Cognitive Decline In Individuals Research Articles

Understanding the Bidirectional Relationship between Alzheimer's and Depression

Abstract: With an ageing global population, understanding the potential links between mental health and neurodegenerative disorders has become increasingly crucial for comprehensive patient care. A comprehensive search of electronic databases yielded a selection of studies encompassing clinical trials, longitudinal cohorts, and cross-sectional analyses, published between 2000 and 2023. Key inclusion criteria focused on investigations involving both Alzheimer's disease and depression, encompassing a range of methodologies, including neuroimaging, epidemiological surveys, and clinical assessments. The analysis reveals compelling evidence of a bidirectional relationship, where depression serves as a potential precursor to Alzheimer's disease, and vice versa. Neurobiological mechanisms, including neuroinflammation, neurotransmitter imbalances, and genetic predispositions, emerge as significant contributors to this complex association. Furthermore, psychosocial factors, such as chronic stress and social isolation, are identified as potential accelerators of cognitive decline in individuals with co-occurring depression and Alzheimer's. Additionally, therapeutic interventions targeting both conditions concurrently exhibit promising outcomes in mitigating cognitive decline and ameliorating depressive symptoms. Approaches encompassing cognitive behavioural therapy, pharmacological interventions, and lifestyle modifications demonstrate potential avenues for integrated treatment strategies. This review underscores the imperative for a multidisciplinary approach to patient care, emphasizing the importance of early detection and intervention for individuals presenting with symptoms of depression and cognitive impairment. Future research avenues should prioritize longitudinal studies with larger cohorts to delineate the causal pathways and further elucidate effective treatment modalities for this intricate comorbidity. By unravelling the complexities of the Alzheimer's-depression nexus, we pave the way for more targeted and comprehensive interventions to improve the lives of those affected by these debilitating conditions.

Does the coexistence of pain and depressive symptoms accelerate cognitive decline?

Objectives Investigate whether the coexistence of pain and depressive symptoms is a risk factor for cognitive decline in individuals aged 50 or older. Method Longitudinal trajectory study involving 4,718 participants from the English Longitudinal Study of Ageing (ELSA). Joint pain was self-reported, and intensity was classified as mild, moderate/intense. Depressive symptoms were investigated using the Centre for Epidemiologic Studies Depression Scale (CES-D-8 ≥ 4). The sample was divided into six groups: no pain and no depression (NP/NDe), mild pain and no depression (MP/NDe), moderate/intense pain and no depression (M-IP/NDe), no pain and depression (NP/De), mild pain and depression (MP/De), and moderate/intense pain and depression (M-IP/De). The outcome of interest was performance in memory, executive function, and global cognition. Generalised linear mixed models were used to analyse performance in the cognitive domains and global cognition score as a function of pain and depressive symptoms during 12 years of follow-up. Results Over time, individuals with M-IP/De had a greater memory decline (-0.038 SD/year, 95%CI: −0.068 to −0.007) and the global cognition score (-0.033 SD/year, 95%CI: −0.063 to −0.002) than those with NP/NDe. Conclusion The coexistence of moderate/intense pain and depressive symptoms is a risk factor for the decline of global cognition and memory.

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.

Examining the Stability and Predictive Utility of Across- and Within-Domain Intra-Individual Variability in Mild Cognitive Impairment.

Dispersion is a form of intra-individual variability across neuropsychological tests that has been shown to predict cognitive decline. However, few studies have investigated the stability and predictive utility of both across- and within-domain dispersion. The current study aims to fill these gaps in the literature by examining multiple indices of dispersion in a longitudinal clinical sample of individuals diagnosed with mild cognitive impairment (MCI) at baseline. Two hundred thirty-eight MCI patients from a cognitive disorders clinic underwent testing at baseline and after approximately 1.5 years. Linear regression was used to examine whether baseline across- and within-domain dispersion predicted cognitive decline in individuals whose diagnostic classification progressed to dementia (i.e., MCI-Decline) and those who retained an MCI diagnosis at follow-up (i.e., MCI-Stable). Cognitive decline was operationalized dichotomously using group status and continuously using standardized regression-based (SRB) z-scores. Dispersion variables at baseline and follow-up were positively correlated in both groups, with the exception of within-domain executive functioning and language dispersion in the MCI-Decline group. None of the dispersion variables predicted diagnostic conversion to MCI. Using SRB z-scores, greater across-domain dispersion predicted greater overall cognitive decline at follow-up, but this was not the case for within-domain variables with the exception of visuospatial skills. Results suggest that across- and within-domain dispersion are relatively stable across time, and that across-domain dispersion is predictive of subtle cognitive decline in patients with MCI. However, these results also highlight that findings may differ based on the tests included in dispersion calculations.

