Positive Childhood Experiences and the Indirect Relationship With Improved Emotion Regulation in Adults With ADHD Through Social Support.

OBJECTIVE: To identify direct and indirect associations between PCEs and social support to emotion regulation outcomes in adults with ADHD. METHOD: Adults with ADHD (n = 81) reported PCEs, current social support, and emotion regulation. Conditional effects modeling examined the direct and indirect relationships between PCEs and emotion dysregulation through social support. RESULTS: Higher PCEs were indirectly related to improved emotion regulation through increased social support generally (ß = -.70, 95% CI [-1.32, -0.17], and specifically through belonging (ß = -.43, 95% CI [ -0.87, -0.05], self-esteem (ß = -.61, 95% CI [-1.08, -0.27], and tangible social support (ß = -.50, 95% CI [-1.07, -0.02]. CONCLUSIONS: PCEs may protect emotion regulation in adults with ADHD through social support, possibly through facilitating social connections, increasing access to social support, and sustaining emotion regulation strategies.

The Relationship Between Parental and Family Functioning and Post-Concussive Symptoms After Pediatric Mild Traumatic Brain Injury: A Scoping Review.

This scoping review aimed to address the following questions: (1) Does mild traumatic brain injury (mTBI) result in more parental distress or poorer family functioning than other injuries? (2) Does pre-injury or acute parental distress and family functioning predict post-concussive symptoms (PCS) after mTBI? and (3) Do acute PCS predict later parental distress and family functioning? The subjects of this review were children/adolescents who had sustained an mTBI before age 18 and underwent assessment of PCS and parent or family functioning. MEDLINE®, PsycInfo, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, and CENTRAL databases were searched to identify original, empirical, peer-reviewed research published in English. PCS measures included parent- and child-reported symptom counts and continuous scales. Parent and family measures assessed parental stress, psychological adjustment, anxiety, psychiatric history, parent-child interactions, family burden, and general family functioning. A total of 11,163 articles were screened, leading to the inclusion of 15 studies, with 2569 participants (mTBI = 2222; control = 347). Collectively, the included articles suggest that mTBI may not result in greater parental distress or poorer family functioning than other types of injuries. Pre-injury or acute phase parental and family functioning appears to predict subsequent PCS after mTBI, depending on the specific family characteristic being studied. Early PCS may also predict subsequent parental and family functioning, although findings were mixed in terms of predicting more positive or negative family outcomes. The available evidence suggests that parent and family functioning may have an important, perhaps bidirectional, association with PCS after pediatric mTBI. However, further research is needed to provide a more thorough understanding of this association.

Vascular Burden Moderates the Relationship Between ADHD and Cognition in Older Adults.

OBJECTIVES: Recent evidence suggests attention-deficit/hyperactivity disorder (ADHD) is a risk factor for cognitive impairment in later life. Here, we investigated cerebrovascular burden, quantified using white matter hyperintensity (WMH) volumes, as a potential mediator of this relationship. DESIGN: This was a cross-sectional observational study. SETTING: Participants were recruited from a cognitive neurology clinic where they had been referred for cognitive assessment, or from the community. PARTICIPANTS: Thirty-nine older adults with clinical ADHD and 50 age- and gender-matched older adults without ADHD. MEASUREMENTS: A semiautomated structural MRI pipeline was used to quantify periventricular (pWMH) and deep WMH (dWMH) volumes. Cognition was measured using standardized tests of memory, processing speed, visuo-construction, language, and executive functioning. Mediation models, adjusted for sex, were built to test the hypothesis that ADHD status exerts a deleterious impact on cognitive performance via WMH burden. RESULTS: Results did not support a mediated effect of ADHD on cognition. Post hoc inspection of the data rather suggested a moderated effect, which was investigated as an a posteriori hypothesis. These results revealed a significant moderating effect of WMH on the relationship between ADHD memory, speed, and executive functioning, wherein ADHD was negatively associated with cognition at high and medium levels of WMH, but not when WMH volumes were low. CONCLUSIONS: ADHD increases older adults' susceptibility to the deleterious cognitive effects of WMH in the brain. Older adults with ADHD may be at risk for cognitive impairment if they have deep WMH volumes above 61 mm3 and periventricular WMH above 260 mm3.

Risk of neurodegenerative disease or dementia in adults with attention-deficit/hyperactivity disorder: a systematic review.

