Related Cognitive Decline Research Articles

Cognitive decline in relation to later-life high temperature exposure in a Chinese nationwide cohort

Cognitive decline in relation to later-life high temperature exposure in a Chinese nationwide cohort

Association between risk of Alzheimer’s disease and related dementias and angiotensin receptor Ⅱ blockers treatment for individuals with hypertension in high-volume claims data

Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer's disease and related dementias (AD/ADRD) and cognitive decline have been inconclusive. Individuals with hypertension who do not have any prior ADRD diagnosis were included in this retrospective cohort study from Optum's de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood-brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan-Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses. From 6,390,826 individuals with hypertension, there were 1,839,176 ARB users, 3,366,841 non-ARB AHM users, and 1,184,809 AHM non-users. The unadjusted KM curve showed that ARB users had lower cumulative hazard than other AHM users or AHM non-users (P<0.0001). In Cox PH analysis, ARB users showed a 20% lower adjusted hazard of developing ADRD compared to angiotensin-converting enzyme inhibitor (ACEI) users and a 29% and 18% reduced hazard when compared to non-ARB/ACEI AHM users and AHM non-users (all P<0.0001). Consumption of BBB-crossing ARBs was linked to a lower hazard of ADRD development than non-BBB-crossing ARBs, undetermined ARBs, and non-consumption of AHMs by 11%, 25%, and 31% (all P<0.0001). This study suggests that ARBs are superior to ACEIs, non-ARB/ACEI AHMs, or non-use of AHMs in reducing the hazard of ADRD among patients with hypertension. Also, BBB-permeability in ARBs was associated with lower ADRD incidence. There is no cure for AD, ADRD, or vascular dementia; hence, these findings are significant in preventing those disorders in an inexpensive, convenient, and safe way. Limitations in claims data should be considered when interpreting our findings. This research was supported by the National Institute on Aging grants (R01AG084236, R01AG083039, RF1AG072799, R56AG074604).

Predictors of Verbal Fluency Decline in People with Cognitive Dysfunctions

Background: Verbal fluency impairment is a prospective risk for dementia and conversion from Mild Cognitive Impairment (MCI) to dementia. In elderly may be related to the deficits in other cognitive domains and also with age and duration of cognitive decline. The AIM: The purpose of this study was to analyze the results of Verbal Fluency Tests (VFT) in people with cognitive decline in relation to age, duration of the cognitive decline and the level of cognitive dysfunction. Methods: 279 (177 females and 102 males) people with cognitive decline (MCI and dementia), aged 50-91 years were included in the study. For the evaluation of general cognitive abilities Mini Mental State Examination (MMSE) and for assessment of verbal fluency– Verbal Fluency Test (phonological and categorical) was applied. Statistical analysis was performed using nonparametric tests. Factor analysis of the main components of Verbal Fluency Test and MMSE were used and one-way ANOVA test in the prediction analysis was applied. Results: All dimensions of verbal fluency subscales and MMSE are explained by one factor, which indicate their similar etiological mechanism. The longer duration of the cognitive impairment the worse results in VFT and MMSE. Worse results of MMSE were associated with worse performance on VFT, the most important critical moment of deterioration was associated with scores in the range of 25-23 and 17-18 MMSE points, however there are some differences between verbal fluency categories. The most significant periods of duration of the disease for VFT performance were months 6 and 9, and for the category of categorical fluency months 6,9, as well as 26, 31-32 and 36. No significant associations between the age and VFT and MMSE results were observed. Conclusions: Verbal fluency decline is related to global cognitive functioning. Longer duration time of the disease was associated with the level of verbal fluency and cognitive decline, while the age of patients is not an important factor. The verbal fluency deterioration occurs in leaps and bounds, the critical moments for verbal fluency decline may be established based on the duration of the illness and global functioning measured by MMSE.

Predicting white-matter hyperintensity progression and cognitive decline in patients with cerebral small-vessel disease: a magnetic resonance-based habitat analysis.

