Preliminary Validation of the Global Neuropsychological Assessment in Alzheimer's Disease and Healthy Volunteers.

METHODS: We administered the Global Neuropsychological Assessment (GNA), an abbreviated cognitive battery, to 105 adults aged 73.0 ± 7.1 years, including 28 with probable Alzheimer's disease, 9 with amnestic mild cognitive impairment, and 68 healthy controls. We examined group differences in baseline performance, test-retest reliability, and correlations with other conventional tests. RESULTS: Healthy adults outperformed patients on all five GNA subtests. Test-retest intraclass correlation coefficients were significant for all GNA subtests. Among patients with healthy controls, GNA Story Memory correlated best with Wechsler Memory Scale-Revised (WMS-R) Logical Memory for learning and delayed recall, GNA Digit Span correlated most highly with the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) Digit Span, GNA Perceptual Comparison correlated most highly with the Trail Making Test, and GNA Animal Naming correlated most highly with Supermarket Item Naming. CONCLUSIONS: Preliminary findings suggest that the GNA shows good test-retest validity, clear convergent and discriminant construct validity, and excellent diagnostic criterion validity for dementia and mild cognitive impairment in an American sample.

Event-Related Potentials, Inhibition, and Risk for Alzheimer's Disease Among Cognitively Intact Elders.

BACKGROUND: Despite advances in understanding Alzheimer's disease (AD), prediction of AD prior to symptom onset remains severely limited, even when primary risk factors such as the apolipoprotein E (APOE) ɛ4 allele are known. OBJECTIVE: Although executive dysfunction is highly prevalent and is a primary contributor to loss of independence in those with AD, few studies have examined neural differences underlying executive functioning as indicators of risk for AD prior to symptom onset, when intervention might be effective. METHODS: This study examined event-related potential (ERP) differences during inhibitory control in 44 cognitively intact older adults (20 ɛ4+, 24 ɛ4-), relative to 41 young adults. All participants completed go/no-go and stop-signal tasks. RESULTS: Overall, both older adult groups exhibited slower reaction times and longer ERP latencies compared to young adults. Older adults also had generally smaller N200 and P300 amplitudes, except at frontal electrodes and for N200 stop-signal amplitudes, which were larger in older adults. Considered with intact task accuracy, these findings suggest age-related neural compensation. Although ɛ4 did not distinguish elders during go or no-go tasks, this study uniquely showed that the more demanding stop-signal task was sensitive to ɛ4 differences, despite comparable task and neuropsychological performance with non-carriers. Specifically, ɛ4+ elders had slower frontal N200 latency and larger N200 amplitude, which was most robust at frontal sites, compared with ɛ4-. CONCLUSION: N200 during a stop-signal task is sensitive to AD risk, prior to any evidence of cognitive dysfunction, suggesting that stop-signal ERPs may be an important protocol addition to neuropsychological testing.

Executive functioning and risk for Alzheimer's disease in the cognitively intact: Family history predicts Wisconsin Card Sorting Test performance.

OBJECTIVE: Alzheimer's disease (AD) research typically focuses on memory. However, executive functioning (EF) deficits are also common among AD patients; these deficits are associated with decreased functioning in activities of daily living, an important criterion in diagnosing AD. A classic test of EF ability, the Wisconsin Card Sort Test (WCST), has demonstrated sensitivity to differentiating individuals with AD from healthy controls, discriminating AD groups based on disease severity, and distinguishing AD from other types of dementia. Such sensitivity to AD raises the possibility that the WCST is also sensitive to very early, preclinical differences between those who have heightened risk for AD and those with lower risks. METHOD: The current study, therefore, examined WCST performance in healthy, cognitively intact older adults with a first-degree (i.e., sibling or parent) family history (FH) of AD (n = 18) and those with no such FH of AD (n = 24). RESULTS: Results revealed significant group differences for Categories Achieved, Percent Conceptual Level Responses, Total Errors, Perseverative Errors, and Non-Perseverative Errors, with the FH+ group consistently exhibiting poorer performance. Moreover, hierarchical regression analyses indicated that after accounting for age, sex, and education, FH significantly predicted all 5 of these variables. CONCLUSIONS: These results speak to the potential role of EF in bolstering the current understanding of early cognitive markers of future decline. Furthering what is known about the relationship between AD and nonmemory specific domains of cognition such as executive functioning may allow for better prediction of cognitive decline and potential progression to AD.

Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease.

We examined the impact of physical activity (PA) on longitudinal change in hippocampal volume in cognitively intact older adults at varying genetic risk for the sporadic form of Alzheimer's disease (AD). Hippocampal volume was measured from structural magnetic resonance imaging (MRI) scans administered at baseline and at an 18-month follow-up in 97 healthy, cognitively intact older adults. Participants were classified as High or Low PA based on a self-report questionnaire of frequency and intensity of exercise. Risk status was defined by the presence or absence of the apolipoprotein E-epsilon 4 (APOE-ε4) allele. Four subgroups were studied: Low Risk/High PA (n = 24), Low Risk/Low PA (n = 34), High Risk/High PA (n = 22), and High Risk/Low PA (n = 17). Over the 18 month follow-up interval, hippocampal volume decreased by 3% in the High Risk/Low PA group, but remained stable in the three remaining groups. No main effects or interactions between genetic risk and PA were observed in control brain regions, including the caudate, amygdala, thalamus, pre-central gyrus, caudal middle frontal gyrus, cortical white matter (WM), and total gray matter (GM). These findings suggest that PA may help to preserve hippocampal volume in individuals at increased genetic risk for AD. The protective effects of PA on hippocampal atrophy were not observed in individuals at low risk for AD. These data suggest that individuals at genetic risk for AD should be targeted for increased levels of PA as a means of reducing atrophy in a brain region critical for the formation of episodic memories.

Frontal theta reflects uncertainty and unexpectedness during exploration and exploitation.

In order to understand the exploitation/exploration trade-off in reinforcement learning, previous theoretical and empirical accounts have suggested that increased uncertainty may precede the decision to explore an alternative option. To date, the neural mechanisms that support the strategic application of uncertainty-driven exploration remain underspecified. In this study, electroencephalography (EEG) was used to assess trial-to-trial dynamics relevant to exploration and exploitation. Theta-band activities over middle and lateral frontal areas have previously been implicated in EEG studies of reinforcement learning and strategic control. It was hypothesized that these areas may interact during top-down strategic behavioral control involved in exploratory choices. Here, we used a dynamic reward-learning task and an associated mathematical model that predicted individual response times. This reinforcement-learning model generated value-based prediction errors and trial-by-trial estimates of exploration as a function of uncertainty. Mid-frontal theta power correlated with unsigned prediction error, although negative prediction errors had greater power overall. Trial-to-trial variations in response-locked frontal theta were linearly related to relative uncertainty and were larger in individuals who used uncertainty to guide exploration. This finding suggests that theta-band activities reflect prefrontal-directed strategic control during exploratory choices.

Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold.

It takes effort and time to tame one's impulses. Although medial prefrontal cortex (mPFC) is broadly implicated in effortful control over behavior, the subthalamic nucleus (STN) is specifically thought to contribute by acting as a brake on cortico-striatal function during decision conflict, buying time until the right decision can be made. Using the drift diffusion model of decision making, we found that trial-to-trial increases in mPFC activity (EEG theta power, 4-8 Hz) were related to an increased threshold for evidence accumulation (decision threshold) as a function of conflict. Deep brain stimulation of the STN in individuals with Parkinson's disease reversed this relationship, resulting in impulsive choice. In addition, intracranial recordings of the STN area revealed increased activity (2.5-5 Hz) during these same high-conflict decisions. Activity in these slow frequency bands may reflect a neural substrate for cortico-basal ganglia communication regulating decision processes.

Task-related dissociation in ERN amplitude as a function of obsessive-compulsive symptoms.

Hyperactive cortico-striatal circuits including the anterior cingulate cortex (ACC) have been implicated to underlie obtrusive thoughts and repetitive behaviors in obsessive-compulsive disorder (OCD). Larger error-related negativities (ERNs) in OCD patients during simple flanker tasks have been proposed to reflect an amplified error signal in these hyperactive circuits. Such amplified error signals typically are associated with an adaptive change in response, yet in OCD these same repetitive responses persist to the point of distress and impairment. In contrast to this repetitive character of OC behavior, larger ERN amplitudes have been linked to better avoidance learning in reinforcement learning tasks. Study I thus investigated if OC symptomatology in non-patients predicted an enhanced ERN after suboptimal choices in a probabilistic learning task. Absent any behavioral differences, higher OC symptoms predicted smaller ERNs. Study II replicated this effect in an independent sample while also replicating findings of a larger ERN in a flanker task. There were no relevant behavioral differences in reinforcement learning or error monitoring as a function of symptom score. These findings implicate different, yet overlapping neural mechanisms underlying the negative deflection in the ERP following the execution of an erroneous motor response and the one following a suboptimal choice in a reinforcement learning paradigm. OC symptomatology may be dissociated in these neural systems, with hypoactivity in a system that enables learning to avoid maladaptive choices, and hyperactivity in another system that enables the same behavior to be repeated when it was assessed as not quite good enough the first time.