Research Letter: TBI Severity Moderates the Association Between Subjective and Objective Attention in Older Veterans.

OBJECTIVE: This study examined the moderating effect of traumatic brain injury (TBI) history on subjective and objective cognition across multiple cognitive domains. SETTING, PARTICIPANTS, AND DESIGN: Participants included 242 Vietnam-era veterans with a history of no TBI (n = 86), mild TBI (n = 74), or moderate-to-severe TBI (n = 82) from the observational Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) study. MAIN MEASURES: Objective cognition was the outcome and was measured using neuropsychological measures in the domains of memory, attention/executive functioning, and language. Subjective cognition was measured using the memory, divided attention, and language subscales from the Everyday Cognition (ECog) measure. TBI severity status was the moderating variable. RESULTS: Veterans with a history of moderate-to-severe TBI had a stronger negative association between subjective and objective attention relative to participants without a TBI (P = .002). Although this association did not differ between mild TBI and no TBI history groups (P = .100), the association between subjective and objective attention for the mild TBI group was intermediate to the no TBI and moderate-to-severe TBI history groups. TBI status did not moderate associations between subjective and objective memory or language. CONCLUSION: Results highlight the importance of assessing subjective and objective cognition in older veterans and the relevance of attention in the context of TBI history. More work is needed to better understand the intersection of TBI and aging and how these factors may be used to guide individualized assessment and treatment approaches for older veterans.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Diffusion MRI tractography of the locus coeruleus-transentorhinal cortex connections using GO-ESP.

PURPOSE: The locus coeruleus (LC) is implicated as an early site of protein pathogenesis in Alzheimer's disease (AD). Tau pathology is hypothesized to propagate in a prion-like manner along the LC-transentorhinal cortex (TEC) white matter (WM) pathway, leading to atrophy of the entorhinal cortex and adjacent cortical regions in a progressive and stereotypical manner. However, WM damage along the LC-TEC pathway may be an earlier observable change that can improve detection of preclinical AD. THEORY AND METHODS: Diffusion-weighted MRI (dMRI) allows reconstruction of WM pathways in vivo, offering promising potential to examine this pathway and enhance our understanding of neural mechanisms underlying the preclinical phase of AD. However, standard dMRI analysis tools have generally been unable to reliably reconstruct this pathway. We apply a novel method, geometric-optics based entropy spectrum pathways (GO-ESP) and produce a new measure of connectivity: the equilibrium probability (EP). RESULTS: We demonstrated reliable reconstruction of LC-TEC pathways in 50 cognitively normal older adults and showed a negative association between LC-TEC EP and cerebrospinal fluid tau. Using Human Connectome Project data, we demonstrated replicability of the method across acquisition schemes and scanners. Finally, we compared our findings with the only other existing LC-TEC tractography template, and replicated their pathway as well as investigated the source of these discrepant findings. CONCLUSIONS: AD-related tau pathology may be detectable within GO-ESP-identified LC-TEC pathways. Furthermore, there may be multiple possible routes from LC to TEC, raising important questions for future research on the LC-TEC connectome and its role in AD pathogenesis.

Elevated plasma neurofilament light predicts a faster rate of cognitive decline over 5 years in participants with objectively-defined subtle cognitive decline and MCI.

INTRODUCTION: Neurofilament light (NFL) reflects neuroaxonal damage and is implicated in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Little is known about NFL in pre-MCI stages, such as in individuals with objectively-defined subtle cognitive decline (Obj-SCD). METHODS: Two hundred ninety-four participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent baseline blood draw and serial neuropsychological testing over 5 years of follow-up. RESULTS: Individuals with Obj-SCD and MCI showed elevated baseline plasma NFL relative to the cognitively normal (CN) group. Across the sample, elevated NFL predicted faster rate of cognitive and functional decline. Within the Obj-SCD and MCI groups, higher NFL levels predicted faster rate of decline in memory and preclinical AD composite score compared to the CN group. DISCUSSION: Findings demonstrate the utility of plasma NFL as a biomarker of early AD-related changes, and provide support for the use of Obj-SCD criteria in clinical research to better capture subtle cognitive changes.