Purpose of review: Several psychiatric disorders have been associated with an increased risk of developing a neurodegenerative disease and/or dementia. Attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental disorder, has been understudied in relation to dementia risk. We summarized existing literature investigating the risk of incident neurodegenerative disease or dementia associated with ADHD. Recent findings: We searched five databases for cohort, case-control, and clinical trial studies investigating associations between ADHD and neurodegenerative diseases/dementia in May 2023. Study characteristics were extracted by two independent raters, and risk of bias was assessed using the Newcastle Ottawa Scale. Search terms yielded 2,137 articles, and seven studies (five cohort and two case-control studies) ultimately met inclusion criteria. Studies examined the following types of neurodegeneration: all-cause dementia, Alzheimer's disease, Parkinson's and Lewy body diseases, vascular dementia, and mild cognitive impairment. Heterogeneity in study methodology, particularly covariates used in analyses and types of ratios for risk reported, prevented a meta-analysis and data were therefore summarized as a narrative synthesis. The majority of studies (4/7) demonstrated an overall low risk of bias. Summary: The current literature on risk of developing a neurodegenerative disease in ADHD is limited. Although the studies identified present evidence for a link between ADHD and subsequent development of dementia, the magnitude of the direct effect of ADHD on neurodegeneration is yet to be determined and better empirically designed studies are first needed. Furthermore, the mechanism of how or why ADHD is associated with an increased risk of developing a neurocognitive disorder is still unclear and should be explored in future studies. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022348976, the PROSPERO number is CRD42022348976.

Characterizing mild cognitive impairment to predict incident dementia in adults with bipolar disorder: What should the benchmark be?

Objective: Although mild cognitive impairment (MCI) is generally considered a risk state for dementia, its prevalence and association with dementia are impacted by the number of tests and cut-points used to assess cognition and define "impairment," and sources of norms. Here, we investigate how these methodological variations impact estimates of incident dementia in adults with bipolar disorder (BD), a vulnerable population with pre-existing cognitive deficits and increased dementia risk. Method: Neuropsychological data from 148 adults with BD and 13,610 healthy controls (HC) were drawn from the National Alzheimer's Coordinating Center. BD participants' scores were standardized against published norms and again using regression-based norms generated from HC within the same catchment area as individual BD patients ("site-specific norms"), varying the number of within-domain tests (one vs. two) and the cut-points (-1 vs. -1.5 SD) used to operationalize MCI. Results: Site-specific norms were more sensitive to incident dementia (88.6%-94.3%) than published norms (74.3%-88.6%), but only when using a "single test" definition of impairment. Specificity (22.1%-74.3%), accuracy (37.8%-68.9%), and positive predictive values (26.1%-38.3%) were overall poor. Applying a "single test" definition of impairment resulted in better negative predictive values using site-specific (92.3%-93.3%) than published norms (83.6%-86.2%), and a substantial increase in relative risk of incident dementia relative to published norms. Conclusions: Neuropsychologists should define "impairment" as scores below -1.0 or -1.5 SD on at least two within-domain measures when using published norms to interpret cognitive performance in adults with BD.

Sex differences in risk factors that predict progression from mild cognitive impairment to Alzheimer's dementia.

OBJECTIVES: To evaluate whether cerebrospinal fluid biomarkers, apolipoprotein e4, neuroimaging abnormalities, and neuropsychological data differentially predict progression from mild cognitive impairment (MCI) to dementia for men and women. METHODS: Participants who were diagnosed with MCI at baseline (n = 449) were classified as either progressing to Alzheimer's dementia at follow-up or as not progressing. Men and women were first compared using bivariate analyses. Sex-stratified Cox proportional hazard regressions were performed examining the relationship between baseline data and the likelihood of progressing to dementia. Sex interactions were subsequently examined. RESULTS: Cox proportional hazard regression controlling for age and education indicated that all variables significantly predicted subsequent progression to dementia for men and women. Sex interactions indicated that only Rey Auditory Verbal Learning Test (RAVLT) delayed recall and Functional Activities Questionnaire (FAQ) were significantly stronger risk factors for women. When all variables were entered into a fully adjusted model, significant risk factors for women were Aß42, hippocampal volume, RAVLT delayed recall, Boston Naming Test, and FAQ. In contrast, for men, Aß42, p-tau181, p-tau181/Aß42, hippocampal volume, category fluency and FAQ were significant risk factors. Interactions with sex were only significant for p-tau181/Aß42 and RAVLT delayed recall for the fully adjusted model. CONCLUSIONS: Men and women with MCI may to differ for which factors predict subsequent dementia although future analyses with greater power are needed to evaluate sex differences. We hypothesize that brain and cognitive reserve theories may partially explain these findings.