White-matter hyperintensity (WMH) is the key magnetic resonance imaging (MRI) marker of cerebral small-vessel disease (CSVD). This study aimed to investigate whether habitat analysis based on physiologic MRI parameters can predict the progression of WMH and cognitive decline in CSVD. Diffusion- and perfusion-weighted imaging data were obtained from 69 patients with CSVD at baseline and at 1-year of follow-up. The white-matter region was classified into constant WMH, growing WMH, shrinking WMH, and normal-appearing white matter (NAWM) according to the T2-fluid-attenuated inversion recovery (FLAIR) sequences images at the baseline and follow-up. We employed k-means clustering on a voxel-wise basis to delineate WMH habitats, integrating multiple diffusion metrics and cerebral blood flow (CBF) values derived from perfusion data. The WMH at the baseline and the predicted WMH from the habitat analysis were used as regions of avoidance (ROAs). The decreased rate of global efficiency for the whole brain structural connectivity was calculated after removal of the ROA. The association between the decreased rate of global efficiency and Montreal Cognitive Assessment (MoCA) and mini-mental state examination (MMSE) scores was evaluated using Pearson correlation coefficients. We found that the physiologic MRI habitats with lower fractional anisotropy and CBF values and higher mean diffusivity, axial diffusivity, and radial diffusivity values overlapped considerably with the new WMH (growing WMH of baseline) after a 1-year follow-up; the accuracy of distinguishing growing WMH from NAWM was 88.9%±12.7% at baseline. Similar results were also found for the prediction of shrinking WMH. Moreover, after the removal of the predicted WMH, a decreased rate of global efficiency had a significantly negative correlation with the MoCA and MMSE scores at follow-up. This study revealed that a habitat analysis combining perfusion with diffusion parameters could predict the progression of WMH and related cognitive decline in patients with CSVD.

Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome.

We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer's disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolatedfrom postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.

Moderation of thyroid hormones for the relationship between amyloid and tau pathology

BackgroundAltered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aβ) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aβ and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aβ and tau deposition.MethodsThis cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [11C]-Pittsburgh compound B (PiB)- PET and [18F] AV-1451 PET.ResultsNo associations were found between either thyroid hormones or TSH and Aβ and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aβ on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aβ deposition was not significant, whereas the interaction between fT3 and Aβ deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aβ and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aβ on tau deposition.ConclusionOur findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aβ and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aβ-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results.

Antigen-specific age-related memory CD8 T cells induce and track Alzheimer’s-like neurodegeneration

Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer's disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T ("hiT") cells act upstream of Aβ/pTau after brain injury. Here, we examine whether hiT cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in our hiT mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. We identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.

RAGE inhibition to decrease cancer therapy related cardiotoxicity in women with early breast cancer (RAGE).