Detecting and Predicting Cognitive Decline in Individuals with Traumatic Brain Injury: A Longitudinal Telephone-Based Study.

Traumatic brain injuries (TBIs) can lead to long-lasting cognitive impairments, and some survivors experience cognitive decline post-recovery. Early detection of decline is important for care planning, and understanding risk factors for decline can elucidate targets for prevention. While neuropsychological testing is the gold standard approach to characterizing cognitive function, there is a need for brief, scalable tools that are capable of detecting clinically significant changes in post-TBI cognition. This study examines whether a clinically significant change can be detected using the Brief Test of Adult Cognition by Telephone (BTACT) in a sample of individuals with chronic TBI and investigates whether potentially modifiable factors are associated with cognitive decline. Ninety participants aged 40 or older with complicated mild-to-severe TBI participated in two telephone-based study visits ∼1 year apart. Demographic, head trauma exposure, comorbid medical conditions, physical, and psychosocial functioning data were collected via self-report. The BTACT, a brief measure of global cognitive function, was used to assess cognitive performance across six domains. A reliable change index for quantifying clinically significant changes in BTACT performance was calculated. Results revealed cognitive decline in 10-27% of participants across various cognitive domains. More specifically, only depressive symptoms, including depressed affect and anhedonia, were significantly associated with cognitive decline after correcting for multiple comparisons using false discovery rate (FDR). Other factors such as the number of blows to the head, male gender, dyspnea, increased anxiety symptoms, seizures, illicit drug use, and fewer cardiovascular comorbidities should be considered hypothesis generating. Importantly, age was not a significant predictor of cognitive decline, which challenges the assumption that cognitive decline is solely related to the natural aging process. It suggests that there are unique factors associated with TBI that impact cognitive function, and these factors can affect individuals across the lifespan. The BTACT is a brief and sensitive tool for identifying clinically meaningful changes in cognitive function over a relatively brief period (i.e., 1 year) in a sample of individuals in the chronic stages of TBI (i.e., x̄ = 6.7 years post-TBI). Thus, the BTACT may be useful in surveillance efforts aimed at understanding and detecting decline, particularly in situations where in-person cognitive screening is impractical or unfeasible. We also identified potentially modifiable targets for the prevention of post-TBI cognitive decline. These findings can offer insights into treatment goals and preventive strategies for individuals at risk for cognitive decline, as well as help to facilitate early identification efforts.

Trajectories of cognitive function among people aged 45 years and older living with diabetes in China: Results from a nationally representative longitudinal study (2011~2018).

Diabetes is associated with decline of cognitive function. Exploring different trajectories of cognitive function occurring in people with diabetes is important to improved prognosis. This study aimed to investigate differential patterns of trajectories of cognitive function and baseline determinants of trajectory group membership utilizing data from middle-aged and older Chinese adults with diabetes. Participants of the Chinese Health And Retirement Longitudinal Study (CHARLS) aged 45 years and above received biennial assessments between 2011 and 2018. The primary outcome was overall cognitive function score operationalized as sum of mental intactness and episodic memory scores derived from the Telephone Interview of Cognitive Status (TICS). A weighted growth mixture model was used to estimate cognitive function trajectories of CHARLS participants with diabetes, and baseline factors associated with trajectory group membership were investigated with weighted multinomial logistic regression. Data from 1,463 participants with diabetes aged 45 years and above were analyzed, a three-group trajectory model showed the best fit for overall cognitive scores: low baseline, linear declining (22.1%); moderate baseline, linear declining (37.5%) and high-stable (40.3%). Older participants, females, participants with low education, with nighttime sleep <6 h, without daytime napping habits, and with depressive symptoms were at a higher risk of unfavorable cognitive function trajectories. We identified heterogeneous trajectories of cognitive function among middle-aged and older people living with diabetes in China. Socially vulnerable groups including females, rural residents, and those with low education were at a higher risk for unfavorable trajectories. In health programs aimed at preventing and mitigating cognitive decline in individuals with diabetes more attention should be given to vulnerable groups. Reduced nighttime sleep, lack of daytime napping, and depressive symptoms appear to be modifiable risk factors.

