APOE Genotype Disclosure Influences Decisions About Future Planning but not Adoption of Healthy Lifestyle Changes in Cognitively Unimpaired Individuals.

BACKGROUND: Studies have shown apolipoprotein E (APOE) genotype disclosure to be safe and well-tolerated in cognitively unimpaired (CU) older adults. This study aimed to examine the effect of the disclosure process on decisions about future directives and health behaviors in community-dwelling CU older adults from the Butler Alzheimer's Prevention Registry (BAPR). METHODS: CU APOE E4 non-carriers (n = 106) and carriers (n = 80) aged 58-78 completed in-person psychological readiness screening to undergo APOE disclosure. Follow-up assessments were completed online 3 days, 6 weeks, and 6 months post-disclosure. The primary outcomes were future directives, dietary habits, and physical activity scores. RESULTS: Disclosure was associated with decision making on future directives in E4 carriers (t = 3.59, P = .01) at 6 months compared to baseline, but not non-carriers. Family history of memory impairment, SCD endorsement, and education consistently predicted scores on future directives. A significant interaction between E4+ and SCD endorsement on future directive scores was noted (OR = 163.06, 9.5-2,799.8). E4 + carrier status was associated with physical activity (W = 60,148, P = .005) but not dietary habits scores. CONCLUSIONS: Our findings indicate that disclosure led to a change in future directives but not protective health behaviors, specifically in E4 carriers. Future work will explore whether pairing disclosure with education about the role of lifestyle factors in AD risk and providing guidelines on making risk-lowering lifestyle modifications as an intervention approach leads to positive change.

Compensatory strategy use in diverse older adults with subjective cognitive complaints.

OBJECTIVES: The current study aimed to evaluate the relationship between subjective cognitive complaints (SCC) and compensatory strategy (CS) use in a diverse sample of non-Latinx White (NLW), Black, and Latinx American older adults. METHOD: 807 older adults (Mage = 65.38, 62.7% female) were recruited through Amazon's Mechanical Turk (MTurk) and Qualtrics Panel to complete questionnaires on SCC and CS use. Kruskall-Wallis tests were used to evaluate differences in SCC across groups given non-normal distributions. Analysis of variance (ANOVA) was used to evaluate group differences in CS use. The PROCESS macro for SPSS was used to examine whether demographic factors moderated the relationship between SCC and CS use. RESULTS: NLWs reported higher levels of SCC and greater overall use of CS in comparison to Latinx and Black individuals. Several demographic and psychosocial factors including age, ethno-racial group, education, and anxiety level were found to be associated with CS use. Education was found to moderate the association between SCC and CS use. CONCLUSION: Inconsistent with prior studies, our study found that NLWs reported the highest levels of SCC. CS were used across all racial/ethnic groups, but the frequency of CS use may be impacted by education level. While all education groups increased their CS in response to higher levels of SCC, this increase was more substantial for those with lower levels of education. Future work should consider individuals' cultural and educational background when examining SCC and/or developing CS-based intervention for the aging population.

Longitudinal post-shunt outcomes in idiopathic normal pressure hydrocephalus with and without comorbid Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) is highly comorbid with idiopathic normal pressure hydrocephalus (iNPH) and may diminish the benefits of shunting; however, findings in this area are mixed. We examined postoperative outcomes, with emphases on cognition and utilization of novel scoring procedures to enhance sensitivity. METHODS: Using participant data from an iNPH outcome study at Butler Hospital, a mixed effect model examined main and interaction effects of time since surgery (baseline, 3 months, 12 months, and 24-60 months) and AD comorbidity (20 iNPH and 11 iNPH+AD) on activities of daily living (ADLs) and iNPH symptoms. Regression modeling explored whether baseline variables predicted improvements 3 months postoperatively. RESULTS: There were no group differences in gait, incontinence, and global cognition over time, and neither group showed changes in ADLs. Cognitive differences were observed postoperatively; iNPH patients showed stable improvements in working memory (p = 0.012) and response inhibition (p = 0.010), while iNPH + AD patients failed to maintain initial gains. Regarding predicting postoperative outcomes, baseline AD biomarkers did not predict shunt response at 3 months; however, older age at surgery predicted poorer cognitive outcomes (p = 0.04), and presurgical Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (p = 0.035) and Mini-Mental Status Examination (MMSE) scores (p = 0.009) predicted improvements incontinence. CONCLUSION: iNPH + AD may be linked with greater declines in aspects of executive functioning postoperatively relative to iNPH alone. While baseline AD pathology may not prognosticate shunt response, younger age appears linked with postsurgical cognitive improvement, and utilizing both brief and comprehensive cognitive measures may help predict improved incontinence. These results illustrate the potential benefits of surgery and inform postoperative expectations for those with iNPH + AD.