TPS619 Background: Anthracyclines are commonly used to treat high risk early-stage breast cancer (BC). Anthracycline-induced myocardial toxicity is a rare but morbid complication in BC survivors. The mechanism is not completely elucidated but may involve the generation of reactive oxygen species and other inflammatory mediators. RAGE, the receptor for advanced glycation end-products, signaling is upregulated in inflammatory conditions and has been linked to the development and progression of cardiovascular disease and cancer. In experimental models, blocking RAGE protects against cardiac damage and reduces the development of metastases. TTP488 is an orally bioavailable small molecule inhibitor of RAGE. This project is designed to characterize the role of TTP488 to decrease therapy related cardiac toxicity, and it will provide preliminary data about the safety, tolerability, and pharmacokinetics (PK) of common BC (neo)adjuvant chemotherapy agents in the presence of TTP488. Methods: Eligible patients have stage I-III breast cancer and are planned to receive chemotherapy. Enrolled patients will be assigned to 1 of 4 cohorts based on the chemotherapy regimen assigned for the last 2 doses of planned therapy. In Cohort 1, 6 patients will receive dose dense paclitaxel (ddT). In Cohort 2, 6 patients will receive docetaxel and cyclophosphamide (TC). In Cohort 3, 6 patients will receive docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). In Cohort 4, 6 patients will receive dose dense doxorubicin and cyclophosphamide (ddAC). All chemotherapy is dosed per standard institutional operational practice. For each patient, the first dose of chemotherapy is given in the absence of study drug to serve as the control for the safety and PK assessments. On day -7, prior to the 2nd dose of chemotherapy, TTP 488, 60mg daily for 6 days followed by 20mg daily, is administered and then subjects receive the 2nd dose of chemotherapy. With each cycle, hs-troponin and B-type natriuretic peptide (BNP) are collected prior to chemotherapy administration, and at 4hrs(hs-troponin only) and 24hrs after chemotherapy administration. With each cycle, PK sampling occurs prior to and immediately after chemotherapy (0hr), 1hr, 4hr, and 24hrs after chemotherapy. Primary objectives are to evaluate the change in high sensitivity troponin level before and during treatment with TTP488 and to evaluate the safety and tolerability of TTP488 when administered with chemotherapy. The secondary objective is to characterize the PK and bioavailability of chemotherapy agents with TTP488. Descriptive statistics for the change in troponin level and safety will be summarized. As of 2/1/24, 4 patients have been enrolled, with 4 undergoing screening. At the completion of this trial, we plan a randomized trial to evaluate the role of TTP488 to decrease cardiotoxicity, cancer related cognitive decline and disease recurrence. Clinical trial information: NCT05256745 .

Impact of Fat Distribution and Metabolic Diseases on Cerebral Microcirculation: A Multimodal Study on Type 2 Diabetic and Obese Patients.

Background: Since metabolic diseases and atherosclerotic vascular events are firmly associated, herein we investigate changes in central microcirculation and atherosclerosis-related body fat distribution in patients with type 2 diabetes mellitus and obesity. Methods: Resting brain perfusion single-photon emission computed tomography (SPECT) imaging with Technetium-99m hexamethylpropylene amine oxime ([99mTc]Tc-HMPAO SPECT) was performed, and the breath-holding index (BHI) and carotid intima-media thickness (cIMT) were measured to characterise central microcirculation. Besides CT-based abdominal fat tissue segmentation, C-peptide level, glycaemic and anthropometric parameters were registered to search for correlations with cerebral blood flow and vasoreactivity. Results: Although no significant difference was found between the resting cerebral perfusion of the two patient cohorts, a greater blood flow increase was experienced in the obese after the breath-holding test than in the diabetics (p < 0.05). A significant positive correlation was encountered between resting and provocation-triggered brain perfusion and C-peptide levels (p < 0.005). BMI and cIMT were negatively correlated (rho = -0.27 and -0.23 for maximum and mean cIMT, respectively), while BMI and BHI showed a positive association (rho = 0.31 and rho = 0.29 for maximum and mean BHI, respectively), which could be explained by BMI-dependent changes in fat tissue distribution. cIMT demonstrated a disproportional relationship with increasing age, and higher cIMT values were observed for the men. Conclusions: Overall, C-peptide levels and circulatory parameters seem to be strong applicants to predict brain microvascular alterations and related cognitive decline in such patient populations.

Sleep Quality Moderates the Associations between Cardiorespiratory Fitness and Hippocampal and Entorhinal Volume in Middle-Aged and Older Adults.