A nomogram based on neuron-specific enolase and substantia nigra hyperechogenicity for identifying cognitive impairment in Parkinson's disease.

One in four individuals with Parkinson's disease (PD) experience cognitive impairment (CI). However, few practical models integrating clinical and neuroimaging biomarkers have been developed to address CI in PD. This study aimed to evaluate the correlation between circulating neuron-specific enolase (NSE) levels, substantia nigra hyperechogenicity (SNH), and cognitive function in PD and to develop a nomogram based on clinical and neuroimaging biomarkers for predicting CI in patients with PD. A total of 385 patients with PD who underwent transcranial sonography (TCS) from January 2021 to December 2022 at Beijing Tiantan Hospital, Capital Medical University, were recruited as the training cohort. For validation, 165 patients with PD treated from January 2023 to December 2023 were enrolled. Data for SNH, plasma NSE, and other clinical measures were collected, and cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Logistic regression analysis was employed to select potential risk factors and establish a nomogram. The receiver operating characteristic curve and calibration curve were generated to evaluate the performance of the nomogram. Patients with PD exhibiting CI displayed advanced age, elevated Unified PD Rating Scale-III (UPDRS-III) score, an increased percentage of SNH, higher levels of plasma NSE and homocysteine (Hcy), a larger SNH area, and lower education levels compared to PD patients without CI. Gender [odds ratio (OR) =0.561, 95% confidence interval (CI): 0.330-0.954, P=0.03], age (OR =1.039; 95% CI: 1.011-1.066; P=0.005), education level (OR =0.892; 95% CI: 0.842-0.954; P<0.001), UPDRS-III scores (OR =1.026; 95% CI: 1.009-1.043; P=0.003), plasma NSE concentration (OR =1.562; 95% CI: 1.374-1.776; P<0.001), and SNH (OR =0.545; 95% CI: 0.330-0.902; P=0.02) were independent predictors of CI in patients with PD. A nomogram developed using these six factors yielded a moderate discrimination performance with an area under the curve (AUC) of 0.823 (95% CI 0.781-0.864; P<0.001). The calibration curve demonstrated acceptable agreement between predicted outcomes and actual values. Validation further confirmed the reliability of the nomogram, with an AUC of 0.864 (95% CI: 0.805-0.922; P<0.001). The level of NSE in plasma and the SNH assessed by TCS are associated with CI in patients with PD. The proposed nomogram has the potential to facilitate the detection of cognitive decline in individuals with PD.

Perceived Stress, Blood Biomarkers, and Cognitive Functioning in Older Adults.

There is a substantial gap in knowledge regarding how perceived stress may influence the relationship between serum-measured biomarkers for Alzheimer's disease and cognitive decline. This study consists of 1118 older adult participants from the Chicago Health and Aging Project (CHAP) (60% Black participants and 63% female participants). Linear mixed effects regression models were conducted to examine the role of perceived stress in the association between three blood biomarkers: total tau (t-tau), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) on global cognitive decline. Stratified analysis by stress level was also conducted to evaluate the associations between each blood biomarker and baseline cognitive function and decline. All models adjusted for age, race, sex, education, time, and their interactions with time. The interaction of stress, NfL concentration, and time was statistically significant on global cognition ( β = -0.064 [SE = 0.028], p = .023) and on episodic memory ( β = -0.097 [SE = 0.036], p = .007). Greater stress level worsens the association between high NfL concentration and cognitive decline. Stress management interventions may be helpful to reduce the rate of cognitive decline in individuals with high concentrations of NfL.

