Memory Test Performance Research Articles

Accelerated long‐term forgetting‐ALF in Mild Cognitive Impairment: A sensitive tool for subtil memory problems

AbstractBackgroundAccelerated long‐term forgetting (ALF) has been considered a memory consolidation problem, whereby a person can learn and recall information accurately for a limited period of time, but then exhibits a long delayed recall deficit. Standard episodic memory tests which assess long delayed recall consider a delay interval up to 40 minutes after the initial learning. ALF could not be detected by this method. The aim of this study was examining ALF phenomenon in a population of Mild Cognitive Impairment (MCI) patients and normal cognitive performance (NC) individuals.MethodPatients with cognitive complaints were included during a period of 1 year, according to selection criteria. A standard neuropsychological test battery was administered. In order to assess ALF we used the Logical Memory (LM) subtest of Signoret’s memory battery. We registered immediate recall, delayed recall at 30‐minutes and long delayed recall at 7‐days. We also proposed that the performance of long delayed recall at 7‐days ≤50% of the value of delayed recall at 30‐minutes in LM could be considered ALF.ResultDuring a 1 year‐period 115 patients were included, as “G1” 84 MCI patients and “G2” 31 NC individuals. Demographics data: 1) G1 mean age was 73.06±9.99 years, mean education was 12.17±4.28 years and 39(46.42%) were females; 2) G2 mean age was 67.03±8.28 years, mean education was 14.4±3.8 years and 24(77.41%) were females. The performance in memory tests showed that G1 had lower values in long delayed recall at 7‐days compared to G2 with statistical significance (G1 3.65±2.59 vs G2 6.16±2.6; p = 0.001). When we applied our proposal for ALF, just 7(22.6%) patients of G1 and 26(31%) of G2 had a performance of long delayed recall at 7‐days ≤50% of the value of delayed recall at 30‐minutes in LM without statistical difference (p = 0.378).ConclusionUntil the date, there isn’t an agreement in memory test to use or delay interval to consider or normative data available to detect ALF. While our proposal doesn’t differentiate between MCI and NC patients, it is necessary to continue studies and produce normative data.

Phase 3 randomized placebo-controlled trial of donepezil for late cancer-related cognitive impairment in breast cancer survivors exposed to chemotherapy from the Wake Forest NCORP Research Base REMEMBER trial (WF97116).

12004 Background: Cancer-related cognitive impairment (CRCI) is common among breast cancer survivors (BCS). Prior studies of late CRCI suggest repurposing cognitive enhancing medication may benefit survivors. The REMEMBER prospective, randomized, double-blind, placebo-controlled trial compared the efficacy of donepezil, an acetylcholine esterase inhibitor, versus placebo to reduce late CRCI among BCS previously exposed to chemotherapy. (Clinical Trials #NCT02822573). Methods: Women ≥ 18 years of age, with a history of breast cancer who completed ≥ 4 cycles of chemotherapy 1 to 5 years prior to enrollment, self-reported CRCI, with evidence of a memory deficit on the Hopkins Verbal Learning Test-Revised (HVLT-R) were eligible. Women were randomized to a 24-week course of donepezil (5mg/daily x 6 wk. titrated to 10mg/daily x 18 wk.) or placebo. A cognitive battery assessing memory, attention, executive function, verbal fluency, and processing speed was administered at baseline, week 12, 24 (end of intervention), and 36 (wash-out) along with patient-reported outcome measures and adverse events. There was 90% power to detect a treatment difference of 2 words for HVLT-IR (effect size=0.47) Mixed effects repeated measures analysis of covariance (RMANCOVA) models were utilized to assess treatment differences in memory (primary outcome) and other cognitive domains (secondary outcomes) with model covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification and an unstructured covariance matrix to account for within participant correlation over time. Results: A total of276 patients from 87 NCORP sites (mean age=57.1yr, SD=10.5) an average of 29.6 months post-chemotherapy completion were randomized to donepezil (n=140) or placebo (n=136). The primary outcome of memory (HVLT-R total) at 24 weeks was not different between treatments (donepezil mean=25.98, placebo = 26.50, p=0.32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks on attention, executive function, verbal fluency, or processing speed. Exploratory analyses additionally adjusting for education, baseline fatigue and depression as well as independent analyses considering treatment interaction with endocrine therapy and menopausal status also did not result in any differences by group for any outcomes. Twenty-five grade 3 or 4 adverse events were reported with no differences by treatment. Conclusions: BCS 1-5 years after completing chemotherapy, randomized to 24 weeks of a daily dose of 5-10mg of donepezil, did not perform differently at the end of treatment on tests of memory or other cognitive functions than survivors randomized to placebo. Funding: NIH/NCI 2UG1CA189824. Clinical trial information: NCT02822573 .