As individuals age, the entorhinal cortex (ERC) and hippocampus-crucial structures for memory-tend to atrophy, with related cognitive decline. Simultaneously, lifestyle factors that can be modified, such as exercise and sleep, have been separately linked to slowing of brain atrophy and functional decline. However, the synergistic impact of fitness and sleep on susceptible brain structures in aging adults remains uncertain. We examined both independent and interactive associations of fitness and subjective sleep quality with regard to ERC thickness and hippocampal volume in 598 middle-aged and older adults from the Human Connectome Lifespan Aging Project. Cardiorespiratory fitness was assessed using the 2-min walk test, whereas subjective sleep quality was measured with the continuous Pittsburgh Sleep Quality Index global score. High-resolution structural magnetic resonance imaging was used to examine mean ERC thickness and bilateral hippocampal volume. Through multiple linear regression analyses, we investigated the moderating effects of subjective sleep quality on the association between fitness and brain structure, accounting for age, sex, education, body mass index, gait speed, and subjective physical activity. We found that greater cardiorespiratory fitness, but not subjective sleep quality, was positively associated with bilateral hippocampal volume and ERC thickness. Notably, significant interaction effects suggest that poor subjective sleep quality was associated with a weaker association between fitness and both hippocampal volume and ERC thickness. Findings suggest the potential importance of both cardiorespiratory fitness and subjective sleep quality in preserving critical, age-vulnerable brain structures. Interventions targeting brain health should consider potential combined effects of sleep and fitness on brain health.

Beyond Frequency Bands: Complementary-Ensemble-Empirical-Mode-Decomposition-Enhanced Microstate Sequence Non-Randomness Analysis for Aiding Diagnosis and Cognitive Prediction of Dementia.

Exploring the spatiotemporal dynamic patterns of multi-channel electroencephalography (EEG) is crucial for interpreting dementia and related cognitive decline. Spatiotemporal patterns of EEG can be described through microstate analysis, which provides a discrete approximation of the continuous electric field patterns generated by the brain cortex. Here, we propose a novel microstate spatiotemporal dynamic indicator, termed the microstate sequence non-randomness index (MSNRI). The essence of the method lies in initially generating a sequence of microstate transition patterns through state space compression of EEG data using microstate analysis. Following this, we assess the non-randomness of these microstate patterns using information-based similarity analysis. The results suggest that this MSNRI metric is a potential marker for distinguishing between health control (HC) and frontotemporal dementia (FTD) (HC vs. FTD: 6.958 vs. 5.756, p < 0.01), as well as between HC and populations with Alzheimer's disease (AD) (HC vs. AD: 6.958 vs. 5.462, p < 0.001). Healthy individuals exhibit more complex macroscopic structures and non-random spatiotemporal patterns of microstates, whereas dementia disorders lead to more random spatiotemporal patterns. Additionally, we extend the proposed method by integrating the Complementary Ensemble Empirical Mode Decomposition (CEEMD) method to explore spatiotemporal dynamic patterns of microstates at specific frequency scales. Moreover, we assessed the effectiveness of this innovative method in predicting cognitive scores. The results demonstrate that the incorporation of CEEMD-enhanced microstate dynamic indicators significantly improved the prediction accuracy of Mini-Mental State Examination (MMSE) scores (R2 = 0.940). The CEEMD-enhanced MSNRI method not only aids in the exploration of large-scale neural changes in populations with dementia but also offers a robust tool for characterizing the dynamics of EEG microstate transitions and their impact on cognitive function.

Yoga improves self-reported cognitive function among cancer survivors: results from the STAYFit trial

IntroductionVarious physical activity-based interventions have been tested to determine their efficacy in improving cancer related cognitive decline (CRCD), however the role of mind-body practices such as yoga remains to be explored. In this manuscript we present preliminary effects of yoga vs. aerobic and stretching-toning modalities of exercise on CRCD among adult cancer survivors.MethodsParticipants (N = 78) were randomized to one of the three exercise groups for a duration of 12-weeks and engaged in ≥150 min per week of supervised group exercises. At baseline and following the 12-week interventions, participants completed the Functional Assessment of Cancer Therapy–Cognitive Function.ResultsResults demonstrated a significant group*time interaction for FACT-Cog perceived cognitive abilities subscale, with participants in the yoga group demonstrating a significant increase as compared to the aerobic and stretching-toning groups. The FACT-Cog total score showed a significant time effect with all groups demonstrating a significant increase at follow-up. Other subscales did not show any significant improvements.DiscussionThese findings provide promising evidence for the effects of yoga on self-reported cognitive function in cancer survivors. Notably, 12-weeks of yoga showed an increase in the perceived cognitive abilities and demonstrated a clinically meaningful increase in total cognitive function as measured by the FACT-Cog, suggesting that this exercise modality has the potential to impact this important health outcome during cancer survivorship.Trial registrationClinicalTrials.gov, identifier: NCT03650322.