Low TGF-β1 plasma levels are associated with cognitive decline in Down syndrome.

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-β1 (TGF-β1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-β1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35years) and older DS subjects without AD (35-60years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-β1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-β1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-β1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1µM for 24h) were able to rescue TGF-β1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-β1 concentrations in DS subjects at higher risk to develop cognitive decline.

The Linguistic-Cognitive Profile in an Adult Population with Parkinson's Disease and Deep Brain Stimulation: A Comparative Study.

Introduction. Individuals with Parkinson's disease (PD) exhibit general impairments, particularly non-motor symptoms that are related to language, communication, and cognition processes. People with this disease may undergo a surgical intervention for the placement of a deep brain stimulation device, which improves their motor symptoms. However, this type of intervention leads to a decline in their linguistic and cognitive abilities that becomes increasingly noticeable as the disease progresses. Objective. The objective of this research was to compare the performance and linguistic-cognitive profile of individuals with Parkinson's disease who underwent deep brain stimulation treatment based on the stage of the disease. Method. A total of 60 participants who were diagnosed with PD by their reference hospital were selected. These participants were divided into three groups based on the stage of the disease that they were in, forming three groups: a Stage I group (n = 20), a Stage II group (n = 20), and a Stage III group (n = 20). The linguistic-cognitive profile was assessed using the MoCA, ACE-III, and MetAphas tests. The design of this study was established as a quasi-experimental, cross-sectional investigation, and statistical analysis was performed using MANOVA to compare the scores between the study groups. Results. The results indicate that individuals in Stage I exhibit better linguistic and cognitive performance compared to the other groups of participants in Stage II and Stage III, with statistically significant differences (p < 0.05). Conclusion. In conclusion, the progression of PD leads to significant linguistic and cognitive decline in individuals with this disease who have a deep brain stimulation device, greatly limiting the autonomy and quality of life for people with PD.

CSF protein ratios with enhanced potential to reflect Alzheimer’s disease pathology and neurodegeneration

BackgroundAmyloid and tau aggregates are considered to cause neurodegeneration and consequently cognitive decline in individuals with Alzheimer’s disease (AD). Here, we explore the potential of cerebrospinal fluid (CSF) proteins to reflect AD pathology and cognitive decline, aiming to identify potential biomarkers for monitoring outcomes of disease-modifying therapies targeting these aggregates.MethodWe used a multiplex antibody-based suspension bead array to measure the levels of 49 proteins in CSF from the Swedish GEDOC memory clinic cohort at the Karolinska University Hospital. The cohort comprised 148 amyloid- and tau-negative individuals (A-T-) and 65 amyloid- and tau-positive individuals (A+T+). An independent sample set of 26 A-T- and 26 A+T+ individuals from the Amsterdam Dementia Cohort was used for validation. The measured proteins were clustered based on their correlation to CSF amyloid beta peptides, tau and NfL levels. Further, we used support vector machine modelling to identify protein pairs, matched based on their cluster origin, that reflect AD pathology and cognitive decline with improved performance compared to single proteins.ResultsThe protein-clustering revealed 11 proteins strongly correlated to t-tau and p-tau (tau-associated group), including mainly synaptic proteins previously found elevated in AD such as NRGN, GAP43 and SNCB. Another 16 proteins showed predominant correlation with Aβ42 (amyloid-associated group), including PTPRN2, NCAN and CHL1. Support vector machine modelling revealed that proteins from the two groups combined in pairs discriminated A-T- from A+T+ individuals with higher accuracy compared to single proteins, as well as compared to protein pairs composed of proteins originating from the same group. Moreover, combining the proteins from different groups in ratios (tau-associated protein/amyloid-associated protein) significantly increased their correlation to cognitive decline measured with cognitive scores. The results were validated in an independent cohort.ConclusionsCombining brain-derived proteins in pairs largely enhanced their capacity to discriminate between AD pathology-affected and unaffected individuals and increased their correlation to cognitive decline, potentially due to adjustment of inter-individual variability. With these results, we highlight the potential of protein pairs to monitor neurodegeneration and thereby possibly the efficacy of AD disease-modifying therapies.

Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.

Verbal fluency patterns associated with the amnestic conversion from mild cognitive impairment to dementia

Patients with amnestic mild cognitive impairment (aMCI) are at a higher risk of converting to Alzheimer's disease. The aim of this study was to examine the potential use of Verbal Fluency (VF) measures as markers for predicting the conversion to dementia. At baseline, 61 aMCI, aged 65 to 80 years, underwent a comprehensive neuropsychological assessment, including phonemic (PVF) and semantic verbal fluency (SVF) tasks. After 18 months, 14 individuals with aMCI had progressed to a diagnosis of dementia. The findings revealed that aMCI-converter group had lower Mini Mental State Examination and Rey Auditory Verbal Learning Task scores than aMCI-no converter and produced fewer clusters in both VF tasks and a lower number of switches in PVF at baseline (p < 0.05). According to receiver operating characteristic curve analysis, the number of clusters in PVF had the highest predictive value (AUC = 0.80) with a threshold of 5.510 for identifying aMCI-converter at baseline. Additionally, participants with higher levels of education exhibited more clusters and switches in VF tasks (p < 0.05). These results suggest that qualitative measures of VF could serve as neuropsychological markers for predicting cognitive decline in individuals with aMCI. Furthermore, the study highlights the potential influence of the education level on cognitive performance in neuropsychological tasks.

Anthranilic Acid, a GPR109A Agonist, and Schizophrenia.

Limited clinical efficiency of current medications warrants search for new antipsychotic agents. Deorphanized G-protein coupled receptor (GPR)109A has not attracted much of attention of schizophrenia researchers. We analyzed literature and our data on endogenous agonists of GPR109A, beta-hydroxybutyrate (BHB), anthranilic (AA), butyric (BA), and nicotinic (NA) acids, in individuals with schizophrenia. Sex specific differences: plasma AA levels were 27% higher in female than in male patients and correlated with PANSS before 6 weeks of antipsychotics treatment (r = .625, P < .019, Spearman's test). There was no sex specific differences of plasma AA levels after treatment. AA plasma levels inversely correlated (-.58, P < .005) with PANSS scores in responders to treatment (at least, 50% improvement) but not in nonresponders. Preclinical studies suggested antipsychotic effect of BHB and BA. Clinical studies observed antipsychotic effect of NA; benzoate sodium, an AA precursor; and interventions associated with BHB upregulation (eg, fasting and ketogenic diets). Upregulation of GPR109A, an anti-inflammatory and neuroprotective receptor, inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that breakdown myelin, lipid-based insulating axonal sheath that protects and promotes nerve conduction. Brain cPLA2 is upregulated in individuals with schizophrenia and subjects at high-risk for development of psychosis. Lower myelin content is associated with cognitive decline in individuals with schizophrenia. Therefore, GPR109A might exert antipsychotic effect via suppression of cPLA2, and, consequently, preservation of myelin integrity. Future research might explore antipsychotic effects of (1) human pegylated kynureninase, an enzyme that catalyzes formation of AA from kynurenine (Kyn); (2) inhibitors of Kyn conversion into kynurenic acid, for example, KYN5356, to patients with already impaired Kyn conversion into 3-hydroxykynurenine; (3) synthetic GPR 109A agonists, for example, MK-1903 and SCH900271 and GSK256073, that underwent clinical trials as anti-dyslipidemia agents. GPR109A expression, that might be a new endophenotype of schizophrenia, especially associated with cognitive impairment, needs thorough assessment.

