A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity.

BACKGROUND: Dopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans. METHODS: Using a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons. RESULTS: Nominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562-treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate. CONCLUSIONS: PF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period. CLINICALTRIALS.GOV IDENTIFIER: NCT02306876.

Deficits in Everyday Function Differ in AD and FTD.

Alzheimer disease (AD) and frontotemporal dementia (FTD) are 2 neurodegenerative diseases with differing cognitive and neuropathologic profiles. Although both diseases ultimately result in functional disability, differences in the profiles of everyday functioning between the 2 groups have not been well characterized. The present study examines potential differences in the types of everyday functional limitations present in these 2 dementias. The present study compared individuals with AD (N=240) or FTD (N=13). The Everyday Cognition (ECog) scale was used to measure distinct domains of everyday cognition: everyday memory, everyday language, everyday visuospatial ability, and a variety of everyday executive abilities. A total ECog score was used to represent global disability level. The groups showed equivalent levels of global disability. However, AD group exhibited worse Everyday Memory and Everyday Visuospatial abilities than the FTD group. Contrary to expectation, FTD was not more impaired in everyday executive abilities. Results remained similar when accounting for severity of cognitive impairment or disease duration. Findings suggest that a somewhat different pattern of everyday functional difficulties can be seen across dementia types.

Everyday cognition in older adults: associations with neuropsychological performance and structural brain imaging.

The recently developed Everyday Cognition scales (ECog) measure multiple cognitively relevant functional domains (e.g., Everyday Memory, Everyday Language, Everyday Visuospatial abilities, and three everyday executive domains). The present study further evaluated the validity of the ECog by examining its relationship with objective measures of neuropsychological function, and neurobiological markers of disease as reflected by structural neuroimaging. Participants included 474 older adults (244 normals, 142 with MCI, 88 with dementia). The neuropsychological domains measured were episodic memory, semantic memory, spatial ability, and executive functioning. Brain MRI volumes included total brain (BV), hippocampus (HC) and dorsolateral prefrontal cortex (DLPFC). Neuropsychological measures of episodic memory and executive function were most consistently related to the ECog domains; spatial abilities had a specific relationship to the Everyday Visuospatial ECog domain. HC and BV volumes were related to most ECog domains, while DLPFC volume was independently related to two everyday executive domains (Everyday Planning and Everyday Organization). The pattern of associations varied somewhat as a function of diagnosis. Episodic memory and HC had more consistent associations with the ECog domains in older adults with MCI/dementia than in cognitively normal elderly.

The independent contributions of cognitive impairment and neuropsychiatric symptoms to everyday function in older adults.

The everyday functional capacities of older adults are determined by multiple factors. The primary goal of the present study was to evaluate whether apathy and depression have unique influences on degree of functional impairment, independent of the effects of specific cognitive impairments. Participants included 344 older adults (199 normal, 87 with MCI, 58 with dementia). The Everyday Cognition (ECog) scales were used to measure both global and domain-specific functional abilities. Neuropsychiatric symptoms of depression and apathy were measured by the Neuropsychiatric Inventory (NPI), and specific neuropsychological domains measured included episodic memory and executive functioning. Results indicated that worse memory and executive function, as well as greater depression and apathy, were all independent and additive determinants of poorer functional abilities. Apathy had a slightly more restricted effect than the other variables across the specific functional domains assessed. Secondary analysis suggested that neuropsychiatric symptoms may be more strongly associated with everyday function within cognitively normal and MCI groups, while cognitive impairment is more strongly associated with everyday function in dementia. Thus, a somewhat different set of factors may be associated with functional status across various clinical groups.

Longitudinal trajectories of everyday function by diagnostic status.

Generalized linear mixed models were used to examine longitudinal trajectories of everyday functional limitations by diagnostic stability/progression. Older adults (N = 384) were followed an average 3.6 years; participants were grouped by diagnosis at study baseline and last follow-up (normal cognition, Mild Cognitive Impairment, or dementia at each time point). At study baseline there were clear group differences; most notably among participants initially characterized as cognitively normal, those who developed Mild Cognitive Impairment or dementia over follow-up already demonstrated greater functional impairment compared with those who remained cognitively normal. Change in functional impairment progressed slowly in the early disease groups, but showed an accelerated worsening in those converting to dementia.

Demographic predictors of cognitive change in ethnically diverse older persons.

