A randomized feasibility trial of the modified Atkins diet in older adults with mild cognitive impairment due to Alzheimer's disease.

Background: Alzheimer's disease (AD) is increasing in prevalence, but effective treatments for its cognitive impairment remain severely limited. This study investigates the impact of ketone body production through dietary manipulation on memory in persons with mild cognitive impairment due to early AD and explores potential mechanisms of action. Methods: We conducted a 12-week, parallel-group, controlled feasibility trial of a ketogenic diet, the modified Atkins diet (MAD), compared to a control diet in patients with cognitive impairments attributed to AD. We administered neuropsychological assessments, including memory tests, and collected blood samples at baseline and after 12 weeks of intervention. We performed untargeted lipidomic and targeted metabolomic analyses on plasma samples to detect changes over time. Results: A total of 839 individuals were screened to yield 38 randomized participants, with 20 assigned to receive MAD and 18 assigned to receive a control diet. Due to attrition, only 13 in the MAD arm and nine in the control arm were assessed for the primary endpoint, with two participants meeting ketosis levels used to define MAD adherence criteria. The average change from baseline in the Memory Composite Score was 1.37 (95% CI: -0.87, 4.90) points higher in the MAD group compared to the control group. The effect size of the intervention on baseline MAD change was moderate (Cohen's D = 0.57, 95% CI: -0.67, 1.33). In the 15 participants (nine MAD, six control) assessed for lipidomic and metabolomic-lipidomics and metabolomics, 13 metabolites and 10 lipids showed significant changes from baseline to 12 weeks, including triacylglycerols (TAGs, 50:5, 52:5, and 52:6), sphingomyelins (SM, 44:3, 46:0, 46:3, and 48:1), acetoacetate, fatty acylcarnitines, glycerol-3-phosphate, and hydroxy fatty acids. Conclusions: Attrition was greatest between baseline and week 6. All participants retained at week 6 completed the study. Despite low rates of adherence by criteria defined a priori, lipidomic and metabolomic analyses indicate significant changes from baseline in circulating lipids and metabolites between MAD and control participants at 12-week postrandomization, and MAD participants showed greater, albeit nonsignificant, improvement in memory.

Identifying and distinguishing cognitive profiles among virally suppressed people with HIV.

OBJECTIVE: Cognitive deficits are common among people with HIV (PWH), even when virally suppressed. We identified cognitive profiles among virally suppressed PWH and determined how sociodemographic, clinical/behavioral, and HIV disease characteristics distinguish profile membership. METHOD: Participants included 704 virally suppressed PWH (Mage = 43.9 [SD = 10.2], 88% male, 58.9% non-Hispanic White) from the HIV Neurobehavioral Research Program. Demographically adjusted T scores were derived from a neuropsychological evaluation comprised of 13 tests. We implemented a pipeline involving dimension reduction and clustering to identify profiles of cognitive performance. Random forest models on a 70/30 training/testing set with internal cross-validation were used to identify sociodemographic, clinical/behavioral, and HIV disease correlates of profile membership. RESULTS: Six cognitive profiles were identified: (a) "unimpaired" (19.9%); (b) weakness in verbal learning and memory (15.5%); (c) weakness in executive function and learning (25.8%); (d) weakness in motor, processing speed, and executive function (8.1%); (e) impaired learning and recall with weak-to-impaired motor, processing speed, and executive function (13.1%); (f) global deficits (17.6%). The most discriminative sociodemographic, clinical/behavioral, and HIV disease characteristics varied by profile with self-reported mood symptoms and cognitive/functional difficulties (e.g., language/communication, memory, and overall everyday function complaints) most consistently associated with profile membership. CONCLUSIONS: Cognitive profiles and their associated factors among PWH are heterogeneous, but learning/memory deficits were most common and self-reported mood, and cognitive/functional difficulties were most consistently related to profile membership. This heterogeneity in cognitive profiles and their correlates in PWH suggests that differing mechanisms contribute to cognitive deficits and, thus, underscores the need for personalized risk reduction and therapeutic strategies among PWH. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Within-Person Test Score Distributions: How Typical Is "Normal"?