Vertigoheel promotes rodent cognitive performance in multiple memory tests.

Cognitive impairment associated with old age or various brain disorders may be very disabling for affected individuals, placing their carers and public health services under considerable stress. The standard-of-care drugs produce only transient improvement of cognitive impairment in older people, so the search for novel, safe and effective therapeutics that would help to reverse or delay cognitive impairment is warranted. Repurposing pharmacological therapies with well-established safety record for additional indications is a promising recent trend in drug development. Vertigoheel (VH-04), a multicomponent drug made of Ambra grisea, Anamirta cocculus L., Conium maculatum, and Petroleum rectificatum, has been successfully used for several decades in the treatment of vertigo. Here, we investigated effects of VH-04 on cognitive performance in standard behavioral tests assessing different types of memory and explored cellular and molecular underpinnings of VH-04's biological activity. In the majority of behavioral experiments, namely in the spontaneous and rewarded alternation tests, passive avoidance test, contextual/cued fear conditioning, and social transmission of food preference, we examined the ability of single and repeated intraperitoneal administrations of VH-04 to improve cognitive parameters of mice and rats disrupted by the application of the muscarinic antagonist scopolamine. In addition, we also assessed how VH-04 affected novel object recognition and influenced performance of aged animals in Morris water maze. Furthermore, we also studied the effects of VH-04 on primary hippocampal neurons in vitro and mRNA expression of synaptophysin in the hippocampus. Administration of VH-04 positively influenced visual recognition memory in the novel object recognition test and alleviated the impairments in spatial working memory and olfactory memory caused by the muscarinic antagonist scopolamine in the spontaneous alternation and social transmission of food preference tests. In addition, VH-04 improved retention of the spatial orientation memory of old rats in the Morris water maze. In contrast, VH-04 did not have significant effects on scopolamine-induced impairments in tests of fear-aggravated memory or rewarded alternation. Experiments in vitro showed that VH-04 stimulated neurite growth and possibly reversed the age-dependent decrease in hippocampal synaptophysin mRNA expression, which implies that VH-04 may preserve synaptic integrity in the aging brain. Our findings allow a cautious conclusion that in addition to its ability to alleviate manifestations of vertigo, VH-04 may be also used as a cognitive enhancer.

Cognitive test performance in chronic cannabis flower users, concentrate users, and non-users

Extremely high-potency cannabis concentrates are becoming increasingly available and popular among consumers. While prior research indicates these products are perceived to have greater detrimental effects relative to cannabis flower, few studies have examined their relative objective effects, and no existing studies have compared the cognitive test performance of sober flower users, concentrate users, and non-users. A total of 198 healthy adults (98 non-users, 46 exclusive flower users, and 54 concentrate users) were administered a battery of tests of memory, psychomotor speed, attention, and executive functioning under sober laboratory-controlled conditions. Significant group differences were detected on tests of verbal free recall and episodic prospective memory, with both the flower users and concentrate users demonstrating significantly worse performance than non-users. Concentrate (but not flower) users performed worse than non-users on a measure of source memory, but contrary to our hypothesis, there were no significant differences between flower and concentrate users on any of the cognitive tests. Results indicate that, under sober conditions, individuals who regularly use concentrates are no more cognitively impacted than those who exclusively use flower. These null findings may reflect the tendency for concentrate users to self-titrate and use significantly lower quantities of concentrates than flower.

