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.

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.

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.

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 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.

Neural correlates of impulsivity factors in psychiatric patients and healthy volunteers: a voxel-based morphometry study.

According to bottom-up/top-down models, impulsivity facets are represented across the cerebral cortex and subcortex. Hypothesized gray matter correlates of motor, attentional and non-planning impulsivity were examined in groups of 35 psychiatric patients characterized by self-control problems and 18 healthy volunteers. Among patients, a positive correlation was found between motor impulsivity and the right cerebellum, and a negative correlation emerged between attentional impulsivity and the left lateral orbitofrontal cortex (OFC). Among controls, attentional and motor impulsivity correlated negatively with the left superior temporal gyrus, while non-planning impulsivity correlated positively with the left OFC and lateral frontopolar cortex. Follow-up analyses revealed convergence in correlation patterns from patients to controls, but not vice versa. That pattern suggested broader neural representation of the trait in the healthy controls, who were less impulsive than the psychiatric patients.

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.