Clinical validation of an aggregate learning ratio from the neuropsychological assessment battery.

Quantifying learning deficits provides valuable information in identifying and diagnosing mild cognitive impairment and dementia. Previous research has found that a learning ratio (LR) metric, derived from the list learning test from the Neuropsychological Assessment Battery (NAB), was able to distinguish between those with normal cognition versus memory impairment. The current study furthers the NAB LR research by validating a NAB story LR, as well as an aggregate LR. The aggregate LR was created by combining the individual list and story LRs. Participants were classified as those with normal cognition (n = 51), those with MCI (n = 39) and those with dementia (n = 35). Results revealed the story LR was able to accurately distinguish normal controls from those with mild cognitive impairment and those with dementia and offers enhanced discriminability beyond the story immediate recall score (sum of trial 1 and trial 2). Further, the aggregate LR provided superior discriminability beyond the individual list and story LRs and accounted for additional variance in diagnostic group classification. The NAB aggregate LR provides improved sensitivity in detecting declines in impaired learning, which may assist clinicians in making diagnoses earlier in a disease process, benefiting the individual through earlier interventions.

Novel learning ratio from the NAB list learning test distinguishes between clinical groups: clinical validation and sex-related differences.

List-learning tasks provide a wealth of information about an individual's cognitive abilities: attention, encoding, storage, retrieval, recognition. A more recently developed metric, the Learning Ratio (LR), supplements information about cognitive ability and can assist the clinician in determining whether an individual has cognitive impairment. The LR is calculated by taking the difference between the individuals' raw score on the first learning trial and their raw score on the last learning trial, which is then divided by the number of words left to be learned after the first learning trial. A LR derived from the list-learning task from the Neuropsychological Assessment Battery (NAB) was evaluated to determine ability to distinguish those with normal cognition from those with mild cognitive impairment (MCI) and dementia. Results from the present study indicate the NAB LR is able to distinguish between clinical groups; recommended cutoffs for the NAB LR scores are provided. We also found a significant female sex-advantage for the NAB LR in those with normal memory ability and demonstrated the female sex advantage decreased with increasing memory impairment. Taken together, the NAB LR may assist clinicians in making an accurate and early diagnosis and may be helpful for tracking learning and functioning across multiple assessments. .

Behavioral variant frontotemporal dementia in a 23-year-old man.

A 23-year-old man presented with behavioral disinhibition, stereotypies, motor apathy, flattened affect, and inappropriate laughter. CT demonstrated generalized cerebral atrophy. He was admitted with a diagnosis of unspecified psychosis and discharged on antipsychotic medication. He was readmitted 3 months later, was diagnosed with schizophrenia, and antipsychotic medication was continued. Owing to symptom progression and aggressive behavior, he was readmitted 2 months later. CT again demonstrated moderate central and cortical cerebral atrophy. MRI showed severe, stable atrophy with frontotemporal predominance, and he was diagnosed with probable behavioral variant frontotemporal dementia (bvFTD).  Over the next year he rapidly deteriorated, with loss of cognitive abilities. Genetic testing revealed several variants, none of which are clearly disease-causing.

Temporal order of clinical and biomarker changes in familial frontotemporal dementia.

Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.

Neuropsychological Assessment and Screening in Heart Failure: a Meta-Analysis and Systematic Review.

A variety of neuropsychological changes secondary to heart failure have been documented in the literature. However, what remains unclear are which neuropsychological abilities are the most impacted by heart failure and what tests have the sensitivity to measure that impact. Eight databases were searched for articles that examined the neuropsychological functioning of patients with heart failure. Some of the inclusion criteria were articles had to have a heart failure group with a demographically comparable control group and standardized neuropsychological testing. Exclusion criteria included articles with a heart failure group with any other type of major organ failure, or comparisons that were between different classes of heart failure rather than between a heart failure and non-heart failure group. A total of 33 articles met the inclusion criteria (total heart failure sample n = 8900) and provided effect size data for 20 neuropsychological domains. All observed domain-level differences between heart failure and non-heart failure groups were statistically significant, except for simple motor functioning and confrontation naming. The greatest differences in performance were in executive functioning, global cognition, complex psychomotor speed, and verbal memory. The highest effect sizes came from Trail-Making Test-Part B, CAMCOG, Symbol Digit Modality Test, and California Verbal Learning Test. The neuropsychological patterns of heart failure suggested diffuse cognitive involvement, with higher-level processes being most affected. It is important to track neurocognition in this clinical population since neuropsychological impairment is prevalent, and screening measures appear to be reliable. Such screening and further assessment would inform future medical treatment and may improve patient care management.

Neuropsychological functioning in opioid use disorder: A research synthesis and meta-analysis.

BACKGROUND: Research has demonstrated that patients with opioid use disorders (OUD; including both opioid abuse and/or dependence) have poorer neuropsychological functioning compared to healthy controls; however, the pattern and robustness of the findings remain unknown. OBJECTIVES: This study meta-analyzed the results from previous research examining the neuropsychological deficits associated with opioids across 14 neurocognitive domains. METHOD: Articles comparing patients with OUD to healthy controls were selected based on detailed inclusion/exclusion criteria and variables of interest were coded. In total, 61 studies were selected for the analyses. These consisted of 2580 patients with OUD and 2102 healthy control participants (15.9% female). Drug-related variables were analyzed as potential moderators. RESULTS: The largest effect size difference in neuropsychological performance was observed in complex psychomotor ability. With the exception of the motor and processing speed domains, which showed no group differences, small-to-medium effect sizes were associated with all neurocognitive domains examined. Meta-regression revealed that increases in the length of abstinence were associated with decreases in effect sizes of the complex psychomotor domain. Additionally, attentional ability predicted effect size differences in executive functioning as well as verbal memory ability. Although the majority of meta-analyzed studies demonstrated significant differences between patients with OUD and controls, the average raw scores for patients with OUD in these studies typically fell within the normal range. CONCLUSION: The pattern of neuropsychological performance among patients with OUD appears to reflect mild generalized cognitive dysfunction, with a large effect in complex psychomotor abilities.

Neuropsychological comparisons of cocaine versus methamphetamine users: A research synthesis and meta-analysis.

BACKGROUND: Previous meta-analytical research examining cocaine and methamphetamine separately suggests potentially different neuropsychological profiles associated with each drug. In addition, neuroimaging studies point to distinct structural changes that might underlie differences in neuropsychological functioning. OBJECTIVES: This meta-analysis compared the effect sizes identified in cocaine versus methamphetamine studies across 15 neuropsychological domains. METHOD: Investigators searched and coded the literature examining the neuropsychological deficits associated with a history of either cocaine or methamphetamine use. A total of 54 cocaine and 41 methamphetamine studies were selected, yielding sample sizes of 1,718 and 1,297, respectively. Moderator analyses were conducted to compare the two drugs across each cognitive domain. RESULTS: Data revealed significant differences between the two drugs. Specifically, studies of cocaine showed significantly larger effect-size estimates (i.e., poorer performance) in verbal working memory when compared to methamphetamine. Further, when compared to cocaine, methamphetamine studies demonstrated significantly larger effect sizes in delayed contextual verbal memory and delayed visual memory. CONCLUSION: Overall, cocaine and methamphetamine users share similar neuropsychological profiles. However, cocaine appears to be more associated with working memory impairments, which are typically frontally mediated, while methamphetamine appears to be more associated with memory impairments that are linked with temporal and parietal lobe dysfunction.

Gray matter abnormalities in opioid-dependent patients: A neuroimaging meta-analysis.

BACKGROUND: Prior research utilizing whole-brain neuroimaging techniques has identified structural differences in gray matter in opioid-dependent individuals. However, the results have been inconsistent. OBJECTIVES: The current study meta-analytically examines the neuroimaging findings of studies published before 2016 comparing opioid-dependent individuals to drug-naïve controls. METHOD: Exhaustive search of five databases yielded 12 studies that met inclusion criteria. Anisotropic Effect-Size Seed-Based d Mapping (AES-SDM) was used to analyze the data extracted by three independent researchers. Voxel-based AES-SDM distinguishes increases and decreases in brain matter significant at the whole-brain level. RESULTS: AES-SDM identified the fronto-temporal region, bilaterally, as being the primary site of gray matter deficits associated with opioid use. Moderator analysis revealed that length of opioid use was negatively associated with gray matter in the left cerebellar vermis and the right Rolandic operculum, including the insula. Meta-regression revealed no remaining significant areas of gray matter reductions, except in the precuneus, following longer abstinence from opioids. CONCLUSIONS: Opioid-dependent individuals had significantly less gray matter in several regions that play a key role in cognitive and affective processing. The findings provide evidence that opioid dependence may result in the breakdown of two distinct yet highly overlapping structural and functional systems. These are the fronto-cerebellar system that might be more responsible for impulsivity, compulsive behaviors, and affective disturbances and the fronto-insular system that might account more for the cognitive and decision-making impairments.

Age-related parieto-occipital and other gray matter changes in borderline personality disorder: A meta-analysis of cortical and subcortical structures.

Previous research suggests that core borderline personality disorder (BPD) symptoms vary in severity with advancing age. While structural neuroimaging studies show smaller limbic and prefrontal gray matter volumes (GMV) in primarily adult and adolescent BPD patients, respectively, findings are inconsistent. Using the effect-size signed differential mapping (ES-SDM) meta-analytic method, we investigated the relationship between advancing age and GMV abnormalities in BPD patients. A total of nine voxel-based morphometry (VBM) studies comparing regional GMV of 256 BPD patients and 272 healthy control subjects were included. Meta-analysis identified lower GMV in the right superior/middle temporal gyri and higher GMV in the right supplementary motor area of BPD patients. Meta-regression showed that increasing age was significantly associated with increased GMV in the left superior parieto-occipital gyri, with younger-aged patients starting at lower GMV compared to controls. In contrast, increasing age was associated with decreased GMV in the right amygdala. These findings suggest that while GMV deficits in limbic structures may become pronounced with advancing age in the course of BPD, parieto-occipital rather than frontal GMV deficits could be especially prominent in younger-aged BPD patients.

Gray matter abnormalities in cocaine versus methamphetamine-dependent patients: a neuroimaging meta-analysis.

BACKGROUND: Voxel-based morphometry has been used to explore gray matter alterations in cocaine and methamphetamine dependence. However, the results of this research are inconsistent. OBJECTIVES: The current study meta-analytically examined neuroimaging findings of all studies published before 2014 using the Anisotropic Effect-Size Signed Differential Mapping (ES-SDM). METHODS: Independent investigators searched four major databases for relevant neuroimaging studies involving cocaine and methamphetamine dependence. Nine cocaine and four methamphetamine studies met inclusion criteria. RESULTS: Results indicated that cocaine- and methamphetamine-dependent patients share overlapping regional gray matter abnormalities compared to healthy controls. However, subgroup analysis showed some regional differences; with methamphetamine showing more prominent reductions in the left superior temporal gyrus and the right inferior parietal lobe. Reductions in the right insula and the left superior frontal gyrus were more prominent in cocaine dependence. Moderator analyses indicated that with longer use, cocaine is associated with reductions in the right hippocampus, right middle temporal gyrus, and right inferior frontal gyrus, while methamphetamine is associated with reductions in the left precentral gyrus and the right supramarginal gyrus. CONCLUSION: These findings indicate that cocaine and methamphetamine dependence are significantly and differentially associated with gray matter abnormalities. Results also point to possible gray matter recovery after abstinence from methamphetamine. Although the sample size was adequate, these findings should be considered preliminary and analyses should be revisited with additional primary research focusing on long or short-term duration of use, as well as the length of abstinence.

White matter abnormalities in long-term heroin users: a preliminary neuroimaging meta-analysis.

BACKGROUND: Diffusion tensor imaging has been used to explore white matter changes in heroin-dependent patients; however, results have been inconsistent. OBJECTIVES: The current study meta-analytically examines the neuroimaging findings of all studies published before 2014 using the novel technique of Effect Size Signed Differential Mapping (ES-SDM). METHODS: Two independent investigators searched three databases for whole-brain voxel-based fractional anisotropy morphometric studies involving heroin use without comorbid polysubstance abuse. Of 59 initial primary studies, four met stringent inclusion criteria. RESULTS: RESULTS from this preliminary analysis indicate that heroin abusers may have significant reductions in fractional anisotropy in the bilateral frontal sub-gyral regions extending from the limbic structures to the prefrontal association cortices, implicating damage to the cingulum and superior longitudinal fasciculus. Exploratory moderator analyses indicate that the potential damage in the left cingulate gyrus may increase with longer use and decrease after long-term abstinence. CONCLUSION: These preliminary findings suggest that heroin abuse is significantly associated with damage to white matter integrity. These results are considered preliminary and analyses should be revisited with more primary studies focusing on either long- or short-term abuse as well as abstinence.

PPARbeta/delta agonists modulate platelet function via a mechanism involving PPAR receptors and specific association/repression of PKCalpha--brief report.

OBJECTIVE: Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a nuclear receptor found in platelets. PPARbeta/delta agonists acutely inhibit platelet function within a few minutes of addition. As platelets are anucleated, the effects of PPARbeta/delta agonists on platelets must be nongenomic. Currently, the particular role of PPARbeta/delta receptors and their intracellular signaling pathways in platelets are not known. METHODS AND RESULTS: We have used mice lacking PPARbeta/delta (PPARbeta/delta(-/-)) to show the effects of the PPARbeta/delta agonist GW501516 on platelet adhesion and cAMP levels are mediated specifically by PPARbeta/delta, however GW501516 had no PPARbeta/delta-specific effect on platelet aggregation. Studies in human platelets showed that PKCalpha, which can mediate platelet activation, was bound and repressed by PPARbeta/delta after platelets were treated with GW501516. CONCLUSIONS: These data provide evidence of a novel mechanism by which PPAR receptors influence platelet activity and thereby thrombotic risk.