APOE interacts with tau PET to influence memory independently of amyloid PET in older adults without dementia.

INTRODUCTION: Apolipoprotein E (APOE) interacts with Alzheimer's disease pathology to promote disease progression. We investigated the moderating effect of APOE on independent associations of amyloid and tau positron emission tomography (PET) with cognition. METHODS: For 297 nondemented older adults from the Alzheimer's Disease Neuroimaging Initiative, regression equations modeled associations between cognition and (1) cortical amyloid beta (Aß) PET levels adjusting for tau and (2) medial temporal lobe (MTL) tau PET levels adjusting for Aß, including interactions with APOE ε4-carrier status. RESULTS: Adjusting for tau PET, Aß was not associated with cognition and did not interact with APOE. In contrast, adjusting for Aß PET, MTL tau was associated with all cognitive domains. Further, there was a stronger moderating effect of APOE on MTL tau and memory associations in ε4-carriers, even among Aß-negative individuals. DISCUSSION: Findings suggest that APOE may interact with tau independently of Aß and that elevated MTL tau confers negative cognitive consequences in Aß-negative ε4 carriers.

Type 2 Diabetes Interacts With Alzheimer Disease Risk Factors to Predict Functional Decline.

OBJECTIVE: The current study examined the interactive effect of type 2 diabetes and Alzheimer disease (AD) risk factors on the rate of functional decline in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative. METHODS: Participants underwent annual assessments that included the Functional Activities Questionnaire, an informant-rated measure of everyday functioning. Multilevel modeling, controlling for demographic variables and ischemic risk, examined the interactive effects of diabetes status (diabetes, n=69; no diabetes, n=744) and AD risk factors in the prediction of 5-year longitudinal change in everyday functioning. One model was run for each AD risk factor, including: objectively-defined subtle cognitive decline (Obj-SCD), and genetic susceptibility [apolipoprotein E ε4 (APOE ε4) as well as cerebrospinal fluid ß-amyloid (Aß), total tau (tau), and hyperphosphorylated tau (p-tau). RESULTS: The 3-way diabetes×AD risk factor×time interaction predicted increased rates of functional decline in models that examined Obj-SCD, APOE ε4, tau, and p-tau positivity, but not Aß positivity. CONCLUSIONS: Participants with both diabetes and at least 1 AD risk factor (ie, Obj-SCD, APOE ε4, tau, and p-tau positivity) demonstrated faster functional decline compared with those without both risk factors (diabetes or AD). These findings have implications for early identification of, and perhaps earlier intervention for, diabetic individuals at risk for future functional difficulty.

Early versus late MCI: Improved MCI staging using a neuropsychological approach.

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) separates "early" and "late" mild cognitive impairment (MCI) based on a single memory test. We compared ADNI's MCI classifications to our neuropsychological approach, which more broadly assesses cognitive abilities. METHODS: Three hundred thirty-six ADNI-2 participants were classified as "early" or "late" MCI. Cluster analysis was performed on neuropsychological test data, and participants were reclassified based on cluster results. These two staging approaches were compared on progression rates, cerebrospinal fluid biomarkers, and cortical thickness profiles. RESULTS: There was little correspondence between the two staging methods. ADNI's early MCI group included a large proportion of false-positive diagnostic errors. The reclassified neuropsychological MCI groups showed steeper survival curves and more abnormal biomarkers. CONCLUSIONS: Our novel neuropsychological approach improved the staging of MCI by (1) capturing individuals at an early symptomatic stage, (2) minimizing false-positive cases, and (3) identifying a late MCI group further along the disease trajectory.

MCI-to-normal reversion using neuropsychological criteria in the Alzheimer's Disease Neuroimaging Initiative.

