56 research outputs found
Genetic Risk Score Predicts Late-Life Cognitive Impairment
Introduction. A family history of Alzheimer's disease is a significant risk factor for its onset, but the genetic risk associated with possessing multiple risk alleles is still poorly understood. Methods. In a sample of 95 older adults (Mean age = 75.1, 64.2% female), we constructed a genetic risk score based on the accumulation of risk alleles in BDNF, COMT, and APOE. A neuropsychological evaluation and consensus determined cognitive status (44 nonimpaired, 51 impaired). Logistic regression was performed to determine whether the genetic risk score predicted cognitive impairment above and beyond that associated with each gene. Results. An increased genetic risk score was associated with a nearly 4-fold increased risk of cognitive impairment (OR = 3.824, P = .013) when including the individual gene polymorphisms as covariates in the model. Discussion. A risk score combining multiple genetic influences may be more useful in predicting late-life cognitive impairment than individual polymorphisms
Hippocampal subfield volumes in COVID-19: a preliminary multicenter study using 7T MRI
Background: Hippocampal formation atrophy is a well-established imaging biomarker of several neurological diseases, including Alzheimer\u27s disease, temporal lobe epilepsy, and schizophrenia. The hippocampus is divided into subfields that have different functions and vary in sensitivity to different diseases. This study investigates the potential interaction between COVID-19 and the various hippocampus subfields, which may shed light on the long-term neurological consequences of the virus.
Method: We obtained high-resolution T1-weighted (T1w) and T2-weighted (T2w) MRI images using 7T scanners located at three sites in two countries: Pittsburgh (n=14) and Texas (San Antonio and Houston) (n=40) in the USA, and Nottingham, UK (n=33). We evaluated the hippocampus subfields using the ASHS package [1-3]. Imaging sets of 51 subjects with minimal or no manual segmentation corrections (Figures 1 and 2) were included in the analysis. We conducted T-tests with Bonferroni correction, adjusting for age and intracranial volume to identify the differences in hippocampus subfield volumes across groups.
Result: Participants who needed admission into the ICU due to Covid-19 showed a significantly lower (p-value=0.0034) left CA1 volume compared to participants who did not require ICU (Figure 3). In addition, several other non-significant trends were observed.
Conclusion: Our preliminary findings suggest that Covid-19 may impact the hippocampus, particularly in patients who required intensive care. However, the study - as of to date - has a small sample size and lacks a comparison group with patients who were admitted into ICU for acute illnesses other than Covid-19. Additionally, longitudinal data is needed to track the long-term effects of the disease on the hippocampal subfields
Covid-19 may have a detrimental impact on sensorimotor function
Background: The long-term impact of COVID-19 on global health is still unknown. Sensorimotor biomarkers may be promising indicators of lasting effects of COVID-19. Although normal aging may cause changes in sensorimotor function, more severe changes may indicate the subsequent impacts of COVID-19 on brain health. The objective of this study was to investigate the association between COVID-19 and sensorimotor markers (grip strength, gait, and smell) in the 7T neuroCOVID consortium, which is comprised of 5 sites: The University of Texas Health Science Center at San Antonio, Houston Methodist Research Institute, The University of Pittsburgh, Massachusetts General Hospital, and Nottingham University (UK).
Methods: We studied 101 adult participants (mean age 60.9 ± 8.5 years, range 45-80 years, 51% women) without prior cognitive impairment or cerebrovascular disease from the 7T consortium across 3 US and 1 UK sites. The sample included 77 COVID-19 survivors and 24 healthy controls. Sensorimotor markers were measured for olfaction (n=59; 12-item Brief Smell Identification Test (B-SIT)), grip strength (n=97; measured using a hand dynamometer), and Gait (n=101; 4-meter normal walk time and n=99; 4-meter fast-paced walk time). To assess the association between COVID-19 and sensorimotor outcomes, we performed a series of linear regression models adjusting for age, sex, site, and handedness (grip strength only). Statistical significance was set at a 5% level.