We evaluated within-person variability across a cognitive test battery by analyzing the shape of the distribution of each individual's scores within a battery of tests. We hypothesized that most healthy adults would produce test scores that are normally distributed around their own personal battery-wide, within-person (wp) mean. Using cross-sectional data from 327 neurologically healthy adults, we computed each person's mean, standard deviation, skew, and kurtosis for 30 neuropsychological measures. Raw scores were converted to T-scores using three degrees of calibration: (a) none, (b) age, and (c) age, sex, race, education, and estimated premorbid IQ. Regardless of calibration, no participant showed abnormal within-person skew (wpskew) and only 10 (3.1%) to 16 (4.9%) showed wpkurtosis greater than 2. If replicated in other samples and measures, these findings could illuminate how healthy individuals are endowed with different cognitive abilities and provide the foundation for a new method of inference in clinical neuropsychology.

Do "effort tests" really test effort?

OBJECTIVE: Little is known about how much effort to do well most people exert on cognitive testing. Here, we describe an experimental paradigm to manipulate and measure cognitive effort. METHOD: After baseline cognitive and performance validity testing (PVT), 38 participants were assigned to a standard (SI) or enhanced (EI) incentive condition. On retesting a week later, EI participants were told that they would receive a financial bonus whose amount depended on how much their retest performance improved over baseline. SI participants were told to do their best and promised a chance-based bonus. RESULTS: Larger improvements on retesting were assumed to reflect less effort at baseline. After calculating differences from baseline to follow-up, we compared the EI and SI groups using multivariate analysis of variance. We sought to identify predictors of lower cognitive effort at baseline by correlating change z scores with baseline PVT performance and other hypothesized markers of low cognitive effort. As hypothesized, the EI group showed larger improvements, including improvements on more cognitive tests, and were rated as and reported trying harder at retesting than the SI group. Standard PVT measures did not correlate with low baseline effort; however, resting one's head or slouching during cognitive testing signified low baseline cognitive effort. CONCLUSIONS: This study provides preliminary support for an experimental paradigm to manipulate and investigate cognitive effort, which still remains poorly understood. While PVTs can detect feigned cognitive impairment, they lack the sensitivity to detect low cognitive effort in persons who pass conventional PVT cutoffs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Microstructural white matter abnormalities in Lesch-Nyhan disease.

Lesch-Nyhan disease is a rare, sex-linked, genetic neurodevelopmental disorder that is characterized by hyperuricemia, dystonia, cognitive impairment and recurrent self-injury. We previously found reduced brain white matter volume in patients with Lesch-Nyhan disease compared with healthy adults using voxel-based morphometry. Here, we address the structural integrity of white matter via diffusion tensor imaging. We hypothesized that white matter integrity would be decreased in men with Lesch-Nyhan disease and to a lesser extent in men with a milder variant of the disease (Lesch-Nyhan variant) relative to healthy men. After acquiring diffusion-weighted brain images from Lesch-Nyhan disease (n = 5), Lesch-Nyhan variant (n = 6) and healthy participants (n = 10), we used both tract-based spatial statistics and a regions of interest approach to analyse between-group fractional anisotropy differences. We first replicated earlier findings of reduced intracranial, grey matter and white matter volumes in patients. We then discovered marked reductions of fractional anisotropy relative to the healthy control group. The Lesch-Nyhan disease group showed more pronounced reductions in white matter integrity than the Lesch-Nyhan variant group. In addition to whole brain fractional anisotropy group differences, reductions in white matter integrity were observed in the corpus callosum, corona radiata, cingulum, internal capsule and superior longitudinal fasciculus. Moreover, the variant group had attenuated dystonia severity symptoms and cognitive deficits. These findings highlight the need to better understand the role of white matter in Lesch-Nyhan disease.

Cognitive Intra-individual Variability in HIV: an Integrative Review.

Nearly 30-50% of people living with HIV experience HIV-Associated Neurocognitive Disorder (HAND). HAND indicates performance at least one standard deviation below the normative mean on any two cognitive domains. This method for diagnosing or classifying cognitive impairment has utility, however, cognitive intraindividual variability provides a different way to understand cognitive impairment. Cognitive intraindividual variability refers to the scatter in cognitive performance within repeated measures of the same cognitive test (i.e., inconsistency) or across different cognitive tests (i.e., dispersion). Cognitive intraindividual variability is associated with cognitive impairment and cognitive decline in various clinical populations. This integrative review of 13 articles examined two types of cognitive intraindividual variability in people living with HIV, inconsistency and dispersion. Cognitive intraindividual variability appears to be a promising approach to detect subtle cognitive impairments that are not captured by traditional mean-based neuropsychological testing. Greater intraindividual variability in people living with HIV has been associated with: 1) poorer cognitive performance and cognitive decline, 2) cortical atrophy, both gray and white matter volume, 3) poorer everyday functioning (i.e., driving simulation performance), specifically medication adherence, and 4) even mortality. This inspires future directions for research. First, greater cognitive intraindividual variability may reflect a greater task demand on executive control to harness and regulate cognitive control over time. By improving executive functioning through cognitive training, it may reduce cognitive intraindividual variability which could slow down cognitive decline. Second, cognitive intraindividual variability may be reconsidered in prior cognitive intervention studies in which only mean-based cognitive outcomes were used. It is possible that such cognitive interventions may actually improve cognitive intraindividual variability, which could have clinical relevance.