INTRODUCTION: The low mild cognitive impairment (MCI) to cognitively normal (CN) reversion rate in the Alzheimer's Disease Neuroimaging Initiative (2-3%) suggests the need to examine reversion by other means. We applied comprehensive neuropsychological criteria (NP criteria) to determine the resulting MCI to CN reversion rate. METHODS: Participants with CN (n = 641) or MCI (n = 569) were classified at baseline and year 1 using NP criteria. Demographic, neuropsychological, and Alzheimer's disease biomarker variables as well as progression to dementia were examined across stable CN, reversion, and stable MCI groups. RESULTS: NP criteria produced a one-year reversion rate of 15.8%. Reverters had demographics, Alzheimer's disease biomarkers, and risk-of-progression most similar to the stable CN group and showed the most improvement on neuropsychological measures from baseline to year 1. DISCUSSION: NP criteria produced a reversion rate that is consistent with, albeit modestly improved from, reversion rates in meta-analyses. Reverters' biomarker profiles and progression rates suggest that NP criteria accurately tracked with underlying pathophysiologic status.

Artificially low mild cognitive impairment to normal reversion rate in the Alzheimer's Disease Neuroimaging Initiative.

INTRODUCTION: We examined reasons for low mild cognitive impairment (MCI)-to-cognitively normal (CN) reversion rates in the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: CN and MCI participants were identified as remaining stable, progressing, or reverting at 1-year of follow-up (Year 1). Application of ADNI's MCI criteria at Year 1 in addition to Alzheimer's disease biomarkers by group were examined. RESULTS: The MCI-to-CN reversion rate was 3.0%. When specific components were examined, 22.5% of stable MCI participants had normal memory performance at Year 1 and their Alzheimer's disease biomarkers were consistent with the stable CN group. At Year 1, when all MCI criteria were not met, the more subjective Clinical Dementia Rating rather than objective memory measure appeared to drive continuation of the MCI diagnosis. DISCUSSION: Results demonstrate an artificially low 1-year MCI-to-CN reversion rate in ADNI-diagnosed participants. If the Logical Memory cutoffs had been consistently applied, the reversion rate would have been at least 21.8%.

Neuropsychological Criteria for Mild Cognitive Impairment in the Framingham Heart Study's Old-Old.

BACKGROUND/AIMS: Mild cognitive impairment (MCI) lacks a "gold standard" operational definition. The Jak/Bondi actuarial neuropsychological criteria for MCI are associated with improved diagnostic stability and prediction of progression to dementia compared to conventional MCI diagnostic approaches, although its utility in diagnosing MCI in old-old individuals (age 75+) is unknown. Therefore, we investigated the applicability of neuropsychological MCI criteria among old-old from the Framingham Heart Study. METHODS: A total of 347 adults (ages 79-102) were classified as cognitively normal or MCI via Jak/Bondi and conventional Petersen/Winblad criteria, which differ on cutoffs for cognitive impairment and number of impaired scores required for a diagnosis. Cox models examined MCI status in predicting risk of progression to dementia. RESULTS: MCI diagnosed by both the Jak/Bondi and Petersen/Winblad criteria was associated with incident dementia; however, when both criteria were included in the regression model together, only the Jak/Bondi criteria remained statistically significant. At follow-up, the Jak/Bondi criteria had a lower MCI-to-normal reversion rate than the Petersen/Winblad criteria. CONCLUSIONS: Our findings are consistent with previous research on the Jak/Bondi criteria and support the use of a comprehensive neuropsychological diagnostic approach for MCI among old-old individuals.

Increasing Inaccuracy of Self-Reported Subjective Cognitive Complaints Over 24 Months in Empirically Derived Subtypes of Mild Cognitive Impairment.

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 Moderates the Association Between Amyloid and 1-Year Change in Everyday Functioning in Older Veterans.