Capturing daily-life executive impairments in adults: Does the choice of neuropsychological tests matter?

OBJECTIVE: Standardized executive functioning (EF) measures do not reliably capture EF-related difficulties reported in daily life. We aim to determine if an ecologically relevant neuropsychological battery is more strongly associated with self-reported everyday EF impairments than classically used tests. METHOD: Fifty-nine adults aged 18-49 self-rated their EF abilities using the Barkley Deficits in EF Scale (BDEFS) and were randomly assigned to complete either a test battery composed of EF measures with hypothesized ecological relevance (Six Elements, Zoo Map, Hayling Sentence Completion, Iowa Gambling, and Auditory Startle Tasks) or one composed of traditional EF tasks (Card Sorting, Trail Making, Color-Word Interference, and Verbal Fluency). Associations were examined using linear regression. RESULTS: There were no strong associations between BDEFS subscales and performance on either test battery. Only the regression model predicting Emotional Regulation from ecological tasks was significant. Iowa Gambling Task performance and corrugator muscle contraction in the Auditory Startle Task individually contributed significantly to the model, with small and moderate effect sizes respectively. CONCLUSION: Results align with evidence that self-reported EF difficulties are not adequately captured by formal neuropsychological measures, even for performance-based measures which directly tap everyday constructs. Findings are interpreted cautiously in the context of a small, high-functioning sample.

Classification Criteria and Rates of Persistent Postconcussive Symptoms in Children: A Systematic Review and Meta-Analysis.

OBJECTIVE: To provide a systematic review of studies examining the proportion of children with persistent postconcussive symptoms (PPCS) and to examine potential moderators of prevalence. STUDY DESIGN: Searches were conducted in MEDLINE, Embase, PsycINFO, Scopus, and Cochrane Central Register of Controlled Trials on April 16, 2020. Criteria for study inclusion were children aged <18 years with concussion or mild traumatic brain injury, operational definition of PPCS, assessment of postconcussive symptoms at least 4 weeks postinjury, sample sizes and proportion with PPCS available, and study published in English. Definition of PPCS, sample size, proportion of participants identified with PPCS, child sex and age at injury, time postinjury, premorbid symptoms, diagnosis (concussion or mild traumatic brain injury), and study publication year were extracted from each article. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Thirteen studies, with a total of 5307 participants, were included in our analysis. The proportion of children identified with PPCS was 35.1% (weighted average; 95% CI, 26.3%-45.0%). The prevalence of PPCS was higher in older and female children who presented for care at concussion clinics, and in more recent publications. CONCLUSIONS: Approximately one-third of children with concussion/mild traumatic brain injury will experience PPCS. Age, sex, and point of care could help identify children at high risk for PPCS.

Cognitive and Neuroimaging Profiles of Older Adults With Attention Deficit/Hyperactivity Disorder Presenting to a Memory Clinic.

OBJECTIVE: Some features of attention-deficit/hyperactivity disorder (ADHD) may resemble those of mild cognitive impairment (MCI) in older adults, contributing to diagnostic uncertainty in individuals seeking assessment in memory clinics. We systematically compared cognition and brain structure in ADHD and MCI to clarify the extent of overlap and identify potential features unique to each. METHOD: Older adults from a Cognitive Neurology clinic (40 ADHD, 29 MCI, 37 controls) underwent neuropsychological assessment. A subsample (n = 80) underwent structural neuroimaging. RESULTS: Memory was impaired in both patient groups, but reflected a storage deficit in MCI (supported by relatively smaller hippocampi) and an encoding deficit in ADHD (supported by frontal lobe thinning). Both groups displayed normal executive functioning. Semantic retrieval was uniquely impaired in MCI. CONCLUSION: Although ADHD has been proposed as a dementia risk factor or prodrome, we propose it is rather a pathophysiologically-unique phenotypic mimic acting via overlap in memory and executive performance.

Longitudinal Cognitive Performance of Older Adults With ADHD Presenting to a Cognitive Neurology Clinic: A Case Series of Change Up to 21 Years.