The Spectrum of Neurological and Sensory Abnormalities in Gaucher Disease Patients: A Multidisciplinary Study (SENOPRO).

Gaucher disease (GD) has been increasingly recognized as a continuum of phenotypes with variable neurological and sensory involvement. No study has yet specifically explored the spectrum of neuropsychiatric and sensory abnormalities in GD patients through a multidisciplinary approach. Abnormalities involving the nervous system, including sensory abnormalities, cognitive disturbances, and psychiatric comorbidities, have been identified in GD1 and GD3 patients. In this prospective study, named SENOPRO, we performed neurological, neuroradiological, neuropsychological, ophthalmological, and hearing assessments in 22 GD patients: 19 GD1 and 3 GD3. First, we highlighted a high rate of parkinsonian motor and non-motor symptoms (including high rates of excessive daytime sleepiness), especially in GD1 patients harboring severe glucocerebrosidase variants. Secondly, neuropsychological evaluations revealed a high prevalence of cognitive impairment and psychiatric disturbances, both in patients initially classified as GD1 and GD3. Thirdly, hippocampal brain volume reduction was associated with impaired short- and long-term performance in an episodic memory test. Fourthly, audiometric assessment showed an impaired speech perception in noise in the majority of patients, indicative of an impaired central processing of hearing, associated with high rates of slight hearing loss both in GD1 and GD3 patients. Finally, relevant structural and functional abnormalities along the visual system were found both in GD1 and GD3 patients by means of visual evoked potentials and optical coherence tomography. Overall, our findings support the concept of GD as a spectrum of disease subtypes, and support the importance of in-depth periodic monitoring of cognitive and motor performances, mood, sleep patterns, and sensory abnormalities in all patients with GD, independently from the patient's initial classification.

Distinct domains of childhood disadvantage and cognitive performance among older Brazilians: Evidence from ELSI-Brazil

ObjectiveTo investigate the relationship between of distinct domains of childhood disadvantage and cognitive performance among older adults within the context of a middle-income country. MethodsThis study used baseline data (2015/2016) from the Brazilian Longitudinal Study of Aging (ELSI), a nationally representative cohort of 9412 adults aged 50 and over. Nine childhood exposure variables were grouped into three domains (family SES, childhood health, and cultural capital), for which scores were created. Survey-weighted Ordinary Least Squares (OLS) regressions estimated the association childhood disadvantage with cognitive performance as measured by immediate memory, late memory and semantic verbal fluency. Mediation analysis assessed whether adulthood socioeconomic status (SES) mediated this relationship of interest. ResultsImportant disparities in cognitive performance were observed, particularly in terms of age, education, income, occupational status. Before controlling for adulthood SES in the multivariable analysis, all domains of childhood disadvantage were found to be associated with lower cognitive performance across all three measures. After inclusion of adulthood SES variables, the observed associations only remained for semantic verbal fluency. Formal mediation analysis indicated that adulthood SES mediates 47.9% (95% CI: 34.3%–78.6%) of the association between later-life verbal fluency and poor childhood health, and 49.9% (95% CI: 43.6%–57.8%) of the association between later-life verbal fluency and low childhood cultural capital. ConclusionsWe found that childhood disadvantage is associated with low performance in memory tests and semantic verbal fluency tests among older Brazilians. Adulthood SES fully mediated the association between all domains of childhood disadvantage and memory performance and only partially mediated its association with verbal fluency. Our findings support policy efforts to enhance early childhood development and improve adulthood SES, and guide additional research to better the mechanisms driving these relationships.

Earlier chronotype in midlife as a predictor of accelerated brain aging: A population-based longitudinal cohort study.