BACKGROUND: Type 2 diabetes mellitus (T2DM) affects ∼25% of Veterans, a prevalence rate double that of the general population. T2DM is associated with greater dementia risk and has been shown to exacerbate the impact of Alzheimer's disease (AD) risk factors on declines in daily functioning; however, there are few studies that investigate these patterns in older Veterans. OBJECTIVE: This study sought to determine whether T2DM moderates the association between amyloid-ß (Aß) positron emission tomography (PET) and 1-year change in everyday functioning in older Veterans. METHODS: One-hundred-ninety-eight predominately male Vietnam-Era Veterans without dementia from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) with (n = 74) and without (n = 124) T2DM completed Aß PET imaging and everyday functioning measures, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Everyday Cognition (ECog). Linear mixed effects models tested the moderating role of T2DM on the association between Aß PET and 1-year change in everyday functioning. RESULTS: The 3-way T2DM×Aß PET×time interaction was significant for CDR-SB (p < 0.001) as well as the Memory (p = 0.007) and Language (p = 0.011) subscales from the ECog. Greater amyloid burden was associated with greater increases in functional difficulties, but only in Veterans with T2DM. CONCLUSIONS: Higher Aß was only associated with declines in everyday functioning over 1 year in Veterans with T2DM. Given that people with T2DM are more likely to have co-occurring cerebrovascular disease, the combination of multiple neuropathologies may result in faster declines. Future studies should examine how diabetes duration, severity, and medications impact these associations.

Cognition and Amyloid-ß in Older Veterans: Characterization and Longitudinal Outcomes of Data-Derived Phenotypes.

Background: Within older Veterans, multiple factors may contribute to cognitive difficulties. Beyond Alzheimer's disease (AD), psychiatric (e.g., PTSD) and health comorbidities (e.g., TBI) may also impact cognition. Objective: This study aimed to derive subgroups based on objective cognition, subjective cognitive decline (SCD), and amyloid burden, and then compare subgroups on clinical characteristics, biomarkers, and longitudinal change in functioning and global cognition. Methods: Cluster analysis of neuropsychological measures, SCD, and amyloid PET was conducted on 228 predominately male Vietnam-Era Veterans from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative. Cluster-derived subgroups were compared on baseline characteristics as well as 1-year changes in everyday functioning and global cognition. Results: The cluster analysis identified 3 groups. Group 1 (n = 128) had average-to-above average cognition with low amyloid burden. Group 2 (n = 72) had the lowest memory and language, highest SCD, and average amyloid burden; they also had the most severe PTSD, pain, and worst sleep quality. Group 3 (n = 28) had the lowest attention/executive functioning, slightly low memory and language, elevated amyloid and the worst AD biomarkers, and the fastest rate of everyday functioning and cognitive decline. CONCLUSIONS: Psychiatric and health factors likely contributed to Group 2's low memory and language performance. Group 3 was most consistent with biological AD, yet attention/executive function was the lowest score. The complexity of older Veterans' co-morbid conditions may interact with AD pathology to show attention/executive dysfunction (rather than memory) as a prominent early symptom. These results could have important implications for the implementation of AD-modifying drugs in older Veterans.

Pulse pressure and APOE ε4 dose interact to affect cerebral blood flow in older adults without dementia.

This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP - diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.

Perceived Discrimination in Health Care for LGBTQIA+ People Living With Parkinson's Disease.