Safety and Tolerability of APOE Genotyping and Disclosure in Cognitively Normal Volunteers From the Butler Alzheimer's Prevention Registry.

AIMS: Alzheimer's disease (AD) is a gradually progressive neurodegenerative disease that ultimately results in total loss of cognitive and functional independence in older adults. This study aimed to examine the safety and tolerability of APOE disclosure in community-dwelling, cognitively normal (CN) older adults from the Butler Alzheimer's Prevention Registry (BAPR), and to determine whether APOE disclosure impacted participant's decisions to participate in AD clinical research. METHODS: 186 (N = 106 ∊4 non-carriers, 80 ∊4 carriers) CN older adults aged 58-78 from the BAPR completed 2 visits: one for psychological readiness screening and genotyping and one for APOE disclosure. Online follow-ups were completed 3 days, 6 weeks, and 6 months post-disclosure. Primary outcomes were scores on self-report measures of depression, anxiety, impact of events, and perceived risk of AD, along with enrollment in AD clinical trials. RESULTS: ∊4 carriers and non-carriers did not differ significantly on measures of depression, anxiety, or suicidal ideation over the 6-month follow-up period. ∊4 carriers reported higher impact of disclosure than non-carriers immediately after disclosure, but both groups' scores on impact of events measures remained sub-clinical. ∊4 carriers and non-carriers were equally likely to participate in AD research after disclosure, with genotype-dependent differences in type of clinical trial enrollment. CONCLUSIONS: APOE genotyping and disclosure was safe and well tolerated in a group of CN, community-dwelling older adults, who were pre-screened after volunteering for AD research through BAPR. Implications for the inclusion of APOE genotyping and disclosure at AD clinical trial sites are discussed.

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease.

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.

Frontal Behavior Syndromes in Idiopathic Normal Pressure Hydrocephalus as a Function of Alzheimer's Disease Biomarker Status.

OBJECTIVES: Cognitive impairment and apathy are well-documented features of idiopathic normal pressure hydrocephalus (iNPH). However, research examining other neuropsychiatric manifestations of iNPH is scant, and it is unknown whether the neuropsychiatric presentation differs for iNPH patients with comorbid Alzheimer's disease (AD) versus iNPH without AD. This study aims to advance our understanding of neuropsychiatric syndromes associated with iNPH. METHODS: Fifty patients from Butler Hospital's Normal Pressure Hydrocephalus Clinic met inclusion criteria. Caregiver ratings on the Frontal Systems Behavior Scale (FrSBe) were examined to appraise changes in apathy, executive dysfunction, and disinhibition. Patients also completed cognitive tests of global cognition, psychomotor speed, and executive functioning. AD biomarker status was determined by either amyloid-beta (Aß) positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) total tau to Aß-42 ratio. RESULTS: Results revealed clinically significant elevations on the FrSBe's apathy and executive dysfunction scales and modest correlations among these scales and cognitive measures. Of the 44 patients with available neuroimaging or CSF draw data, 14 presented with comorbid AD. Relative to the iNPH-only group, the iNPH + AD group showed a larger increase from pre-illness to current informant ratings on the executive dysfunction scale, but not the apathy or disinhibition scales. CONCLUSIONS: These results replicate and extend prior research by identifying apathy and executive dysfunction as prominent neuropsychiatric symptoms of iNPH and suggest comorbid AD exacerbates dysexecutive behaviors. Future research is warranted to examine the effects of comorbid AD pathology in response to shunt surgery for iNPH, neuropsychiatric symptom changes, and resultant caregiver burden.