Tablet-Based Cognitive Impairment Screening for Adults With HIV Seeking Clinical Care: Observational Study.

BACKGROUND: Neurological complications including cognitive impairment persist among people with HIV on antiretrovirals; however, cognitive screening is not routinely conducted in HIV clinics. OBJECTIVE: Our objective for this study was 3-fold: (1) to determine the feasibility of implementing an iPad-based cognitive impairment screener among adults seeking HIV care, (2) to examine the psychometric properties of the tool, and (3) to examine predictors of cognitive impairment using the tool. METHODS: A convenience sample of participants completed Brain Baseline Assessment of Cognition and Everyday Functioning (BRACE), which included (1) Trail Making Test Part A, measuring psychomotor speed; (2) Trail Making Test Part B, measuring set-shifting; (3) Stroop Color, measuring processing speed; and (4) the Visual-Spatial Learning Test. Global neuropsychological function was estimated as mean T score performance on the 4 outcomes. Impairment on each test or for the global mean was defined as a T score ≤40. Subgroups of participants repeated the tests 4 weeks or >6 months after completing the first test to evaluate intraperson test-retest reliability and practice effects (improvements in performance due to repeated test exposure). An additional subgroup completed a lengthier cognitive battery concurrently to assess validity. Relevant factors were abstracted from electronic medical records to examine predictors of global neuropsychological function. RESULTS: The study population consisted of 404 people with HIV (age: mean 53.6 years; race: 332/404, 82% Black; 34/404, 8% White, 10/404, 2% American Indian/Alaskan Native; 28/404, 7% other and 230/404, 58% male; 174/404, 42% female) of whom 99% (402/404) were on antiretroviral therapy. Participants completed BRACE in a mean of 12 minutes (SD 3.2), and impairment was demonstrated by 34% (136/404) on Trail Making Test A, 44% (177/404) on Trail Making Test B, 40% (161/404) on Stroop Color, and 17% (67/404) on Visual-Spatial Learning Test. Global impairment was demonstrated by 103 out of 404 (25%). Test-retest reliability for the subset of participants (n=26) repeating the measure at 4 weeks was 0.81 and for the subset of participants (n=67) repeating the measure almost 1 year later (days: median 294, IQR 50) was 0.63. There were no significant practice effects at either time point (P=.20 and P=.68, respectively). With respect for validity, the correlation between global impairment on the lengthier cognitive battery and BRACE was 0.63 (n=61; P<.001), with 84% sensitivity and 94% specificity to impairment on the lengthier cognitive battery. CONCLUSIONS: We were able to successfully implement BRACE and estimate cognitive impairment burden in the context of routine clinic care. BRACE was also shown to have good psychometric properties. This easy-to-use tool in clinical settings may facilitate the care needs of people with HIV as cognitive impairment continues to remain a concern in people with HIV.

Patterns and Predictors of Cognitive Function Among Virally Suppressed Women With HIV.