OBJECTIVES: People who identify as lesbian, gay, bisexual, transgender, queer/questioning, intersex, asexual, other non-cisgender, and non-heterosexual identities (LGBTQIA+) experience discrimination when accessing health care. We investigated specific experiences of LGBTQIA+ people with Parkinson's disease (PwP) as they are less known. METHODS: Data were obtained from Fox Insight for PwP identifying as LGBTQIA+ (n = 210), cisgender, heterosexual women (n = 2,373) or cisgender, heterosexual men (n = 2,453). Discrimination in Medical Settings Scale responses and reports of whether gender identity or sexual orientation played a role in the perceived discrimination were compared across the groups. RESULTS: Parkinson's diagnosis age was the youngest for LGBTQIA+ PwP. Despite similar levels of education with cisgender, heterosexual men, LGBTQIA+ people had lower levels of income and were more likely to be unemployed. Cisgender, heterosexual women and LGBTQIA+ PwP reported greater discrimination than cisgender, heterosexual men. Compared to cisgender, heterosexual men; LGBTQIA+ people (25%) and cisgender, heterosexual women (20%) were more likely to report their gender affected how they were treated; LGBTQIA+ PwP (19%) were more likely to report their sexual orientation affected how they were treated. DISCUSSION: Women and LGBTQIA+ PwP may be at a higher risk for discrimination in medical settings. Facing disparities while receiving health care based on gender or sexual orientation can affect the health care utilization of PwP. Health care providers should consider their behaviors and interactions with PwP to ensure inclusive and welcoming health care environments.

Cognitive reserve moderates the association between cerebral blood flow and language performance in older adults with mild cognitive impairment.

Higher cognitive reserve (CR) may offer protection from cognitive changes associated with reduced cerebral blood flow (CBF). We investigated CR as a moderator of the effect of CBF on cognition in older adults with mild cognitive impairment (MCI; N = 46) and those who are cognitively unimpaired (CU; N = 101). Participants underwent arterial spin labeling MRI, which was used to quantify CBF in 4 a priori regions. Estimated verbal intelligence quotient (VIQ) served as a proxy for CR. Multiple linear regressions examined whether VIQ moderated associations between CBF and cognition and whether this differed by cognitive status. Outcomes included memory and language performance. There were 3-way interactions (CBF*VIQ*cognitive status) on category fluency when examining hippocampal, superior frontal, and inferior frontal CBF. Follow-up analyses revealed that, within the MCI but not CU group, there were CBF*VIQ interactions on fluency in all a priori regions examined, where there were stronger, positive associations between CBF and fluency at higher VIQ. Conclusion: In MCI, higher CR plays a role in strengthening CBF-fluency associations.

APOE differentially moderates cerebrospinal fluid and plasma phosphorylated tau181 associations with multi-domain cognition.

Biofluid markers of phosphorylated tau181 (p-tau181) are increasingly popular for the detection of early Alzheimer's pathologic changes. However, the differential dynamics of cerebrospinal fluid (CSF) and plasma p-tau181 remain under investigation. We studied 727 participants from the Alzheimer's Disease Neuroimaging Initiative with plasma and CSF p-tau181 data, apolipoprotein (APOE) ε4 carrier status, amyloid positron emission tomography (PET) imaging, and neuropsychological data. Higher levels of plasma and CSF p-tau181 were observed among APOE ε4 carriers. CSF and plasma p-tau181 were significantly associated with memory, and this effect was greater in APOE ε4 carriers. However, whereas CSF p-tau181 was not significantly associated with language or attention/executive function among ε4 carriers or non-carriers, APOE ε4 status moderated the association of plasma p-tau181 with both language and attention/executive function. These findings lend support to the notion that p-tau181 biofluid markers are useful in measuring AD pathologic changes but also suggest that CSF and plasma p-tau181 have unique properties and dynamics that should be considered when using these markers in research and clinical practice.

