog discrepancy scores over time. This was driven by an increase in informant-reported SCC, which corresponded to participants’ objective cognitive decline, despite stable self-reported SCC. Increasing unawareness was associated with cerebrospinal fluid Alzheimer’s disease biomarker positivity and progression to Alzheimer’s disease. In contrast, CDN and NC groups over-reported cognitive difficulty and demonstrated normal cognition at all time points. Conclusions: MCI participants’ discrepancy scores indicate progressive underappreciation of their evolving cognitive deficits. Consistent over-reporting in the CDN and NC groups despite normal objective cognition suggests that self-reported SCC do not predict impending cognitive decline. Results demonstrate that self-reported SCC become increasingly misleading as objective cognitive impairment becomes more pronounced. (JINS, 2018, 24, 842–853)

Type 2 diabetes mellitus (T2DM) increases risk for dementia, including Alzheimer's disease (AD). Many previous studies of brain changes underlying cognitive impairment in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect macrostructural changes associated with cerebrovascular disease such as white matter hyperintensities or infarcts. However, such pathology likely reflects end-stage manifestations of chronic decrements in cerebral blood flow (CBF). MRI techniques that measure CBF may (1) elucidate mechanisms that precede irreversible parenchymal damage and (2) serve as a marker of risk for cognitive decline. CBF measured with arterial spin labeling (ASL) MRI may be a useful marker of perfusion deficits in T2DM and related conditions. We examined associations among T2DM, CBF, and cognition in a sample of 49 well-characterized nondemented older adults. Along with a standard T1-weighted scan, a pseudocontinuous ASL sequence optimized for older adults (by increasing post-labeling delays to allow more time for the blood to reach brain tissue) was obtained on a 3T GE scanner to measure regional CBF in FreeSurfer derived regions of interest. Participants also completed a neuropsychological assessment. Results showed no significant differences between individuals with and without T2DM in terms of cortical thickness or regional brain volume. However, adjusting for age, sex, comorbid vascular risk factors, and reference CBF (postcentral gyrus) older adults with T2DM demonstrated reduced CBF in the hippocampus, and inferior temporal, inferior parietal, and frontal cortices. Lower CBF was associated with poorer memory and executive function/processing speed. When adjusting for diabetes, the significant associations between lower regional CBF and poorer executive function/processing speed remained. Results demonstrate that CBF is reduced in older adults with T2DM, and suggest that CBF alterations likely precede volumetric changes. Notably, relative to nondiabetic control participants, those with T2DM showed lower CBF in predilection sites for AD pathology (medial temporal lobe and inferior parietal regions). Findings augment recent research suggesting that perfusion deficits may underlie cognitive decrements frequently observed among older adults with T2DM. Results also suggest that CBF measured with ASL MRI may reflect an early and important marker of risk of cognitive impairment in T2DM and related conditions.

Objectives: Careful characterization of how functional decline co-evolves with cognitive decline in older adults has yet to be well described. Most models of neurodegenerative disease postulate that cognitive decline predates and potentially leads to declines in everyday functional abilities; however, there is mounting evidence that subtle decline in instrumental activities of daily living (IADLs) may be detectable in older individuals who are still cognitively normal. Methods: The present study examines how the relationship between change in cognition and change in IADLs are best characterized among older adults who participated in the ACTIVE trial. Neuropsychological and IADL data were analyzed for 2802 older adults who were cognitively normal at study baseline and followed for up to 10 years. Results: Findings demonstrate that subtle, self-perceived difficulties in performing IADLs preceded and predicted subsequent declines on cognitive tests of memory, reasoning, and speed of processing. Conclusions: Findings are consistent with a growing body of literature suggesting that subjective changes in everyday abilities can be associated with more precipitous decline on objective cognitive measures and the development of mild cognitive impairment and dementia. (JINS, 2018, 24, 104–112)

Intraindividual variability (IIV) across neuropsychological measures within a single testing session is a promising marker predictive of cognitive decline and development of Alzheimer’s disease (AD). We have previously shown that greater IIV is cross-sectionally associated with reduced cerebral blood flow (CBF), but not with cortical thickness or brain volume, in older adults without dementia who were amyloid beta (Aβ) positive. However, there is little known about the association between change in IIV and CBF over time. Therefore, we examined 12-month longitudinal change in IIV and interactions of IIV and AD biomarker status on changes in regional CBF. Fifty-three nondemented Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants underwent lumbar puncture to obtain cerebrospinal fluid (CSF) at baseline and neuropsychological testing and magnetic resonance imaging (MRI) exams at baseline and 12-month follow-up evaluation. IIV was calculated as the intraindividual standard deviation across 6 demographically-corrected neuropsychological measures. Pulsed arterial spin labeling (ASL) MRI was acquired to quantify CBF and FreeSurfer-derived a priori CBF regions of interest (ROIs) were examined. AD biomarker positivity was determined using a published CSF p-tau/Aβ ratio cut-score. Change scores were calculated for IIV, CBF, and mean neuropsychological performance from baseline to 12 months. Hierarchical linear regression models showed that after adjusting for age and gender, there was a significant interaction between IIV change and biomarker-positivity (p-tau/Aβ+) for change in entorhinal and hippocampal CBF but not for the other ROIs. Specifically, increases in IIV were associated with reductions in entorhinal and hippocampal CBF among individuals who were biomarker-positive (n=21). In contrast, there were no significant associations between change in IIV and CBF among those who were biomarker-negative (n=32). Findings remained similar when analyses were performed adjusting for change in mean level of neuropsychological performance. Changes in IIV may be sensitive to changes in regional hypoperfusion in AD-vulnerable regions among AD biomarker-positive individuals, above and beyond demographics and mean neuropsychological performance. These findings provide further evidence supporting IIV as a potential marker of cerebrovascular brain changes in individuals at risk for dementia.