Discrepancy-Based Evidence for Loss of Thinking Abilities (DELTA): Development and Validation of a Novel Approach to Identifying Cognitive Changes.

OBJECTIVE: To develop and validate the Discrepancy-based Evidence for Loss of Thinking Abilities (DELTA) score. The DELTA score characterizes the strength of evidence for cognitive decline on a continuous spectrum using well-established psychometric principles for improving detection of cognitive changes. METHODS: DELTA score development used neuropsychological test scores from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (two tests each from Memory, Executive Function, and Language domains). We derived regression-based normative reference scores using age, gender, years of education, and word-reading ability from robust cognitively normal ADNI participants. Discrepancies between predicted and observed scores were used for calculating the DELTA score (range 0-15). We validated DELTA scores primarily against longitudinal Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Functional Activities Questionnaire (FAQ) scores (baseline assessment through Year 3) using linear mixed models and secondarily against cross-sectional Alzheimer's biomarkers. RESULTS: There were 1359 ADNI participants with calculable baseline DELTA scores (age 73.7 ± 7.1 years, 55.4% female, 100% white/Caucasian). Higher baseline DELTA scores (stronger evidence of cognitive decline) predicted higher baseline CDR-SOB (ΔR2 = .318) and faster rates of CDR-SOB increase over time (ΔR2 = .209). Longitudinal changes in DELTA scores tracked closely and in the same direction as CDR-SOB scores (fixed and random effects of mean + mean-centered DELTA, ΔR2 > .7). Results were similar for FAQ scores. High DELTA scores predicted higher PET-Aß SUVr (ρ = 324), higher CSF-pTau/CSF-Aß ratio (ρ = .460), and demonstrated PPV > .9 for positive Alzheimer's disease biomarker classification. CONCLUSIONS: Data support initial development and validation of the DELTA score through its associations with longitudinal functional changes and Alzheimer's biomarkers. We provide several considerations for future research and include an automated scoring program for clinical use.

Added value of inflammatory plasma biomarkers to pathologic biomarkers in predicting preclinical Alzheimer's disease.

BACKGROUND: Plasma biomarkers have recently emerged for the diagnosis, assessment, and disease monitoring of Alzheimer's disease (AD), but have yet to be fully validated in preclinical AD. In addition to AD pathologic plasma biomarkers (amyloid-ß (Aß) and phosphorylated tau (p-tau) species), a proteomic panel can discriminate between symptomatic AD and cognitively unimpaired older adults in a dementia clinic population. OBJECTIVE: Examine the added value of a plasma proteomic panel, validated in symptomatic AD, over standard AD pathologic plasma biomarkers and demographic and genetic (apolipoprotein (APOE) ɛ4 status) risk factors in detecting preclinical AD. METHODS: 125 cognitively unimpaired older adults (mean age = 66 years) who completed Aß PET and plasma draw were analyzed using multiple regression with Aß PET status (positive versus negative) as the outcome to determine the best fit for predicting preclinical AD. Model 1 included age, education, and gender. Model 2 and 3 added predictors APOE ɛ4 status (carrier versus non-carrier) and AD pathologic blood biomarkers (Aß42/40 ratio, p-tau181), respectively. Random forest modeling established the 5 proteomic markers from the proteomic panel that best predicted Aß PET status, and these markers were added in Model 4. RESULTS: The best model for predicting Aß PET status included age, years of education, APOE ɛ4 status, Aß42/40 ratio, and p-tau181. Adding the top 5 proteomic markers did not significantly improve the model. CONCLUSIONS: Proteomic markers in plasma did not add predictive value to standard AD pathologic plasma biomarkers in predicting preclinical AD in this sample.