Evidence suggests that sleep-wake cycle disruption could be an early manifestation of neurodegeneration and might even be a risk factor for developing diseases in healthy adults. We investigated the impact of circadian phase change on structural and functional brain deterioration in a late-adulthood population. We analyzed the data of 1,874 participants (mean age 58.6 ± 6.3 years, 50.3% female) from the Korean Genome and Epidemiology Study, who were identified as cognitively unimpaired. The mid-sleep time on free days corrected for sleep debt on workdays (MSFsc) at baseline was adopted as an indicator of the chronotype and used to categorize the participants into three groups. The relationships between the chronotype and longitudinal changes in the gray matter volume (GMV) and cognitive function were investigated (mean interval: 4.2 ± 0.5 years). The mean MSFsc of the participants was 2:45 am. The earlier MSFsc was linearly associated with smaller right entorhinal GMV (β [SE] = 0.02 [0.01]; p = .001) and lower visual memory function test scores at baseline. Longitudinally, the earlier MSFsc at baseline was only significantly associated with more rapid atrophy in the temporal lobe (β [SE] = 0.18 [0.07]; p = .018) and not with other brain lobes or subregions. Moreover, the earlier MSFsc was associated with more deteriorated verbal learning and visual memory function test scores. An earlier chronotype in midlife, measured using a questionnaire, can be a valuable indicator for individuals who should be closely monitored for the development of neurodegenerative disorders.

Functional Network Alterations Associated with Cognition in Pre-Clinical Alzheimer's Disease.

Objective: Accumulation of cerebral amyloid-β (Aβ) is a risk factor for cognitive decline and defining feature of Alzheimer's disease (AD). Aβ is implicated in brain network disruption, but the extent to which these changes correspond with observable cognitive deficits in pre-clinical AD has not been tested. This study utilized individual-specific functional parcellations to sensitively evaluate the relationship between network connectivity and cognition in adults with and without Aβ deposition. Participants and Methods: Cognitively unimpaired adults ages 45-85 completed amyloid positron emission tomography, resting-state-functional magnetic resonance imaging (fMRI), and neuropsychological tests of episodic memory and executive function (EF). Participants in the upper tertile of mean standard uptake value ratio were considered Aβ+ (n = 50) while others were Aβ- (n = 99). Individualized functional network parcellations were generated from resting-state fMRI data. We examined the effects of group, network, and group-by-network interactions on memory and EF. Results: We observed several interactions such that within the Aβ+ group, preserved network integrity (i.e., greater connectivity within specific networks) was associated with better cognition, whereas network desegregation (i.e., greater connectivity between relative to within networks) was associated with worse cognition. This dissociation was most apparent for cognitive networks (frontoparietal, dorsal and ventral attention, limbic, and default mode), with connectivity relating to EF in the Aβ+ group specifically. Conclusions: Using an innovative approach to constructing individual-specified resting-state functional connectomes, we were able to detect differences in brain-cognition associations in pre-clinical AD. Our findings provide novel insight into specific functional network alterations occurring in the presence of Aβ that relate to cognitive function in asymptomatic individuals. Impact statement Elevated cerebral amyloid-β is a biomarker of pre-clinical Alzheimer's disease (AD). Associations between amyloidosis, functional network disruption, and cognitive impairment are evident in the later stages of AD, but these effects have not been substantiated in pre-clinical AD. Using individual-specific parcellations that maximally localize functional networks, we identify network alterations that relate to cognition in pre-clinical AD that have not been previously reported. We demonstrate that these effects localize to networks implicated in cognition. Our findings suggest that there may be subtle, amyloid-related alterations in the functional connectome that are detectable in pre-clinical AD, with potential implications for cognition in asymptomatic individuals.

The Benson Complex Figure Test detects deficits in visuoconstruction and visual memory in symptomatic familial frontotemporal dementia: A GENFI study