Background The 2018 NIA-AA Alzheimer’s Disease (AD) Research Framework states that subtle cognitive decline in cognitively unimpaired individuals can be measured by subjective reports or evidence of objective decline on neuropsychological measures. Both subjective memory complaint (SMC) and objective subtle cognitive decline (Obj-SCD) have been shown to be associated with future cognitive decline and AD biomarkers. We examined whether there are differences in tau PET levels between (a) SMC− vs. SMC+ participants, (b) Obj-SCD− vs. Obj-SCD+ participants, and (c) participants with overlapping vs. discrepant SMC and Obj-SCD classifications. Methods Cognitively unimpaired participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 236) were classified at baseline as positive or negative for SMC (SMC− n = 77; SMC+ n = 159) based on the first 12 items of the Cognitive Change Index and/or classified as positive or negative for Obj-SCD (Obj-SCD− n = 173; Obj-SCD+ n = 63) based on previously defined neuropsychological criteria. Analyses of covariance, adjusting for age, sex, APOE ε4 carrier status, and pulse pressure, examined the group differences in tau PET (AV-1451) using a composite standardized uptake variable ratio (SUVR) for regions consistent with Braak stage III/IV. The chi-squared tests examined the tau positivity rates across the groups. Results Obj-SCD+ participants had higher tau continuous SUVR levels ( p = .035, η p 2 = .019) and higher rates of tau positivity (15.8% Obj-SCD− vs. 30.2% Obj-SCD+) than Obj-SCD− participants. Neither tau levels ( p = .381, η p 2 = .003) nor rates of tau positivity (18.2% SMC− and 20.1% SMC+) differed between the SMC groups. There was very little agreement between SMC and Obj-SCD classifications (42%; κ = 0.008, p = .862). Participants who were Obj-SCD+ without SMC had the highest tau PET levels and differed from participants who were SMC+ without Obj-SCD ( p = .022). Tau levels in participants with both SMC and Obj-SCD did not differ from those with only Obj-SCD ( p = .216). Tau positivity rates across the SMC-/Obj-SCD−, SMC+/Obj-SCD−, SMC−/Obj-SCD+, and SMC+/Obj-SCD+ groups were 10.5%, 18.1%, 40.0%, and 25.6%, respectively. Conclusion Participants with Obj-SCD had a greater tau PET burden than those without Obj-SCD, but SMC was not associated with higher tau levels. The combination of SMC and Obj-SCD did not have higher tau levels than Obj-SCD alone. Findings add to the evidence that the Obj-SCD classification is associated with AD biomarkers and faster cognitive decline in ADNI participants, but further work is needed to validate this approach in more representative/diverse cohorts.

Cerebral blood flow (CBF) alterations and amyloid-β (Aβ) accumulation have been independently linked to cognitive deficits in older adults at risk for dementia. Less is known about how CBF and Aβ may interact to affect cognition in cognitively normal older adults. Therefore, we examined potential statistical interactions between CBF and Aβ status in regions typically affected in Alzheimer's disease (AD) within a sample of older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Sixty-two cognitively normal participants (mean age = 72 years) underwent neuroimaging and memory testing. Arterial spin labeling magnetic resonance imaging was used to quantify CBF and florbetapir PET amyloid imaging was used to measure Aβ deposition. Aβ status (i.e., positivity versus negativity) was determined based on established cutoffs (Landau et al., 2013). The Rey Auditory Verbal Learning Test was used to assess memory. Linear regression models adjusted for age, education, and sex, demonstrated significant interactions between CBF and Aβ status on memory performance. Among Aβ positive older adults, there were significant negative associations between higher CBF in hippocampus, posterior cingulate, and precuneus and poorer memory performance. In contrast, among Aβ negative older adults, there were no significant associations between CBF and cognition. Our findings extend previous CBF studies of dementia risk by reporting interactions between Aβ status and CBF on memory performance in a sample of well-characterized, cognitively normal older adults. Results suggest that differential CBF-cognition associations can be identified in healthy, asymptomatic Aβ positive older adults relative to Aβ negative individuals. Associations between higherCBF and poorer memory among Aβ positive older adults may reflect a cellular and/or vascular compensatory response to pathologic processes whereby higher CBF is needed to maintain normal memory abilities. Findings indicate that CBF and its associations with cognition may have utility as a reliable marker of brain function early in the AD process when interventions are likely to be beneficial.