Relationship of physical activity and cognitive functioning among breast cancer survivors: a cross-sectional analysis.

Cancer related cognitive decline is a common long-term side effect of cancer and its treatments among breast cancer survivors. Physical activity is a modifiable risk factor related to cognitive decline. However, existing research lacks consensus regarding the relationship between cognition and exercise as well as the impact of cancer treatments on this relationship. Baseline data from an ongoing randomized clinical trial was utilized to examine the relationship between self-reported and objectively measured cognition with physical activity. Exploratory analyses examined cancer treatments as potential moderators. Breast cancer survivors (N = 253) completed a battery of neurocognitive tests, the PROMIS Cognitive abilities questionnaire, medical charts abstracted for treatment information, and wore an ActiGraph accelerometer at the waist for 7 days. Data were analyzed using multiple linear regression models. Participants were on average 58.5 (SD = 8.88) years old, diagnosed 3 years prior to enrollment (SD = 1.27) with 57% treated with chemotherapy and 80% receiving hormone therapy at baseline. Better self-reported cognitive ability was significantly associated with greater min of moderate to vigorous physical activity (MVPA; β = 0.070, se = 0.028, p = 0.012). There were no significant associations with any objectively measured cognitive domains. Time since diagnosis (years) was a significant moderator of MVPA and Processing Speed (β = -0.103, se = 0.043, p = 0.017). Treatment with chemotherapy and/or hormones did not significantly moderate the relationship between MVPA and any of the cognitive measures or domains. Findings suggest that physical activity is related to self-reported cognition but not objectively measured cognition. Greater physical activity was associated with faster processing speed in participants closer in time to their cancer diagnosis. These results emphasize the need for more research to understand when cancer survivors may benefit from physical activity and what aspects of cognition may be improved.

Correlational patterns of neuronal activation and epigenetic marks in the basolateral amygdala and piriform cortex following olfactory threat conditioning and extinction in rats.

Cumulative evidence suggests that sensory cortices interact with the basolateral amygdala (BLA) defense circuitry to mediate threat conditioning, memory retrieval, and extinction learning. The olfactory piriform cortex (PC) has been posited as a critical site for olfactory associative memory. Recently, we have shown that N-methyl-D-aspartate receptor (NMDAR)-dependent plasticity in the PC critically underpins olfactory threat extinction. Aging-associated impairment of olfactory threat extinction is related to the hypofunction of NMDARs in the PC. In this study, we investigated activation of neuronal cFos and epigenetic marks in the BLA and PC using immunohistochemistry, following olfactory threat conditioning and extinction learning in rats. We found highly correlated cFos activation between the posterior PC (pPC) and BLA. cFos was correlated with the degree of behavioral freezing in the pPC in both adult and aged rats, and in the BLA only in adult rats. Markers of DNA methylation 5 mC and histone acetylation H3K9/K14ac, H3K27ac, and H4ac exhibited distinct training-, region-, and age-dependent patterns of activation. Strong correlations of epigenetic marks between the BLA and pPC in adult rats were found to be a general feature. Conversely, aged rats only exhibited correlations of H3 acetylations between the two structures. Histone acetylation varied as a function of aging, revealed by a reduction of H3K9/K14ac and an increase of H4ac in aged brains at basal condition and following threat conditioning. These findings underscore the coordinated role of PC and BLA in olfactory associative memory storage and extinction, with implications for understanding aging related cognitive decline.

A mediation analysis of the role of total free fatty acids on pertinence of gut microbiota composition and cognitive function in late life depression

BackgroundExtensive evidence demonstrates correlations among gut microbiota, lipid metabolism and cognitive function. However, there is still a lack of researches in the field of late-life depression (LLD). This research targeted at investigating the relationship among gut microbiota, lipid metabolism indexes, such as total free fatty acids (FFAs), and cognitive functions in LLD.MethodsTwenty-nine LLD patients from the Cognitive Outcome Cohort Study of Depression in Elderly were included. Cognitive functions were estimated through the Chinese version of Montreal Cognitive Assessment (MoCA). Blood samples were collected to evaluate serum lipid metabolism parameters. Fecal samples were evaluated for gut microbiota determination via 16S rRNA sequencing. Spearman correlation, linear regression and mediation analysis were utilized to explore relationship among gut microbiota, lipid metabolism and cognitive function in LLD patients.ResultsSpearman correlation analysis revealed significant correlations among Akkermansia abundance, total Free Fatty Acids (FFAs) and MoCA scores (P < 0.05). Multiple regression indicated Akkermansia and total FFAs significantly predicted MoCA scores (P < 0.05). Mediation analysis demonstrated that the correlation between decreased Akkermansia relative abundance and cognitive decline in LLD patients was partially mediated by total FFAs (Bootstrap 95%CI: 0.023–0.557), accounting for 43.0% of the relative effect.ConclusionThese findings suggested a significant relationship between cognitive functions in LLD and Akkermansia, as well as total FFAs. Total FFAs partially mediated the relationship between Akkermansia and cognitive functions. These results contributed to understanding the gut microbial-host lipid metabolism axis in the cognitive function of LLD.

Exercise leads to sex-specific recovery of behavior and pathological AD markers following adolescent ethanol exposure in the TgF344-AD model.

Human epidemiological studies suggest that heavy alcohol consumption may lead to earlier onset of Alzheimer's Disease (AD), especially in individuals with a genetic predisposition for AD. Alcohol-related brain damage (ARBD) during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study investigates if voluntary exercise in mid-adulthood can recover memory deficits caused by the interactions between adolescence ethanol exposure and AD-transgenes. Male and female TgF344-AD and wildtype F344 rats were exposed to an intragastric gavage of water (control) or 5 g/kg of 20% ethanol (adolescent intermittent ethanol; AIE) for a 2 day on/off schedule throughout adolescence (PD27-57). At 6 months old, rats either remained in their home cage (stationary) or were placed in a voluntary wheel running apparatus for 4 weeks and then underwent several behavioral tests. The number of cholinergic neurons in the basal forebrain and measure of neurogenesis in the hippocampus were assessed. Voluntary wheel running recovers spatial working memory deficits selectively in female TgF344-AD rats exposed to AIE and improves pattern separation impairment seen in control TgF344-AD female rats. There were sex-dependent effects on brain pathology: Exercise improves the integration of recently born neurons in AIE-exposed TgF344-AD female rats. Exercise led to a decrease in amyloid burden in the hippocampus and entorhinal cortex, but only in male AIE-exposed TgF344-AD rats. Although the number of basal forebrain cholinergic neurons was not affected by AD-transgenes in either sex, AIE did reduce the number of basal forebrain cholinergic neurons in female rats. These data provide support that even after symptom onset, AIE and AD related cognitive decline and associated neuropathologies can be rescued with exercise in unique sex-specific ways.

Cognitive Benefits of Physical Activity in the Elderly: A Narrative Review

Abstract A huge focus of research has been on the pharmacological trials to find drugs that work to stall the onset of age related cognitive decline and subsequent neurodegenerative disorders like dementia, but pharmacological interventions have not been able to help with cure and hence there has been a shift of focus to other nonpharmacological and behavioral interventions like physical activity (PA) along with the use of medications. There is moderate evidence supporting different forms of exercise for lowering the risk of cognitive decline and dementia. PA has positive effects on the global cognition of the elderly and helps maintain hippocampal volume. Aerobic exercise was found to be the most beneficial among different other forms of PA. Regular involvement in PA not only helps in the prevention and control of various diseases but also is increasingly recommended as a strategy to promote health and encourage the maintenance of functional capacity in the elderly. The main objective of this review is to discuss the effects of PA on brain health and cognitive functions of older adults from a psychophysiological perspective. Important underlying molecular mechanisms have also been discussed which would provide an idea of the biological basis of the same.

Effects of enlarged perivascular space in Parkinson’s disease and related cognitive decline

AbstractBackgroundThe glymphatic system plays a key role in brain toxics clearance. Many studies demonstrated that disrupted glymphatic system is responsible for insufficient clearance of Aβ and tau protein in Alzheimer’s disease. Its contribution in Parkinson’s disease (PD) and related cognitive function decline has not been fully studied. Enlarged perivascular space (PVS) may be a sign of glymphatic function decline, hence leading to PD pathology and PD‐related cognitive function decline. Our objective was to study the PVS in PD and related cognitive function decline.MethodHigh‐resolution T1‐weighted and T2‐weighted MRI data were acquired from 60 PD patients and 58 age‐ and sex‐matched controls. The PVS from the centrum semiovale of the white matter (CS), striatum (ST) and midbrain (MB) of the basal ganglia were segmented using the enhanced images from T1‐ and T2‐weighted images. Total intracranial volumes (TIV) were obtained to account for individual head sizes. Montreal Assessment of Cognition (MoCA) was used to quantify cognitive function. MDS‐UPDRS III scores were obtained for motor function deficits. ANCOVA was used to compare PVS metrics between PD patients and controls adjusted for age, sex, and TIV. Multiple regression was used to corelate PVS metrics and MoCA in PD patients with age, sex, MDS‐UPDRS III score and TIV as covariates.ResultCompared to controls, PD patients had enlarged PVS in MB (p = 0.0028), but not in CS and ST. PVS metrics were strongly associated with age (p &lt; 0.0001 for CS, p &lt; 0.0001 for ST, and p = 0.0092 for MB), but only PVS in MB was associated sex (p = 0.0001). In PD patients, the MoCA was associated with the PVS in CS (p = 0.0132), MB (p = 0.0275) and total PVS (p = 0.0088) but only trending with PVS in ST (p = 0.0737). There is no association between MoCA and PVS metrics in controls.ConclusionOur findings suggested that PD patients have enlarged PVS in the midbrain, and their cognitive function is associated with enlarged PVS in both CS and MB. The enlarged PVS might be an etiological factor for PD pathology and related cognitive decline.

Cognitive Decline Associated with Longitudinal Changes in 24‐h Ambulatory Blood Pressure Variability

AbstractBackgroundCognitive decline has been associated with variability in blood pressure (BP). However, whether the increment of the BP variability during follow‐up precedes cognitive decline remains undocumented. We aimed this study to investigate cognitive decline in relation to longitudinal changes in 24‐h reading‐to‐reading BP variability.MethodsWe conducted an observational longitudinal study that included 717 dementia‐free participants from the Maracaibo Aging Study who underwent follow‐up assessment in both 24‐h ambulatory BP monitoring and cognitive tests between 1998 and 2015. Cognitive domains consisted of selective reminding tests (total, long‐term, short‐term, and recognition memory) and the Mini‐Mental State Examination (MMSE). Cognitive decline was a longitudinal decrease in cognitive scores. Participants underwent 24‐h ambulatory BP monitoring between 2‐4 times – with at least one‐year interval. Systolic and diastolic BP variability was studied during 24‐h and divided into daytime (from 06h00 to 23h00), and nighttime (23h00 to 06h00) periods. To account for BP level, we used variability independent of the mean (VIM) to compute systolic and diastolic BP variability. Other measures of BP variability included the nocturnal BP drop in comparison to the daytime BP level, which was estimated as the night‐to‐day ratio. Statistics included multivariate linear regression mixed models.ResultsOverall, the mean age was 65.6±7.36 years old and 66.5% (n = 447) of the participants were women. In mixed models, a decline in all memory domains was associated with greater variability in the 24‐h, daytime, and nighttime systolic BP during follow‐up, with an estimated decline in cognitive scores ranging from ‐0.2 to ‐0.04 points per unit increase in VIM systolic BP during follow‐up (P values ranged from 0.022 to 0.003). Decline in total, short‐term, and MMSE memory domains was associated with greater 24‐h and daytime diastolic BP variability (P≤0.015). A lower night‐to‐day dipping ratio during follow‐up increased the risk of cognitive decline, with a ‐5.8 to ‐1.6 decline in long‐term memory and MMSE scores; respectively (P≤0.037).ConclusionsCognitive decline associates with greater reading‐to‐reading 24‐h BP variability and lower falls in nocturnal BP over time. These findings might be indicative of deteriorated regulatory mechanisms to maintain steady BP levels as individuals age.

Changes in cortical thickness along the Alzheimer disease continuum in people with Down syndrome

AbstractBackgroundTriplication of the APP allele in Down syndrome (DS) leads to excess amyloid production and Alzheimer’s disease (AD) related cognitive decline. Key biomarkers (amyloid, tau, neurodegeneration) can identify pathological processes that occur before clinical symptoms and more precisely stage adults with DS along the AD continuum. Previous research has used changes in cortical thickness (CT) as an indicator of neurodegeneration in autosomal‐dominant AD1, but not DS‐related AD. It is unclear when and where cortical thinning occurs along the AD continuum in DS and if these differences are associated with increasing AD pathology.MethodCross‐sectional analysis compared DS participants from the Alzheimer Biomarkers Consortium‐Down Syndrome (106 amyloid‐/cognitively unimpaired, nonclinical, 20% reserved for receiver‐operating characteristic, ROC, analyses; 45 amyloid+/cognitively unimpaired, preclinical; 27 amyloid+/cognitively impaired, clinical) who had amyloid positron emission tomography and magnetic resonance imaging (MRI). Amyloid positivity was defined using standardized uptake value ratio (partial volume corrected) cortical mean values (1.42/1.19 for PIB/AV452) and impairment was based on consensus diagnosis. CT differences between nonclinical and clinical groups were calculated in FreeSurfer v5.3 for multiple thresholds (p&lt;.05/.01/.005/.001/.0005/.0001) using a cluster‐wise false discovery rate of .001, corrected across hemispheres, after controlling for age and sex. CT values were extracted for each threshold and used in ROC analyses (nonclinical reserved participants compared against preclinical and preclinical compared against clinical) to identify key cortical regions that best discriminated amyloid positivity and between unimpaired and impaired.ResultSignificant decreases in parietal and inferior temporal CT were observed between nonclinical and clinical (Figures 1 and 2). ROC analyses identified regions in the left (threshold .05) and right (threshold .005) hemispheres that best differentiated nonclinical from preclinical. Observed area under the curves (AUCs) of .772 and .830 exceeded those previously reported for autosomal‐dominant AD (.547/.540)1. Analyses differentiating preclinical from clinical observed AUCs of .786 for left (threshold .0005) and .770 for right (threshold .0005) hemispheres.ConclusionCT differences primarily within posterior cortical regions differentiated adults with DS by amyloid status and cognitive impairment. CT differences were more diffuse for amyloid positivity but more focal for impairment.1. Dincer (2020). NeuroImage: Clinical, 28, 102491.2. Su (2019). Alzheimer’s Dement, 11, 180‐190.