ObjectiveSensitive cognitive markers are still needed for frontotemporal dementia (FTD). The Benson Complex Figure Test (BCFT) is an interesting candidate test, as it assesses visuospatial, visual memory, and executive abilities, allowing the detection of multiple mechanisms of cognitive impairment. To investigate differences in BCFT Copy, Recall and Recognition in presymptomatic and symptomatic FTD mutation carriers, and to explore its cognitive and neuroimaging correlates. MethodWe included cross-sectional data from 332 presymptomatic and 136 symptomatic mutation carriers (GRN, MAPT or C9orf72 mutations), and 290 controls in the GENFI consortium. We examined gene-specific differences between mutation carriers (stratified by CDR® NACC-FTLD score) and controls using Quade's / Pearson Χ2 tests. We investigated associations with neuropsychological test scores and grey matter volume using partial correlations and multiple regression models respectively. ResultsNo significant differences were found between groups at CDR® NACC-FTLD 0–0.5. Symptomatic GRN and C9orf72 mutation carriers had lower Copy scores at CDR® NACC-FTLD ≥2. All three groups had lower Recall scores at CDR® NACC-FTLD ≥2, with MAPT mutation carriers starting at CDR® NACC-FTLD ≥1. All three groups had lower Recognition scores at CDR® NACC FTLD ≥2. Performance correlated with tests for visuoconstruction, memory, and executive function. Copy scores correlated with frontal-subcortical grey matter atrophy, while Recall scores correlated with temporal lobe atrophy. ConclusionsIn the symptomatic stage, the BCFT identifies differential mechanisms of cognitive impairment depending on the genetic mutation, corroborated by gene-specific cognitive and neuroimaging correlates. Our findings suggest that impaired performance on the BCFT occurs relatively late in the genetic FTD disease process. Therefore its potential as cognitive biomarker for upcoming clinical trials in presymptomatic to early-stage FTD is most likely limited.

Progressive Ataxia, Memory Impairments, and Seizure Episodes in Spna2 R1098Q Mouse Variant Affecting Alpha II Spectrin’s Scaffold Stability

SPTAN1 spectrinopathies refer to a group of rare, inherited diseases associated with damage to non-erythrocytic α-II spectrin (α-II). They are linked to a range of mild to severe neuropathologies of the central and peripheral nervous systems, such as early infantile epileptic encephalopathy type 5, cerebellar ataxia, inherited peripheral neuropathy, and spastic paraplegia. Modeling human SPTAN1 encephalopathies in laboratory animals has been challenging partially because no haploinsufficiency-related phenotypes unfold in heterozygous Spna2 deficient mice nor stable transgenic lines of mice mimicking missense human SPTAN1 mutations have been created to date. Here, we assess the motor and memory performance of a dominant-negative murine Spna2 (SPTAN1) variant carrying a spontaneous point mutation replacing an arginine 1098 in the repeat 10th of α-II with the glutamine (R1098Q). By comparing groups of heterozygous R1098Q mice at different ages, we find evidence for progressive ataxia, and age-related deterioration of motor performance and muscle strength. We also document stress-induced, long-lasting seizure episodes of R1098Q mice and their poor performance in novel object recognition memory tests. Overall, we propose that the complexity of neuropathology-related phenotypes presented by the R1098Q mice recapitulates a number of symptoms observed in human patients carrying SPTAN1 mutations affecting α-II scaffold stability. This makes the R1098Q mice a valuable animal model for preclinical research.

Exercise Associated with Cognitive Function in Older Men with Prostate Cancer Undergoing Androgen Deprivation Therapy.

To examine associations between exercise and cognitive function in older men undergoing hormone therapy for prostate cancer. Men ≥ 65years old with prostate cancer, currently undergoing androgen deprivation therapy for ≥ 6months (n = 50), completed the Godin-Shephard Leisure-Time Physical Activity Questionnaire, and standard neuropsychological tests. Pearson's correlations and linear regressions were used to examine associations between exercise and cognitive performance. Exercise was significantly positively correlated with performance on tests of memory, attention, and executive function. Linear regressions showed that when controlling for age and education, exercise remained a significant predictor of attention and executive function performance (p < 0.05), and showed moderate, but statistically non-significant effects on memory performance (p < 0.10). Greater exercise is associated with better functioning in multiple cognitive domains in men with prostate cancer undergoing hormone therapy, providing proof-of-concept evidence that exercise may be a feasible intervention to limit cognitive dysfunction in prostate cancer patients.

Exploring the associations of daily movement behaviours and mid-life cognition: a compositional analysis of the 1970 British Cohort Study

BackgroundMovement behaviours (eg, sedentary behaviour (SB), moderate and vigorous physical activity (MVPA), light intensity physical activity (LIPA) and sleep) are linked to cognition, yet the relative importance of each component...

TRPV4-induced Neurofilament Injury Contributes to Memory Impairment after High Intensity and Low Frequency Noise Exposures

ObjectiveExposure to high intensity, low frequency noise (HI-LFN) causes vibroacoustic disease (VAD), with memory deficit as a primary non-auditory symptomatic effect of VAD. However, the underlying mechanism of the memory deficit is unknown. This study aimed to characterize potential mechanisms involving morphological changes of neurons and nerve fibers in the hippocampus, after exposure to HI-LFN. MethodsAdult wild-type and transient receptor potential vanilloid subtype 4 knockout (TRPV4-/-) mice were used for construction of the HI-LFN injury model. The new object recognition task and the Morris water maze test were used to measure the memory of these animals. Hemoxylin and eosin and immunofluorescence staining were used to examine morphological changes of the hippocampus after exposure to HI-LFN. ResultsThe expression of TRPV4 was significantly upregulated in the hippocampus after HI-LFN exposure. Furthermore, memory deficits correlated with lower densities of neurons and neurofilament-positive nerve fibers in the cornu ammonis 1 (CA1) and dentate gyrus (DG) hippocampal areas in wild-type mice. However, TRPV4-/- mice showed better performance in memory tests and more integrated neurofilament-positive nerve fibers in the CA1 and DG areas after HI-LFN exposure. ConclusionTRPV4 up-regulation induced neurofilament positive nerve fiber injury in the hippocampus, which was a possible mechanism for memory impairment and cognitive decline resulting from HI-LFN exposure. Together, these results identified a promising therapeutic target for treating cognitive dysfunction in VAD patients.

Photobiomodulation improves frontal lobe cognitive functions and mental health of older adults with non-amnestic mild cognitive impairment: Case studies.

This study investigated the effects of transcranial photobiomodulation (tPBM) on improving the frontal lobe cognitive functions and mental health of older adults. Three older adults with mild cognitive impairment (MCI) of the non-amnestic type received 18-session tPBM stimulation for 9 weeks and were assessed with neuropsychological tests of memory and executive functions and standardized questionnaires on depressive and anxiety symptoms, global cognitive functions, and daily functioning abilities before and after tPBM stimulation. At baseline, their intrusion and/or perseveration errors in a verbal memory test and a fluency test, as measures of the frontal lobe cognitive functions, were in the borderline to severely impaired range at baseline. After tPBM stimulation, the three older adults showed various levels of improvement in their frontal lobe cognitive functions. One older adult's intrusion and perseveration errors improved from the <1st-2nd percentile (moderately to severely impaired range) to the 41st-69th percentile (average range), another older adult's intrusion errors improved from the 11th percentile to the 83rd percentile, and the third older adult's intrusion errors improved from the 5th percentile to the 56th percentile. Moreover, improvements in their anxiety and/or depressive symptoms were also observed. One older adult's depressive and anxiety symptoms improved from the severe range at baseline to the mild range after the intervention. The other two older adults' depressive symptoms improved from the mild range at baseline to the normal range after the intervention. These findings provide preliminary support for the potential of tPBM to improve the frontal lobe cognitive functions and mental health of older adults with MCI. Given the small sample size of only three older adults and the absence of a placebo control group, larger randomized controlled studies are needed to confirm its potential.

Continuous positive airway pressure improved daytime sleepiness and memory function in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a sleep disorder which results in daytime sleepiness and impaired memory function. The aim of this study was to investigate the effect of continuous positive airway pressure (CPAP) on daytime sleepiness and memory function in OSA patients. We also investigated whether CPAP compliance impacted the effect of this treatment. The nonrandomized, nonblinded clinical trial enrolled 66 patients with moderate-to-severe OSA subjects. All subjects completed a polysomnographic study, daytime sleepiness questionnaires (the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index), and four memory function tests (working memory; processing speed [PS]; logical memory [LM]; face memory [FM]). Before CPAP treatment, no significant differences (P < 0.05) were noted in the demographic data, daytime sleepiness, or memory function between two groups (with/without CPAP). However, OSA patients treated with CPAP for 2 months showed significant improvements in daytime sleepiness, PS, mostly of LM, and FM comparing to 2 months ago. As compared to those who did not receive CPAP treatment, CPAP can improve only parts of LM (delayed LM [DLM] and LM percentage [LMP]). In addition, compared to control group, a significant improvement of daytime sleepiness and LM (LM learning, DLM, and LMP) in good compliance with CPAP treatment group and of DLM and LMP in the low compliance with CPAP treatment group was found. CPAP treatment for 2 months could improve some of LM in OSA patients, especially in patients exhibiting good CPAP compliance.

Clinical Significance of Physical Frailty in Subjects With Subjective Cognitive Decline: A Prospective Study With Amyloid PET Data.

Physical frailty is known to be closely associated with cognitive impairment and to be an early sign of Alzheimer's disease. We aimed to understand the characteristics of physical frailty and define factors associated with physical frailty in subjects with subjective cognitive decline (SCD) by analyzing amyloid data. We prospectively enrolled subjects with SCD from a cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from SCD (CoSCo). All of the subjects underwent brain magnetic resonance imaging, and brain amyloid positron-emission tomography (PET) to detect amyloid beta plaques. Self-reported exhaustion, handgrip strength, and gait speed were used to measure physical frailty. Of 120 subjects with SCD, 26 (21.7%) were amyloid-positive in PET. Female (odds ratio [OR]=3.79, p=0.002) and amyloid-PET-positive (OR=3.80, p=0.008) subjects with SCD were at high risks of self-reported exhaustion. Amyloid PET positivity (OR=3.22, p=0.047) and high burden from periventricular white-matter hyperintensity (OR=3.34, 95% confidence interval=1.18-9.46, p=0.023) were significantly associated with a weaker handgrip. The subjects with SCD with self-reported exhaustion and weaker handgrip presented with lower cognitive performance in neuropsychological tests, especially for information processing speed and executive function. Subjects with a slower gait performed worse in visual memory function tests. Amyloid PET positivity was associated with a higher risk of self-reported exhaustion and weaker handgrip in subjects with SCD. The subjects with SCD and physical frailty also performed worse in neuropsychological tests.

CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease

BackgroundEfavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. MethodsThis pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain.ResultsIn subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects.ConclusionsOur findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology.Trial registrationClinicalTrials.gov, NCT03706885.

Evaluation of the effects of phenylephrine and prazosin injection into basolateral amygdala on the post-stress experience of memory retrieval in rats

The present study explored the effect of α1-adrenergic receptors in the basolateral amygdala (BLA) on memory formation in the hippocampus under repeated stress. Male rats received injections of the α1-adrenergic receptor agonist (phenylephrine) or antagonist (prazosin) bilaterally into the BLA five min before foot-shock stress, and emotional and spatial memory and in-vivo long-term potentiation (LTP) in the Cornu Ammonis (CA1) region of the hippocampus were examined. Foot-shock stress impaired performance in emotional and spatial memory tests. However, it had no significant effect on any of the LTP parameters in the hippocampus. Intra-BLA phenylephrine injection significantly impaired emotional and spatial memory performance in stressed animals. On the other hand, administration of intra-BLA prazosin significantly reduced emotional and spatial memory in the control (intact) animals. Neither of the two drugs had any significant effects on LTP parameters. Prazosin effectively impaired memory in the control, but not in the stressed rats. Stress appears to have suppressed the effect of prazosin, and it seems to be a significantly stronger stimulus than prazosin. Taken together, these findings provide new insights into the effects of α1-adrenergic receptors in the BLA on memory storage, during the stress experience.