INTRODUCTION This study aimed to identify phenotypes of subtle variation in multidomain cognitive performance and examine their longitudinal associations with Alzheimer's disease and related dementias (AD/ADRD) biomarkers and cognitive outcomes. METHODS Among 1192 cognitively unimpaired (CU) older adults from the Baltimore Longitudinal Study of Aging, latent profile analysis (LPA) identified phenotypes based on baseline patterns of neuropsychological test performance. Mixed‐effects and Cox models examined longitudinal differences in cognitive status and AD/ADRD biomarkers (phosphorylated tau‐181 [pTau181], amyloid‐beta 42/40 ratio [Aβ42/Aβ40], neurofilament light [NfL], and glial fibrillary acidic protein [GFAP]) across phenotypes. RESULTS LPA identified the following cognitive phenotypes: Overall Low Average, Dysexecutive (n = 112); Overall Average, Low Memory (n = 284); Overall Average, High Memory (n = 449); High Executive, Relatively Low Memory (n = 214); and Overall High Performing (n = 133). Phenotypes differed in longitudinal rates of cognitive decline and increases in NfL. DISCUSSION Subtle variations in neuropsychological performance among CU older adults have implications for long‐term cognitive health and may help inform Alzheimer's disease and related dementias diagnosis and disease monitoring. Highlights Significant cognitive heterogeneity exists in CU older adults. LPA identified phenotypes based on cognitive performance. Personality and psychosocial characteristics differed by cognitive phenotype. Cognition over time and risk of cognitive impairment differed by cognitive phenotypes. The phenotype with greatest executive dysfunction had the fastest increase in NfL.

Background: Cerebrovascular dysfunction has been proposed as a possible mechanism underlying cognitive impairment in the context of type 2 diabetes mellitus (DM). Although magnetic resonance imaging (MRI) evidence of cerebrovascular disease, such as white matter hyperintensities (WMH), is often observed in DM, the vascular dynamics underlying this pathology remain unclear. Thus, we assessed the independent and combined effects of DM status and different vascular hemodynamic measures (i.e., systolic, diastolic, and mean arterial blood pressure and pulse pressure index [PPi]) on WMH burden in cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI). Methods: 559 older adults (mean age: 72.4 years) from the Alzheimer’s Disease Neuroimaging Initiative were categorized into those with diabetes (DM+; CU = 43, MCI = 34) or without diabetes (DM-; CU = 279; MCI = 203). Participants underwent BP assessment, from which all vascular hemodynamic measures were derived. T2-FLAIR MRI was used to quantify WMH burden. Hierarchical linear regression, adjusting for age, sex, BMI, intracranial volume, CSF amyloid, and APOE ε4 status, examined the independent and interactive effects of DM status and each vascular hemodynamic measure on total WMH burden. Results: The presence of DM ( p = 0.046), but not PPi values ( p = 0.299), was independently associated with greater WMH burden overall after adjusting for covariates. Analyses stratified by cognitive status revealed a significant DM status x PPi interaction within the MCI group ( p = 0.001) such that higher PPi values predicted greater WMH burden in the DM + but not DM- group. No significant interactions were observed in the CU group (all p s > 0.05). Discussion: Results indicate that higher PPi values are positively associated with WMH burden in diabetic older adults with MCI, but not their non-diabetic or CU counterparts. Our findings suggest that arterial stiffening and reduced vascular compliance may have a role in development of cerebrovascular pathology within the context of DM in individuals at risk for future cognitive decline. Given the specificity of these findings to MCI, future exploration of the sensitivity of earlier brain markers of vascular insufficiency (i.e., prior to macrostructural white matter changes) to the effects of DM and arterial stiffness/reduced vascular compliance in CU individuals is warranted.

Introduction Objectively‐defined subtle cognitive decline (Obj‐SCD) and plasma phosphorylated‐tau181 (p‐tau181) are promising early Alzheimer's disease (AD) markers. However, associations between Obj‐SCD and p‐tau181, and their combined prognostic potential, are unknown. Methods Baseline and 4‐year longitudinal p‐tau181 changes were compared across cognitively unimpaired (CU; n = 402), Obj‐SCD (n = 199), and mild cognitive impairment (MCI; n = 346) groups. CU and Obj‐SCD participants were further classified as p‐tau181‐positive or negative. Results CU and Obj‐SCD has lower baseline p‐tau181 than MCI and did not differ from one another. Longitudinally, Obj‐SCD had the steepest p‐tau181 increase. Obj‐SCD/p‐tau181‐positive participants had the fastest rates of amyloid accumulation, cognitive decline, and functional decline. Conclusions Despite assumptions that cognitive changes invariably follow biomarker changes, early neuropsychological difficulties may emerge before/concurrently with plasma p‐tau181 changes. Combining Obj‐SCD and p‐tau181, two potentially accessible early markers, was associated with the faster declines in AD‐related outcomes.