Related amyloid burden and cortical atrophy in individuals with subtle cognitive decline.

BACKGROUND AND PURPOSE: Subtle cognitive decline represents a stage of cognitive deterioration in which pathological biomarkers may be present, including early cortical atrophy and amyloid deposition. Using individual items from the Montreal Cognitive Assessment and k-modes cluster analysis, we previously identified three clusters of individuals without overt cognitive impairment: (1) High Performing (no deficits in performance), (2) Memory Deficits (lower memory performance), and (3) Compound Deficits (lower memory and executive function performance). In this study, we sought to understand the relationships found in our clusters between cortical atrophy on MR and amyloid burden on PET. METHODS: Data were derived from the Alzheimer's Disease Neuroimaging Initiative and comprised individuals from our previous analyses with available MR and amyloid PET scans (n = 272). Using multiple-group structural equation modeling, we regressed amyloid standardized uptake value ratio on volumetric regions to simultaneously evaluate unique associations within each cluster. RESULTS: In our Compound Deficits cluster, greater whole cerebral amyloid burden was significantly related to right entorhinal cortical and left hippocampal atrophy, rs  = -.412 (p = .005) and -.304 (p = .049), respectively. Within this cluster, right entorhinal cortical atrophy was significantly related to greater amyloid burden within multiple frontal regions. CONCLUSIONS: The Compound Deficits cluster, which represents a group potentially at higher risk for decline, was observed to have significantly more cortical atrophy, particularly within the entorhinal cortex and hippocampus, associated with whole brain and frontal lobe amyloid burden. These findings point to a pattern of early pathological deterioration that may place these individuals at risk for future decline.

Using the Montreal cognitive assessment to identify individuals with subtle cognitive decline.

OBJECTIVE: Dementia is a devastating neurological disease that may be better managed if diagnosed earlier when subclinical neurodegenerative changes are already present, including subtle cognitive decline and mild cognitive impairment. In this study, we used item-level performance on the Montreal Cognitive Assessment (MoCA) to identify individuals with subtle cognitive decline. METHOD: Individual MoCA item data from the Alzheimer's Disease Neuroimaging Initiative was grouped using k-modes cluster analysis. These clusters were validated and examined for association with convergent neuropsychological tests. The clusters were then compared and characterized using multinomial logistic regression. RESULTS: A three-cluster solution had 77.3% precision, with Cluster 1 (high performing) displaying no deficits in performance, Cluster 2 (memory deficits) displaying lower memory performance, and Cluster 3 (compound deficits) displaying lower performance on memory and executive function. Age at MoCA (older in compound deficits), gender (more females in memory deficits), and marital status (fewer married in compound deficits) were significantly different among clusters. Age was not associated with increased odds of membership in the high-performing cluster compared to the others. CONCLUSIONS: We identified three clusters of individuals classified as cognitively unimpaired using cluster analysis. Individuals in the compound deficits cluster performed lower on the MoCA and were older and less often married than individuals in other clusters. Demographic analyses suggest that cluster identity was due to a combination of both cognitive and clinical factors. Identifying individuals at risk for future cognitive decline using the MoCA could help them receive earlier evidence-based interventions to slow further cognitive decline. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A Neuropsychological Perspective on Defining Cognitive Impairment in the Clinical Study of Alzheimer's Disease: Towards a More Continuous Approach.