Background: The neuropsychological features of older adults with ADHD are largely unknown. This retrospective chart review aims to elucidate their cognitive trajectories using a case series of six older adults with ADHD presenting with memory complaints to a cognitive neurology clinic, whom we argue are a particularly relevant group to study due to their potential to mimic neurodegenerative syndromes. Methods: Participants were included if they were age 40 or older at intake, had ADHD based on DSM-5 criteria, and had cognitive data collected prior to 2014 with follow-up at least 5 years later. Results: Five men and one woman were included (M = 53.8 years at intake) and had an average of 135.0 months of follow-up data available. Despite notable between- and within-subject variability, cognition generally improved or remained stable across visits. Two participants experienced notable memory decline, but a global consideration of their performance in other domains suggests these deficits may be frontally-mediated. Conclusion: In this small sample, cognition remained generally unchanged across 5-21 years. Isolated impairments likely reflect substantial intra-individual variability across time and measures.

Contribution of vascular risk factors to the relationship between ADHD symptoms and cognition in adults and seniors.

Symptoms of attention-deficit/hyperactivity disorder (ADHD) in childhood have been found to be predictive of compromised cognitive function, and possibly even dementia, in later adulthood. This study aimed to test vascular risk as a hypothesized moderator or mediator of this association, because individuals with elevated ADHD symptoms frequently have comorbid vascular disease or risk factors which are recognized to contribute to later-life cognitive decline. Data from 1,092 adults aged 18-85 were drawn from the Enhanced Nathan Kline Institute Rockland Sample. Childhood ADHD symptoms (assessed using the Adult ADHD Clinical Diagnostic Scale) were assessed as predictors of cognitive functioning in adulthood (assessed using subtests from the University of Pennsylvania Computerized Neurocognitive Battery, the Delis-Kaplan Executive Functioning System, and the Wechsler Memory Scale). Vascular risk factors (including diabetes, tobacco use, obesity, hypertension, and hypercholesterolemia) were tested as both a moderator and mediator of this relationship. Childhood ADHD symptoms and vascular risk factors were both independently associated with later-life cognition, but vascular risk was not a significant moderator or mediator of relationships between ADHD symptoms and cognition in statistical models. Results from this large community sample suggest that the relationship between ADHD symptoms and cognition is not accounted for by vascular risk. This question should also be investigated in clinical samples.

How Does Dementia Begin to Manifest in Bipolar Disorder? A Description of Prodromal Clinical and Cognitive Changes.

BACKGROUND: Older adults with bipolar disorder (BD) have increased dementia risk, but signs of dementia are difficult to detect in the context of pre-existing deficits inherent to BD. OBJECTIVE: To identify the emergence of indicators of early dementia in BD. METHODS: One hundred and fifty-nine non-demented adults with BD from the National Alzheimer's Coordinating Center (NACC) data repository underwent annual neuropsychological assessment up to 14 years (54.0 months average follow-up). Cognitive performance was examined longitudinally with linear mixed-effects models, and yearly differences between incident dementia cases and controls were examined in the six years prior to diagnosis. RESULTS: Forty participants (25.2%) developed dementia over the follow-up period ('incident dementia cases'). Alzheimer's disease was the most common presumed etiology, though this was likely a result of sampling biases within NACC. Incident dementia cases showed declining trajectories in memory, language, and speeded attention two years prior to dementia onset. CONCLUSION: In a sample of BD patients enriched for Alzheimer's type dementia, prodromal dementia in BD can be detected up to two years before onset using the same cognitive tests used in psychiatrically-healthy older adults (i.e., measures of verbal recall and fluency). Cognition in the natural course of BD is generally stable, and impairment or marked decline on measures of verbal episodic memory or semantic retrieval may indicate an early neurodegenerative process.

Cerebrovascular and Neurodegenerative Pathologies in Long-Term Stable Mild Cognitive Impairment.

BACKGROUND: Mild cognitive impairment (MCI) is considered by some to be a prodromal phase of a progressive disease (i.e., neurodegeneration) resulting in dementia; however, a substantial portion of individuals (ranging from 5-30%) remain cognitively stable over the long term (sMCI). The etiology of sMCI is unclear but may be linked to cerebrovascular disease (CVD), as evidence from longitudinal studies suggest a significant proportion of individuals with vasculopathy remain stable over time. OBJECTIVE: To quantify the presence of neurodegenerative and vascular pathologies in individuals with long-term (>5-year) sMCI, in a preliminary test of the hypothesis that CVD may be a contributor to non-degenerative cognitive impairment. We expect frequent vasculopathy at autopsy in sMCI relative to neurodegenerative disease, and relative to individuals who convert to dementia. METHODS: In this retrospective study, using data from the National Alzheimer's Coordinating Center, individuals with sMCI (n = 28) were compared to those with MCI who declined over a 5 to 9-year period (dMCI; n = 139) on measures of neurodegenerative pathology (i.e., Aß plaques, neurofibrillary tangles, TDP-43, and cerebral amyloid angiopathy) and CVD (infarcts, lacunes, microinfarcts, hemorrhages, and microbleeds). RESULTS: Alzheimer's disease pathology (Aß plaques, neurofibrillary tangles, and cerebral amyloid angiopathy) was significantly higher in the dMCI group than the sMCI group. Microinfarcts were the only vasculopathy associated with group membership; these were more frequent in sMCI. CONCLUSION: The most frequent neuropathology in this sample of long-term sMCI was microinfarcts, tentatively suggesting that silent small vessel disease may characterize non-worsening cognitive impairment.

ADHD and Neurodegenerative Disease Risk: A Critical Examination of the Evidence.

In this review, we undertake a critical appraisal of eight published studies providing first evidence that a history of attention-deficit/hyperactivity disorder (ADHD) may increase risk for the later-life development of a neurodegenerative disease, in particular Lewy body diseases (LBD), by up to five-fold. Most of these studies have used data linked to health records in large population registers and include impressive sample sizes and adequate follow-up periods. We identify a number of methodological limitations as well, including potential diagnostic inaccuracies arising from the use of electronic health records, biases in the measurement of ADHD status and symptoms, and concerns surrounding the representativeness of ADHD and LBD cohorts. Consequently, previously reported risk associations may have been underestimated due to the high likelihood of potentially missed ADHD cases in groups used as "controls", or alternatively previous estimates may be inflated due to the inclusion of confounding comorbidities or non-ADHD cases within "exposed" groups that may have better accounted for dementia risk. Prospective longitudinal studies involving well-characterized cases and controls are recommended to provide some reassurance about the validity of neurodegenerative risk estimates in ADHD.

A Systematic Review and Comparison of Neurocognitive Features of Late-Life Attention-Deficit/Hyperactivity Disorder and Dementia With Lewy Bodies.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) in adulthood and dementia with Lewy bodies (DLB) share many cognitive and noncognitive similarities. The overlapping features between both disorders complicate differential diagnosis. The aim of the current systematic review was to compare patterns of neuropsychological profiles in older adults with ADHD and DLB. METHOD: Of the 1989 ADHD-related articles and 1332 DLB-related articles screened, 3 ADHD and 25 DLB articles were retained for qualitative synthesis and review. RESULTS: A synthesis of individual study findings revealed isolated working memory deficits for late-life ADHD, and performance deficits in areas of attention, memory, language, and visuoperceptual abilities for DLB. Results were limited by small samples and absence of data in some cognitive domains. CONCLUSION: These initial findings support potentially unique neurocognitive profiles for ADHD in later life and DLB that would enable practitioners to differentially diagnose and appropriately treat older adults presenting with these phenotypically similar disorders.

A Call for Research on the Validity of the Age-of-Onset Criterion Application in Older Adults Being Evaluated for ADHD: A Review of the Literature in Clinical and Cognitive Psychology.

Roughly 3% of adults aged 50 years or older experience significant symptoms of attention-deficit/hyperactivity disorder (ADHD). They are often diagnosed for the first time in later adulthood, because ADHD is a relatively new diagnosis with only recent awareness of later-life cases, and because many symptomatic adults have high early-life functioning due to supportive environmental and social structures. Current Diagnostic and Statistical Manual of Mental Disorders-5 criteria require evidence of symptom onset prior to age 12, which rests on self-report in older adults for whom ancillary sources are unavailable or unreliable. In this review, we summarize evidence from several bodies of literature which suggest this criterion may be invalid in older adults. The authors hypothesize that demonstrating childhood symptom onset in older adults is not feasible (i.e., no awareness of ADHD prior to 1970; no good current ancillary sources of childhood behaviors), unreliable (i.e., severely flawed retrospective self-report) and unethical (i.e., unreasonable denial of support to people who need it, with demonstrated poor outcomes associated with untreated ADHD in adults). The authors outline additional research that is needed to establish the validity of self-reported childhood symptom onset in this under-studied demographic, including the identification of contextual factors (perhaps unique to late life) that are associated with the emergence of ADHD symptoms in older adulthood; determining the impact of memory biases on recall of childhood symptoms in older adults with ADHD; quantifying self-perception deficits; and investigating the usefulness of executive functioning rating scales to complement diagnostic assessment in older adults.

Evaluating the Real-World Representativeness of Participants with Mild Cognitive Impairment in Canadian Research Protocols: a Comparison of the Characteristics of a Memory Clinic Patients and Research Samples.

BACKGROUND: Studies of mild cognitive impairment (MCI) employ rigorous eligibility criteria, resulting in sampling that may not be representative of the broader clinical population. OBJECTIVE: To compare the characteristics of MCI patients in a Calgary memory clinic to those of MCI participants in published Canadian studies. METHODS: Clinic participants included 555 MCI patients from the PROspective Registry of Persons with Memory SyMPToms (PROMPT) registry in Calgary. Research participants included 4,981 individuals with MCI pooled from a systematic literature review of 112 original, English-language peer-reviewed Canadian studies. Both samples were compared on baseline sociodemographic variables, medical and psychiatric comorbidities, and cognitive performance for MCI due to Alzheimer's disease and Parkinson's disease. RESULTS: Overall, clinic patients tended to be younger, more often male, and more educated than research participants. Psychiatric disorders, traumatic brain injury, and sensory impairment were commonplace in PROMPT (up to 83% affected) but > 80% studies in the systematic review excluded these conditions. PROMPT patients also performed worse on global cognition measures than did research participants. CONCLUSION: Stringent eligibility criteria in Canadian research studies excluded a considerable subset of MCI patients with comorbid medical or psychiatric conditions. This exclusion may contribute to differences in cognitive performance and outcomes compared to real-world clinical samples.

Operationalizing Impaired Performance in Neuropsychological Assessment: A Comparison of the Use of Published Versus Sample-Based Normative Data for the Prediction of Dementia.

OBJECTIVES: To compare the sensitivity, specificity, and predictive value of published versus sample-based norms to detect early dementia in the Uniform Data Set (UDS). METHODS: The UDS was administered to 526 nondemented participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Baseline scores were standardized using published norms and healthy control data from ADNI corrected for age, education, and sex. Subjects obtaining two scores < -1 SD (determined separately using published and sample norms) were labeled "at risk for dementia." Both methods were compared on sensitivity, specificity, and positive/negative predictive value (PPV/NPV) for dementia at follow-up. RESULTS: Risk scores derived from published data had 86.1% sensitivity, 62.0% specificity, 68.6% accuracy, 46.1% PPV, and 92.2% NPV. Those from sample norms were more sensitive (91.0%), less specific (52.9%), and less accurate (63.3%), with worse PPV (42.1%) and similar NPV (94.0%). Sample norms were better at identifying incident dementia cases with relatively lower education than those with higher education. Discrepancies between both methods were more common in women. CONCLUSIONS: Sample norms are marginally more sensitive than published norms for predicting dementia, while published norms are slightly more accurate. Accuracy of risk estimates for women and those with lower education may be increased using locally generated norms.

Investigating the Association Between Verbal Forgetting and Pathological Markers of Alzheimer's and Lewy Body Diseases.

BACKGROUND: The percentage of verbal forgetting (VF%) measure of the Rey Auditory Verbal Learning Test (RAVLT) has been proposed to differentiate patients diagnosed clinically with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). OBJECTIVE: To determine if VF% aligns with gold-standard biomarker and autopsy evidence of AD and DLB neuropathology. METHODS: Clinical, cognitive, sociodemographic, and biomarker data were collected from 315 patients with baseline cognitive impairment and 485 normal controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). AD markers included reduced cerebrospinal fluid (CSF) amyloid-ß, elevated total-tau and phosphorylated-tau, hippocampal atrophy, and the presence of amyloid plaques and neurofibrillary tangles at autopsy. DLB markers included reduced CSF α-synuclein, preserved hippocampus, atrophied putamen, occipital glucose metabolism, and the presence of Lewy bodies at autopsy. Cognitively impaired participants were classified as ADVF% (n = 190) or DLBVF% (n = 125) based on their RAVLT VF% scores using a 75% cut-off (≥75%  = ADVF%, <75%  = DLBVF%). Postmortem data were available for 13 ADVF% participants, 13 DLBVF% patients, and six healthy controls. RESULTS: ADVF% and DLBVF% participants did not differ on CSF or neuroimaging biomarkers, with the exception of total tau levels which were higher in ADVF%. In the subset of participants with autopsy data, comorbid AD and DLB pathology was most frequent in ADVF% participants, and pure DLB pathology was most frequent in DLBVF% participants, however, these differences were not statistically significant. CONCLUSION: The RAVLT VF% measure does not reliably align with AD and DLB neuropathology in ADNI participants.

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.