Cognitive impairment remains frequent and heterogeneous in presentation and severity among virally suppressed (VS) women with HIV (WWH). We identified cognitive profiles among 929 VS-WWH and 717 HIV-uninfected women from 11 Women's Interagency HIV Study sites at their first neuropsychological (NP) test battery completion comprised of: Hopkins Verbal Learning Test-Revised, Trail Making, Symbol Digit Modalities, Grooved Pegboard, Stroop, Letter/Animal Fluency, and Letter-Number Sequencing. Using 17 NP performance metrics (T-scores), we used Kohonen self-organizing maps to identify patterns of high-dimensional data by mapping participants to similar nodes based on T-scores and clustering those nodes. Among VS-WWH, nine clusters were identified (entropy = 0.990) with four having average T-scores ≥45 for all metrics and thus combined into an "unimpaired" profile (n = 311). Impaired profiles consisted of weaknesses in: (1) sequencing (Profile-1; n = 129), (2) speed (Profile-2; n = 144), (3) learning + recognition (Profile-3; n = 137), (4) learning + memory (Profile-4; n = 86), and (5) learning + processing speed + attention + executive function (Profile-5; n = 122). Sociodemographic, behavioral, and clinical variables differentiated profile membership using Random Forest models. The top 10 variables distinguishing the combined impaired vs. unimpaired profiles were: clinic site, age, education, race, illicit substance use, current and nadir CD4 count, duration of effective antiretrovirals, and protease inhibitor use. Additional variables differentiating each impaired from unimpaired profile included: depression, stress-symptoms, income (Profile-1); depression, employment (Profile 2); depression, integrase inhibitor (INSTI) use (Profile-3); employment, INSTI use, income, atazanavir use, non-ART medications with anticholinergic properties (Profile-4); and marijuana use (Profile-5). Findings highlight consideration of NP profile heterogeneity and potential modifiable factors contributing to impaired profiles.

Sex Differences in the Patterns and Predictors of Cognitive Function in HIV.

Despite advancements in antiretroviral therapy, mild cognitive deficits persist in nearly half of people with HIV (PWH). The profile of impairment in HIV is highly variable with deficits observed in a range of cognitive domains. Despite evidence of greater cognitive impairment among women with HIV (WWH) vs. men with HIV (MWH), it is unclear how MWH and WWH differ in the type of cognitive impairment and in risk factors associated with cognitive impairment profiles. In a large and well-characterized sample of PWH, we used machine learning to identify profiles of cognitive functioning and their associated factors overall and within sex. Participants included 1,666 PWH (201 WWH; 1,465 MMH) from the HIV Neurobehavioral Research Program who completed a neuropsychological test battery at their baseline visits. Using demographically-adjusted T-scores from 13 test outcomes assessing motor skills, executive functioning, attention/working memory, episodic learning and memory, verbal fluency, and processing speed, we used Kohonen self-organizing maps to identify patterns of high-dimensional data by mapping participants to similar nodes based on T-scores (MCLUST R package). Random forest models were used to determine how sociodemographic (e.g., age, education), clinical (e.g., depressive symptoms, substance use disorder), and biological (e.g., HIV disease characteristics) factors differentially related to membership within a cognitive profile. All analyses were repeated within sex. Three cognitive profiles were identified overall and within each sex. Overall and within MWH, there were unimpaired and global weakness profiles. The third profile in the total sample demonstrated relatively weak auditory attention whereas in MWH showed relative strengths in attention and processing speed. Conversely, there was no unimpaired profile among WWH. Rather, WWH demonstrated separate profiles reflecting weakness in motor skills, a relative weakness in learning and delayed recall, and global weaknesses with spared recognition memory. Despite different cognitive profiles by sex, the most discriminative factors were similar between men and women and included reading level (cognitive reserve), current and nadir CD4 count, plasma HIV viral load, duration of HIV disease, age, depressive symptoms, and race/ethnicity. Findings fill a knowledge gap concerning sex differences in cognitive impairment in PWH and inform personalized risk reduction and therapeutic strategies.

Preliminary Report on the Feasibility and Efficacy of the Modified Atkins Diet for Treatment of Mild Cognitive Impairment and Early Alzheimer's Disease.

Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer's disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD.

Working memory impairment in probands with schizoaffective disorder and first degree relatives of schizophrenia probands extend beyond deficits predicted by generalized neuropsychological impairment.

OBJECTIVE: Working memory impairment is well established in psychotic disorders. However, the relative magnitude, diagnostic specificity, familiality pattern, and degree of independence from generalized cognitive deficits across psychotic disorders remain unclear. METHOD: Participants from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study included probands with schizophrenia (N=289), psychotic bipolar disorder (N=227), schizoaffective disorder (N=165), their first-degree relatives (N=315, N=259, N=193, respectively), and healthy controls (N=289). All were administered the WMS-III Spatial Span working memory test and the Brief Assessment of Cognition in Schizophrenia (BACS) battery. RESULTS: All proband groups displayed significant deficits for both forward and backward span compared to controls. However, after covarying for generalized cognitive impairments (BACS composite), all proband groups showed a 74% or greater effect size reduction with only schizoaffective probands showing residual backward span deficits compared to controls. Significant familiality was seen in schizophrenia and bipolar pedigrees. In relatives, both forward and backward span deficits were again attenuated after covarying BACS scores and residual backward span deficits were seen in relatives of schizophrenia patients. CONCLUSIONS: Overall, both probands and relatives showed a similar pattern of robust working memory deficits that were largely attenuated when controlling for generalized cognitive deficits.

Prefrontal brain network connectivity indicates degree of both schizophrenia risk and cognitive dysfunction.

OBJECTIVE: Cognitive dysfunction is a core feature of schizophrenia, and persons at risk for schizophrenia may show subtle deficits in attention and working memory. In this study, we investigated the relationship between integrity of functional brain networks and performance in attention and working memory tasks as well as schizophrenia risk. METHODS: A total of 235 adults representing 3 levels of risk (102 outpatients with schizophrenia, 70 unaffected first-degree relatives of persons with schizophrenia, and 63 unrelated healthy controls [HCs]) completed resting-state functional magnetic resonance imaging and a battery of attention and working memory tasks (Brief Test of Attention, Hopkins Verbal Learning Test, and Brief Visuospatial Memory Test) on the same day. Functional networks were defined based on coupling with seeds in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and primary visual cortex. Networks were then dissected into regional clusters of connectivity that were used to generate individual interaction matrices representing functional connectivity within each network. RESULTS: Both patients with schizophrenia and their first-degree relatives showed cognitive dysfunction compared with HCs. First canonicals indicated an inverse relationship between cognitive performance and connectivity within the DLPFC and MPFC networks. Multivariate analysis of variance revealed multivariate main effects of higher schizophrenia risk status on increased connectivity within the DLPFC and MPFC networks. CONCLUSIONS: These data suggest that excessive connectivity within brain networks coupled to the DLPFC and MPFC, respectively, accompany cognitive deficits in persons at risk for schizophrenia. This might reflect compensatory reactions in neural systems required for cognitive processing of attention and working memory tasks to brain changes associated with schizophrenia.

Bupropion sustained release added to group support for smoking cessation in schizophrenia: a new randomized trial and a meta-analysis.

OBJECTIVE: To clarify the efficacy and tolerability of bupropion sustained release (SR) for the treatment of cigarette smoking in people with schizophrenia. METHOD: The first study is a double-blind, placebo-controlled clinical trial with 32 outpatients from the Maryland Psychiatric Research Center. From May 2003 to July 2007, clinically stable people with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who smoked at least 10 cigarettes per day and who were interested in quitting smoking or cutting down were recruited for participation. All participated in a 9-week support group and were randomly assigned to receive 12 weeks of bupropion SR or placebo. The primary outcome measure was 4 weeks' sustained abstinence over the last 4 study weeks. Secondary outcome measures included decrease in smoking behavior and change in symptoms, neuropsychological performance, and side effects. In the second study, we performed an electronic literature search of MEDLINE in September 2008. Articles in English published between 2003 and 2008 were searched for the terms schizophrenia, bupropion SR, and smoking. Bibliographies of studies identified through the MEDLINE search were also examined. Case reports, open-label studies, crossover studies, and studies using nonstandard dosing of bupropion SR were excluded. In this way, 4 studies similar in methodology to the currently presented clinical trial were identified and the individual data combined in a meta-analysis. A random effects meta-analysis using Comprehensive Meta-Analysis software was used to obtain a pooled estimate of the odds ratio for 4-week smoking abstinence between bupropion SR and placebo. RESULTS: There were no significant results on the primary or secondary smoking measures for the clinical trial, although a numeric advantage favored the bupropion SR group. There were no significant findings for secondary symptom or side effect measures and no significant change in neuropsychological performance. For the meta-analysis totaling 226 subjects, there were significant findings in favor of bupropion SR. The pooled estimate of the odds ratio for 4-week abstinence was 2.7 (95% CI, 1.3 to 5.7; P = .009), and clinically significant greater smoking reduction in the bupropion SR group, with pooled difference estimates increasing over time between groups, became statistically significant by week 5 of study medication (P < .02). CONCLUSIONS: New clinical trial data and a meta-analysis strongly support the tolerability and efficacy of bupropion SR for the treatment of cigarette smoking in people with schizophrenia TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00176449.