The purpose of this study was to evaluate how demographic variables relate to cognitive change and address whether cross-sectional demographic effects on cognitive tests are mirrored in differences in longitudinal trajectories of cognitive decline. We hypothesized that race and ethnicity, education, and language of test administration would relate to cross-sectional status and that the rate of cognitive decline would differ among African Americans, Hispanics, and Caucasians, across levels of educational attainment, and according to linguistic background. Participants were 404 educationally, ethnically, and cognitively diverse older adults enrolled in an ongoing longitudinal study of cognition. Mixed-effects regression analysis was used to measure baseline status and longitudinal change in episodic memory, executive functioning, and semantic memory. Results showed that ethnicity and education were strongly associated with baseline scores, but were, at most, weakly associated with change in cognition over time after accounting for confounding variables. There was evidence that the episodic-memory scores of Spanish-speaking Hispanic participants with limited education underestimated their true abilities in the initial evaluation, which may reflect lack of familiarity with the testing environment. These results--consistent with other reports in the literature--suggest that cross-sectional effects of demographic variables on cognitive-test scores result from differences in life experiences that directly influence test performance and do not indicate greater disease effects on cognition in minorities and those with limited education.

Interrater reliability of the new criteria for behavioral variant frontotemporal dementia.

OBJECTIVE: To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD). METHODS: Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings. RESULTS: The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD ("almost perfect agreement"). Interrater reliability for 4 of the 6 core features had "substantial" agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61-0.80), whereas 2 had "moderate" agreement (apathy/inertia, neuropsychological; κ = 0.41-0.6). Clinician years of experience did not significantly influence rater accuracy. CONCLUSIONS: The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

Longitudinal change in neuropsychological performance using latent growth models: a study of mild cognitive impairment.

The goal of the current study was to examine cognitive change in both healthy controls (n = 229) and individuals with mild cognitive impairment (MCI) (n = 397) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We applied latent growth modeling to examine baseline and longitudinal change over 36 months in five cognitive factors derived from the ADNI neuropsychological test battery (memory, executive function/processing speed, language, attention and visuospatial). At baseline, MCI patients demonstrated lower performance on all of the five cognitive factors when compared to controls. Both controls and MCI patients declined on memory over 36 months; however, the MCI patients declined at a significantly faster rate than controls. The MCI patients also declined over 36 months on the remaining four cognitive factors. In contrast, the controls did not exhibit significant change over 36 months on the non-memory cognitive factors. Within the MCI group, executive function declined faster than memory, while the other factor scores changed slower than memory over time. These findings suggest different patterns of cognitive change in healthy older adults and MCI patients. The findings also suggest that, when compared with memory, executive function declines faster than other cognitive factors in patients with MCI. Thus, decline in non-memory domains may be an important feature for distinguishing healthy older adults and persons with MCI.

Confirmatory factor analysis of the ADNI Neuropsychological Battery.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a large multi-center study designed to develop optimized methods for acquiring longitudinal neuroimaging, cognitive, and biomarker measures of AD progression in a large cohort of patients with Alzheimer's disease (AD), patients with Mild Cognitive Impairment, and healthy controls. Detailed neuropsychological testing was conducted on all participants. We examined the factor structure of the ADNI Neuropsychological Battery across older adults with differing levels of clinical AD severity based on the Clinical Dementia Rating Scale (CDR). Confirmatory factor analysis (CFA) of 23 variables from 10 neuropsychological tests resulted in five factors (memory, language, visuospatial functioning, attention, and executive function/processing speed) that were invariant across levels of cognitive impairment. Thus, these five factors can be used as indicators of cognitive function in older adults who are participants in ADNI.

Cortical signatures of cognition and their relationship to Alzheimer's disease.

Recent changes in diagnostic criteria for Alzheimer's disease (AD) state that biomarkers can enhance certainty in a diagnosis of AD. In the present study, we combined cognitive function and brain morphology, a potential imaging biomarker, to predict conversion from mild cognitive impairment to AD. We identified four biomarkers, or cortical signatures of cognition (CSC), from regressions of cortical thickness on neuropsychological factors representing memory, executive function/processing speed, language, and visuospatial function among participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neuropsychological factor scores were created from a previously validated multidimensional factor structure of the neuropsychological battery in ADNI. Mean thickness of each CSC at the baseline study visit was used to evaluate risk of conversion to clinical AD among participants with mild cognitive impairment (MCI) and rate of decline on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. Of 307 MCI participants, 119 converted to AD. For all domain-specific CSC, a one standard deviation thinner cortical thickness was associated with an approximately 50% higher hazard of conversion and an increase of approximately 0.30 points annually on the CDR-SB. In combined models with a domain-specific CSC and neuropsychological factor score, both CSC and factor scores predicted conversion to AD and increasing clinical severity. The present study indicated that factor scores and CSCs for memory and language both significantly predicted risk of conversion to AD and accelerated deterioration in dementia severity. We conclude that predictive models are best when they utilize both neuropsychological measures and imaging biomarkers.