Preliminary Validity of a Telephone-Based Neuropsychological Battery in a Consecutive Series of Persons with HIV Disease Referred for Clinical Evaluation.

The COVID-19 pandemic necessitated use of remote assessments by clinical neuropsychologists. Telehealth was particularly important for vulnerable groups, including persons living with HIV (PLWH); however, limited internet access can be a serious barrier to care. This study examined the preliminary validity of a telephone-based neuropsychological assessment in a clinical sample of PLWH. A consecutive series of 59 PLWH were assessed via telephone at an HIV clinic in the southern U.S. between April 2020 and July 2022. The battery included auditory-verbal neuropsychological tests of memory, attention, and executive functions, and questionnaires assessing self-reported mood and activities of daily living (ADL). Study measures demonstrated acceptable internal consistency. PLWH demonstrated worse neuropsychological performance compared with expectations derived from the normal curve and an HIV-seronegative adult sample (N = 44). PLWH assessed via telephone demonstrated similar impairment rates to that of a consecutive series of PLWH (N = 41) assessed in-person immediately prior to the pandemic. Higher telephone-based global neuropsychological scores were related to younger age, more education, better fund of knowledge, White race/ethnicity, fewer medical conditions, and fewer depression symptoms. Global neuropsychological impairment was strongly and independently associated with greater dependence in ADL domains, particularly for instrumental activities. Although telephone-based approaches to neuropsychological assessment are not ideal, these data provide support for the feasibility, internal consistency, and preliminary validity of this method in a consecutive clinical series of PLWH. The direct comparability of telephone-based and in-person neuropsychological assessments remains to be determined by prospective, counterbalanced study designs examining both PLWH and seronegative individuals.

Association of Liver Fibrosis with Cognitive Test Performance and Brain Volume Changes in the UK Biobank Study

AbstractBackgroundLiver fibrosis is a chronic liver condition that, though frequently subclinical, has widespread systemic effects. We hypothesized that liver fibrosis is associated with worse cognitive performance and corresponding brain imaging changes.MethodWe examined the association of liver fibrosis with cognition and brain volumes among adults in the UK Biobank study, which prospectively enrolled approximately 500,000 people starting in 2007 and subsequently collected cognitive test and brain MRI data for some participants. We included participants with available liver fibrosis, cognitive test, and brain imaging data. Liver fibrosis was defined at baseline using validated cutoffs of the Fibrosis‐4 (FIB‐4) liver fibrosis score. The primary cognitive test outcome was the Digit Symbol Substitution Test (DSST), a multidomain test. Secondary cognitive test outcomes were executive function tests (Trails A, Trails B, Reaction Time) and memory tests (Numeric Memory, Pairs Matching). The primary imaging outcome was white matter hyperintensity volume; secondary outcomes were hippocampal volume and total brain volume. We used multiple linear regression models to evaluate the association of liver fibrosis with cognitive test performance and brain volumes while adjusting for potential confounders.ResultsAmong 105,313 participants with cognitive test data, the mean age was 56.1 years and 56% were women. Standard liver chemistries were largely in the normal range. However, 2.0% (95% CI, 1.9‐2.1%) had liver fibrosis based on FIB‐4 scores. Cognitive tests were completed a median of 5.8 years after baseline liver fibrosis assessment. After adjusting for demographics, socioeconomics, education, body mass index, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with worse performance on the DSST (β = ‐0.40; 95% CI, ‐0.60, ‐0.20; P&lt;0.001) (Figure). Liver fibrosis was associated with worse executive function but not memory test performance (Table). We included 34,730 participants with brain MRI, obtained a median of 9.3 years after baseline. In adjusted models, liver fibrosis was associated with lower hippocampal volume (β = ‐58.8; 95% CI, ‐94.7, ‐22.9; P = 0.001) and higher white matter hyperintensity volumes (β = 1142.8; 95% CI, 311.6, 1973.9; P = 0.007) (Table, Figure).ConclusionLiver fibrosis is associated with worse cognitive performance, perhaps explained by hippocampal volume loss and white matter hyperintensity burden.