The global fight against Alzheimer's disease (AD) poses unique challenges for the field of neuropsychology. Along with the increased focus on early detection of AD pathophysiology, characterizing the earliest clinical stage of the disease has become a priority. We believe this is an important time for neuropsychology to consider how our approach to the characterization of cognitive impairment can be improved to detect subtle cognitive changes during early-stage AD. The present article aims to provide a critical examination of how we define and measure cognitive status in the context of aging and AD. First, we discuss pitfalls of current methods for defining cognitive impairment within the context of research shifting to earlier (pre)symptomatic disease stages. Next, we introduce a shift towards a more continuous approach for identifying early markers of cognitive decline and characterizing progression and discuss how this may be facilitated by novel assessment approaches. Finally, we summarize potential implications and challenges of characterizing cognitive status using a continuous approach.

Prefrontal regional correlates of self-control in male psychiatric patients: Impulsivity facets and aggression.

Investigating the organization of trait aggression and impulsivity in the prefrontal cortex (PFC) advances our understanding of the neuropsychobiology of self-control. While the orbital aspect of the PFC (OFC) has received attention, there is reason to believe the lateral aspect is also relevant. In the current study using magnetic resonance imaging, gray matter volumes in lateral PFC (LPFC) were derived in a heterogeneous male psychiatric sample (N=36) in which OFC volumes had previously been reported. In an analysis using self-report measures of trait impulsivity and aggression, the left LPFC accounted for significant variance in attentional aspects of impulsivity (13%) and aggression (10%) but not motor aspects of impulsivity, as hypothesized. The OFC was associated with motor impulsivity (left-20%; right-14%) and was also more robustly associated with aggression (left-36%; right-16%). A social/emotional information processing model was explored, based upon whether the LPFC or the OFC depended upon one another for their association to trait aggression and impulsivity. It was demonstrated that association of the LPFC to both aggression and attentional impulsivity depended upon the OFC, while the converse was not supported. The LPFC appears relevant to the higher-order aspects of a cortical self-control network, and that relevance is dependent upon the robust contribution of the OFC.

Adding cognition to AT(N) models improves prediction of cognitive and functional decline.

INTRODUCTION: This study sought to determine whether adding cognition to a model with Alzheimer's disease biomarkers based on the amyloid, tau, and neurodegeneration/neuronal injury-AT(N)-biomarker framework predicts rates of cognitive and functional decline in older adults without dementia. METHODS: The study included 465 participants who completed amyloid positron emission tomography, cerebrospinal fluid phosphorylated tau, structural magnetic resonance imaging, and serial neuropsychological testing. Using the AT(N) framework and a newly validated cognitive metric as the independent variables, we used linear mixed effects models to examine a 4-year rate of change in cognitive and functional measures. RESULTS: The inclusion of baseline cognitive status improved model fit in predicting rate of decline in outcomes above and beyond biomarker variables. Specifically, those with worse cognitive functioning at baseline had faster rates of memory and functional decline over a 4-year period, even when accounting for AT(N). DISCUSSION: Including a newly validated measure of baseline cognition may improve clinical prognosis in non-demented older adults beyond the use of AT(N) biomarkers alone.

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.

OBJECTIVE: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD). METHODS: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease. RESULTS: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year). CONCLUSION: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.

The influence of diversity on the measurement of functional impairment: An international validation of the Amsterdam IADL Questionnaire in eight countries.

INTRODUCTION: To understand the potential influence of diversity on the measurement of functional impairment in dementia, we aimed to investigate possible bias caused by age, gender, education, and cultural differences. METHODS: A total of 3571 individuals (67.1 ± 9.5 years old, 44.7% female) from The Netherlands, Spain, France, United States, United Kingdom, Greece, Serbia, and Finland were included. Functional impairment was measured using the Amsterdam Instrumental Activities of Daily Living (IADL) Questionnaire. Item bias was assessed using differential item functioning (DIF) analysis. RESULTS: There were some differences in activity endorsement. A few items showed statistically significant DIF. However, there was no evidence of meaningful item bias: Effect sizes were low (ΔR 2 range 0-0.03). Impact on total scores was minimal. DISCUSSION: The results imply a limited bias for age, gender, education, and culture in the measurement of functional impairment. This study provides an important step in recognizing the potential influence of diversity on primary outcomes in dementia research.

Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease.

Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (nADRC = 381; nDIAN = 145), preclinical (nADRC = 153; nDIAN = 76), and cognitively impaired (nADRC = 54; nDIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11C-Pittsburgh compound B or 18F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.

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.

Relationship of mindful awareness to neural processing of angry faces and impact of mindfulness training: A pilot investigation.

Mindfulness is paying attention, non-judgmentally, to experience in the moment. Mindfulness training reduces depression and anxiety and influences neural processes in midline self-referential and lateralized somatosensory and executive networks. Although mindfulness benefits emotion regulation, less is known about its relationship to anger and the corresponding neural correlates. This study examined the relationship of mindful awareness and brain hemodynamics of angry face processing, and the impact of mindfulness training. Eighteen healthy volunteers completed an angry face processing fMRI paradigm and measurement of mindfulness and anger traits. Ten of these participants were recruited from a Mindfulness-Based Stress Reduction (MBSR) class and also completed imaging and other assessments post-training. Self-reported mindful awareness increased after MBSR, but trait anger did not change. Baseline mindful awareness was negatively related to left inferior parietal lobule activation to angry faces; trait anger was positively related to right middle frontal gyrus and bilateral angular gyrus. No significant pre-post changes in angry face processing were found, but changes in trait mindful awareness and anger were associated with sub-threshold differences in paralimbic activation. These preliminary and hypothesis-generating findings, suggest the analysis of possible impact of mindfulness training on anger may begin with individual differences in angry face processing.

The neural correlates of the dominance dimension of emotion.

Emotion has been conceptualized as a dimensional construct, while the number of dimensions - two or three - has been debated. Research has consistently identified two dimensions - valence and arousal - though ample evidence exists that three dimensions are necessary to describe emotion. One proposed third dimension, identified as dominance, is relevant in clinical syndromes, personality and consumer psychology. Dominance refers to an individual's sense of having an ability to affect the environment. Neuroimaging studies have generally focused on the two dimensions of valence and arousal, leaving the neural correlates of dominance unexplored. The current study used functional magnetic resonance imaging to explore the neural basis of dominance in 17 healthy male controls. Participants viewed images from the International Affective Picture System that were selected to represent high and low dominance conditions. Results indicated activation in paralimbic regions, including the bilateral anterior insula for high dominance and the right precuneus for low. The findings of this exploratory study support the consideration of dominance in dimensional models of emotion and suggest that further research is needed to understand the neural representation of dominance in emotional experience.

The driving competence of 90-year-old drivers: from a hospital-based driving clinic.

OBJECTIVES: To compare the performance on a standardized driving evaluation of a group of oldest old adults (age 90-97) against younger old adults (age 80-87) and examine whether the same cognitive variables and brake reaction time performance were associated with pass-fail status on a road test in both groups. Secondary objectives focused on an examination of the specific driving errors of both groups. METHODS: This retrospective cohort study was conducted in the setting of a clinical driving evaluation program at an academic medical center in the United States. In this study we examined the performance of 88 participants (27 age 90-97 and 61 age 80-87) who completed comprehensive driving evaluations between 1997 and 2011. The outcome variable was performance on a standardized road test. Measures included the Trail Making Test (TMT), the Mini Mental State Examination (MMSE), and brake reaction time (BRT). An exploratory analysis of the possible predictive value of specific MMSE subtests was also performed. RESULTS: Results indicate that the oldest old adults (90-97 years old) were at no greater driving risk than were a younger old (80-87 years old) cohort and made similar types and frequency of driving errors. TMT-B time was associated with pass-fail status in both groups. MMSE attention items discriminated between safe and unsafe younger old drivers, and MMSE orientation items were associated with pass-fail status in the oldest old cohort. CONCLUSION: Drivers age 90 and above were at no greater driving risk than those one decade younger. MMSE orientation questions may be useful to assist in identifying which oldest old drivers could benefit from a comprehensive driving evaluation including an on-road test.