Assessment of neurocognitive functions and information processing ability among type 2 diabetes mellitus patients in Central India – A cross-sectional study

Background: Type 2 diabetes mellitus (T2DM) is a common and prevalent metabolic disorder linked to numerous health complications. Recent research has indicated a potential association between T2DM and cognitive impairment, although the underlying mechanisms remain unclear. Aims and Objectives: This cross-sectional study aimed to investigate neurocognitive functions and information processing ability in T2DM patients compared to healthy individuals. Materials and Methods: A total of 160 participants, including 80 T2DM patients under medication and 80 age- and sex-matched healthy controls, were enrolled. Cognitive assessments were conducted using Addenbrooke’s cognitive examination (ACE-III) and audiovisual reaction time tests. Statistical analyses were performed to assess differences and correlations between groups. Results: The study revealed that T2DM patients exhibited delayed neurocognitive functions, including prolonged auditory and visual reaction times, and lower ACE-III scores compared to healthy controls. Notably, a significant positive correlation between HbA1c levels and cognitive impairment was observed in the diabetic group. Conclusion: This study underscores the presence of cognitive deficits in T2DM patients and highlights the importance of routine cognitive assessment during clinical follow-up. The findings suggest that optimizing glycemic control may offer potential benefits in mitigating cognitive decline in individuals with T2DM. These insights contribute to our understanding of the interplay between T2DM and cognitive function, paving the way for improved patient care and interventions.

Copper and cuproptosis: new therapeutic approaches for Alzheimer's disease.

Copper (Cu) plays a crucial role as a trace element in various physiological processes in humans. Nonetheless, free copper ions accumulate in the brain over time, resulting in a range of pathological changes. Compelling evidence indicates that excessive free copper deposition contributes to cognitive decline in individuals with Alzheimer's disease (AD). Free copper levels in the serum and brain of AD patients are notably elevated, leading to reduced antioxidant defenses and mitochondrial dysfunction. Moreover, free copper accumulation triggers a specific form of cell death, namely copper-dependent cell death (cuproptosis). This article aimed to review the correlation between copper dysregulation and the pathogenesis of AD, along with the primary pathways regulating copper homoeostasis and copper-induced death in AD. Additionally, the efficacy and safety of natural and synthetic agents, including copper chelators, lipid peroxidation inhibitors, and antioxidants, were examined. These treatments can restore copper equilibrium and prevent copper-induced cell death in AD cases. Another aim of this review was to highlight the significance of copper dysregulation and promote the development of pharmaceutical interventions to address it.

Comorbidities associated with symptoms of subjective cognitive decline in individuals aged 45-64.

Early-stage cognitive decline occurs when an individual experiences memory loss or other cognitive impairment but does not meet the criteria for Alzheimer's disease (AD) or other dementias. After diagnosis of mild cognitive impairment (MCI), approximately 5-15 % of cases progress to dementia per year. AD and many other causes of dementia are presently incurable. Early recognition of cognitive decline can allow healthcare providers to reduce the risk of disease progression. Literature is scarce on factors that can increase the incidence of cognitive decline, especially in early ages; this is further exacerbated by difficulty tracking the prevalence of mild cognitive symptoms. This analysis aims to determine demographic and comorbid factors that predispose individuals to higher rates of early-stage subjective cognitive impairment in order to determine which individuals should be screened at earlier stages. We conducted a cross-sectional analysis of data from the Subjective Cognitive Decline module of the 2017-2021 Behavioral Risk Factor Surveillance System (BRFSS). Applying survey design and sampling weights, we constructed binary logistic regression models to assess associations, via odds ratios (OR), between comorbidities and subjective cognitive decline (SCD). Alpha was set at 0.05 and confidence intervals (CIs) are reported at 95 %. Our sample included 110,305 participants representing 13.4 million US adults aged 45-64 years. Results showed that individuals with diabetes (OR: 2.29, CI: 2.09-2.51), hypertension (OR: 1.98, CI: 1.81-2.17), stroke (OR: 4.61, CI: 4.07-5.22), myocardial infarction (MI [OR: 3.09, CI: 2.73-3.49]), coronary heart disease (CHD [OR: 3.26, CI: 2.88-3.69]), depression (OR: 5.65, CI: 5.21-6.11), and chronic kidney disease (CKD [OR: 3.08, CI: 2.66-3.58]) experienced higher rates of SCD. Further, there were higher rates of SCD among individuals who identified as American Indian/Alaskan Native (AI/AN), those with low educational attainment, and those with lower incomes. Our findings show that all comorbidities listed were correlated with higher rates of memory loss or confusion. Investigation of factors that are associated with an increased risk of developing new or worsening cognitive decline allows healthcare professionals to properly screen and treat these individuals early, before progressing to conditions that are currently incurable. Future studies into the mechanisms of these diseases in contributing to cognitive decline can illuminate specific effective treatment options.