Brain Derived Neurotrophic Factor Interacts with White Matter Hyperintensities to Influence Processing Speed and Hippocampal Volume in Older Adults.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in regulating synaptic activity and plasticity. OBJECTIVE: Given that type-2 diabetes (T2DM) increases the risk of cognitive decline, and studies have suggested lower BDNF levels may be a risk factor of diabetic neurovascular complications, we sought to investigate total white matter hyperintensities (WMH) as a moderator of the effect of BDNF on hippocampal volume and cognition. METHODS: Older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative (N = 454 including 49 with T2DM and 405 without diabetes) underwent neuropsychological evaluation, magnetic resonance imaging to quantify hippocampal and WMH volumes, and blood draw to assess BDNF. RESULTS: Adjusting for age, sex, and APOE ɛ4 carrier status, there was a significant interaction between total WMH and BDNF on bilateral hippocampal volume in the non-T2DM group (t = 2.63, p = 0.009). Examination of main effect models with a dichotomous high/low BNDF group revealed a significant main effect for low BDNF (t = -4.98, p < 0.001), such that as WMH increased, bilateral hippocampal volume decreased. There was also a significant interaction between total WMH and BDNF on processing speed in the non-T2DM group (t = 2.91, p = 0.004). There was a significant main effect for low BDNF (t = -3.55, p < 0.001) such that as WMH increased, processing speed decreased. The interactions were not significant in the T2DM group. CONCLUSION: These results further elucidate the protective role that BDNF plays on cognition, as well as the cognitive effects of WMH.

White Matter Hyperintensity Volume and Amyloid-PET Synergistically Impact Memory Independent of Tau-PET in Older Adults Without Dementia.

BACKGROUND: Alzheimer's disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear. OBJECTIVE: To examine whether white matter hyperintensity (WMH) volume moderates the independent association between each AD biomarker and cognition. METHODS: In 586 older adults without dementia, linear regressions tested the interaction between amyloid-ß (Aß) positron emission tomography (PET) and WMH volume on cognition, independent of tau-PET. We also tested the interaction between tau-PET and WMH volume on cognition, independent of Aß-PET. RESULTS: Adjusting for tau-PET, the quadratic effect of WMH interacted with Aß-PET to impact memory. There was no interaction between either the linear or quadratic effect of WMH and Aß-PET on executive function. There was no interaction between WMH volume and tau-PET on either cognitive measure. CONCLUSION: Results suggest that cerebrovascular lesions act synergistically with Aß to affect memory, independent of tau, highlighting the importance of incorporating vascular pathology into biomarker assessment of AD.

What's the cut-point?: a systematic investigation of tau PET thresholding methods.

BACKGROUND: Tau positron emission tomography (PET) is increasing in popularity for biomarker characterization of Alzheimer's disease (AD), and recent frameworks rely on tau PET cut-points to stage individuals along the AD continuum. Given the lack of standardization in tau PET thresholding methods, this study sought to systematically canvass and characterize existing studies that have derived tau PET cut-points and then directly assess different methods of tau PET thresholding in terms of their concurrent validity. METHODS: First, a literature search was conducted in PubMed to identify studies of AD and related clinical phenotypes that used the Flortaucipir (AV-1451) tau PET tracer to derive a binary cut-point for tau positivity. Of 540 articles screened and 47 full-texts reviewed, 23 cohort studies met inclusion criteria with a total of 6536 participants. Second, we derived and compared tau PET cut-points in a 2 × 2 × 2 design that systematically varied region (temporal meta-ROI and entorhinal cortex), analytic method (receiver operating characteristics and 2 standard deviations above comparison group), and criterion/comparison variable (amyloid-beta negative cognitively unimpaired or cognitively unimpaired only) using a sample of 453 older adults from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: For the systematic review, notable variability in sample characteristics, preprocessing methods, region of interest, and analytic approach were observed, which were accompanied by discrepancy in proposed tau PET cut points. The empirical follow-up indicated the cut-point derived based on 2 standard deviations above a either comparison group in either ROI best differentiated tau positive and negative groups on cerebrospinal fluid phosphorylated tau, Mini-Mental State Examination score, and delayed memory performance. CONCLUSIONS: Given the impact of discrepant thresholds on tau positivity rates, biomarker staging, and eligibility for future clinical treatment trials, recommendations are offered to select cut-point derivations based on the unique goals and priorities of different studies.