Results: As compared to healthy controls, COVID-19 survivors, on average had a significantly reduced hand grip in the right hand (β ± standard error: -0.18 ± 0.07, p=0.006). We also observed associations with reduced gait speed. COVID-19 survivors, on average, had a slower walk time in both normal (0.17 ± 0.06, p=0.004) and fast-paced (0.04 ± 0.02, p=0.022) as compared to healthy controls. We did not observe any statistical associations between COVID-19 survivors and left-hand grip strength or B-SIT.
Conclusions: These results highlight that Covid-19 infection may have a detrimental impact on sensorimotor function. Additional analysis with a larger sample size are ongoing, which will allow us to further assess the effect of infection severity. Future studies will look to evaluate the association between sensorimotor markers, cognition, and ultra-high field 7T MRI-based imaging markers
Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging
Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition
Low thalamic activity during a digit-symbol substitution task is associated with symptoms of subjective cognitive decline
IntroductionSubjective cognitive decline (SCD) may represent the earliest preclinical stage of Alzheimer's Disease (AD) for some older adults. However, the underlying neurobiology of SCD is not completely understood. Since executive function may be affected earlier than memory function in the progression of AD, we aimed to characterize SCD symptoms in terms of fMRI brain activity during the computerized digit-symbol substitution task (DSST), an executive function task. We also explored associations of DSST task performance with brain activation, SCD severity, and amyloid-ß (Aß) load.MethodsWe analyzed data from 63 cognitively normal older individuals (mean age 73.6 ± 7.2) with varying degree of SCD symptoms. Participants completed a computerized version of DSST in the MR scanner and a Pittsburgh Compound-B (PiB)-PET scan to measure global cerebral Aß load.ResultsA voxel-wise analysis revealed that greater SCD severity was associated with lower dorsomedial thalamus activation. While task performance was not associated with brain activation nor Aß load, slower reaction time was associated with greater SCD severity.DiscussionThe observed lower dorsomedial thalamus activation may reflect declining familiarity-based working memory and the trans-thalamic executive function pathway in SCD. SCD symptoms may reflect altered neural function and subtle decline of executive function, while Aß load may have an indirect impact on neural function and performance. Self-perceived cognitive decline may serve as a psychological/subjective marker reflecting subtle brain changes
Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer's disease
An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials
Subjective Cognitive Decline in Older Adults: An Overview of Self-Report Measures Used Across 19 International Research Studies
Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures- approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcome
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Cognitive Deficits in Unaffected First-Degree Relatives of Schizophrenia Patients: A Meta-analytic Review of Putative Endophenotypes
Cognitive deficits may index genetic liability for schizophrenia and are candidate endophenotypes for the illness. In order to compare the degree of sensitivity among cognitive tasks to group differences between healthy relatives and controls and the influence of moderator variables, this review reports mean effect sizes for 43 cognitive test scores from 58 studies of cognitive performance in the unaffected adult relatives of schizophrenia patients. Results indicate reliable relative–control differences, in the small to medium effect size range, over a diverse array of tasks, with the largest effect sizes seen in complex versions of continuous performance tasks, auditory verbal learning, design copy tests, and category fluency. Three study design features were found to have significant effects on overall effect size magnitude: groups unmatched on education, groups unmatched on age, and asymmetric psychiatric exclusion criteria. After excluding studies with the latter 2 design features, reliable performance differences were still observed over a smaller subset of cognitive test variables, with the largest effect sizes seen in Trails B (d = 0.50) and performance measures from both simple (d = 0.56) and complex (d = 0.60–0.66) versions of continuous performance tasks. Four of the 6 largest effect sizes reflect tasks with high executive control demands in common, such as working memory demands, set shifting, and inhibition of prepotent responses. Cognitive deficits, particularly those tapping such executive control functions, should continue to prove valuable as endophenotypes of interest in the search for specific genetic factors related to schizophrenia
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