Role of Aging, Genetics after Exposure to Airborne Particulate matter and High Temperatures on a Mouse Model of Alzheimer's Disease

Background: Elevated temperatures are usually accompanied by corresponding increases in concentrations of air pollutants increasing mortality or morbidity, which may feasibly be attributed to an interaction between the two factors. High temperatures and high levels of air pollution are increasingly linked to cognitive decline in individuals over 65 years. We hypothesize that the combined exposures to particulate matter (PM2.5) and heat stress (HS) may alter brain glucose metabolism and gut dysbiosis leading to increased cognitive impairment and accelerated AD phenotype.

Microglial activation interacts with amyloid‐β to drive longitudinal tau tangle accumulation and cognitive decline

AbstractBackgroundActivation of microglial cells in the brain, more commonly known as neuroinflammation, has often been linked to the pathophysiology of Alzheimer’s disease (AD). However, how microglial activation is associated with longitudinal tau tangle accumulation and consequent cognitive decline is poorly understood. Here, we aimed to investigate whether baseline microglial activation impacts tau tangle deposition and cognitive decline in individuals across the AD continuum.MethodWe assessed 92 individuals from the TRIAD cohort (57 cognitively unimpaired and 35 cognitively impaired) with available baseline [11C]PBR28‐PET, a measure of microglial activation and [18F]NAV4694 Aß‐PET, and longitudinal [18F]MK6240 Tau‐PET (mean follow‐up time = 1.93 years) and Mini‐Mental State Exam (MMSE) (mean follow‐up time = 1.84 years). We performed voxel‐wise associations using linear regressions accounting for age and sex and adjusted for multiple comparisons using Random Field Theory (RFT) (p &lt; 0.05). We used the cuneus and superior temporal cortex as a composite ROI for [11C]PBR28‐PET and Aß‐PET since these regions showed a higher association with longitudinal tau accumulation in the temporal meta‐ROI.ResultVoxel‐wise analysis showed that baseline levels of [11C]PBR28‐PET alone are not sufficient to predict longitudinal tau tangle accumulation (Fig. 1a). However, the interaction between [11C]PBR28‐PET levels and Aß burden predicted an increased accumulation of tau tangle, mainly in the cuneus, inferior frontal and lateral occipital regions (Fig. 1b).Individuals with higher baseline [11C]PBR28‐PET and Aß‐PET levels present higher rates of longitudinal tau accumulation in the temporal meta‐ROI (ß = 0.36, t = 3.46, p = 0.0009; Fig. 1c). Similarly, while [11C]PBR28‐PET levels alone did not correlate with longitudinal changes in MMSE score (ß = ‐0.17, t = ‐1.69, p = 0.10), a significant interaction between [11C]PBR28‐PET and Aß‐PET levels on MMSE annual decline was observed (ß = ‐0.24, t = ‐2.25, p = 0.028; Fig. 1d).ConclusionWe found that baseline levels of microglial activation was associated with longitudinal tau tangle accumulation and cognitive decline in individuals across the AD continuum in the presence of Aß burden. Our results indicate that microglial activation might act potentiating the deleterious effects of Aß on forthcoming tau tangle deposition.

Life’s Simple 7 Relates to Better Cognitive and Brain Health in Individuals with Autosomal Dominant Frontotemporal Dementia

AbstractBackgroundCardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life’s Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD.Method243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD.ResultMutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values&lt;0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913)ConclusionBetter cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD.