Loneliness and global cognitive functioning in racially and ethnically diverse US midlife and older adults.

Introduction: Few studies have examined the association of loneliness and cognitive functioning in the US. We used two common measures of loneliness and examined their association in a large sample of US Black, Latino, and White adults (ages ≥ 50). Methods: We analyzed Wave 3 of the National Social Life, Health, and Aging Project (N = 2,757). We examined loneliness using one item from the CES-D and the Felt Loneliness Measure (NFLM); cognitive functioning was assessed using the Montreal Cognitive Assessment (MoCA) tool, where higher scores indicated better functioning. We used weighted ordinary least squares regressions to examine the effects of loneliness (CES-D loneliness and NFLM in separate models) on MoCA scores. In exploratory analyses, we examined if these relationships varied by race and ethnicity. We adjusted all models for sociodemographic and other salient factors (e.g., chronic disease, depressive symptoms, living alone). Results: Mean age was 63.49 years, 52% were female, and 9% were Black and 6% Latino persons. Approximately 54% endorsed feeling lonely on at least one measure; 31% (CES-D) and 46% (NFLM). The relationship between loneliness measures was positive and significant, X 2 (1, N = 2,757) = 435.493 p < 0.001. However, only 40% of lonely individuals were identified as lonely on both assessments. CES-D loneliness was inversely (߈ = -0.274, p = 0.032) associated with MoCA scores and this association did not vary by race and ethnicity. Greater NFLM loneliness was positively associated (߈ = 0.445, p < 0.001) with higher MoCA scores for Latino participants only. Discussion: Loneliness appears to be an important predictor of cognitive functioning. However, the association of loneliness and cognitive functioning varied when using the CES-D loneliness item or the NFLM. Future work is needed to understand how loneliness and its clinically relevant dimensions (social, emotional, existential, chronicity) relate to global and individual cognitive domains. Research is needed with racially and ethnically diverse midlife and older adults, particularly to understand our counterintuitive finding for Latino participants. Finally, findings also support the need for research on interventions to prevent cognitive decline targeting loneliness.

Multi-omics reveals Dengzhan Shengmai formulation ameliorates cognitive impairments in D-galactose-induced aging mouse model by regulating CXCL12/CXCR4 and gut microbiota.

Dengzhan Shengmai (DZSM), a traditional Chinese medicine formulation, has been administered extensively to elderly individuals with cognitive impairment (CI). However, the underlying mechanisms by which Dengzhan Shengmai improves cognitive impairment remains unknown. This study aimed to elucidate the underlying mechanism of the effect of Dengzhan Shengmai on aging-associated cognitive impairment via a comprehensive combination of transcriptomics and microbiota assessment. Dengzhan Shengmai was orally administered to a D-galactose-induced aging mouse model, and evaluation with an open field task (OFT), Morris water maze (MWM), and histopathological staining was performed. Transcriptomics and 16S rDNA sequencing were applied to elucidate the mechanism of Dengzhan Shengmai in alleviating cognitive deficits, and enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (PCR), and immunofluorescence were employed to verify the results. The results first confirmed the therapeutic effects of Dengzhan Shengmai against cognitive defects; specifically, Dengzhan Shengmai improved learning and impairment, suppressed neuro loss, and increased Nissl body morphology repair. Comprehensive integrated transcriptomics and microbiota analysis indicated that chemokine CXC motif receptor 4 (CXCR4) and its ligand CXC chemokine ligand 12 (CXCL12) were targets for improving cognitive impairments with Dengzhan Shengmai and also indirectly suppressed the intestinal flora composition. Furthermore, in vivo results confirmed that Dengzhan Shengmai suppressed the expression of CXC motif receptor 4, CXC chemokine ligand 12, and inflammatory cytokines. This suggested that Dengzhan Shengmai inhibited CXC chemokine ligand 12/CXC motif receptor 4 expression and modulated intestinal microbiome composition by influencing inflammatory factors. Thus, Dengzhan Shengmai improves aging-related cognitive impairment effects via decreased CXC chemokine ligand 12/CXC motif receptor 4 and inflammatory factor modulation to improve gut microbiota composition.

Case Report: A novel mutation in WFS1 gene (c.1756G>A p.A586T) is responsible for early clinical features of cognitive impairment and recurrent ischemic stroke.

Wolfram syndrome 1 (WFS1) gene mutations can be dominantly or recessively inherited, and the onset of the clinical picture is highly heterogeneity in both appearance and degree of severity. Different types of WFS1 mutations have been identified. Autosomal recessive mutations in the WFS1 gene will underlie Wolfram syndrome 1 (WS1), a rare and severe neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and other neurological, urological and psychiatric abnormalities. Other WFS1-related disorders such as low-frequency sensorineural hearing impairment (LFSNHI) and Wolfram syndrome-like disease with autosomal dominant transmission have been described. It is difficult to establish genotype-phenotype correlations because of the molecular complexity of wolframin protein. In this report, we presented a case of WSF1 gene mutation-related disease with cognitive impairment as the initial symptom and recurrent cerebral infarction in the course of the disease. Brain structural imaging results suggested decreased intracranial volume, dramatically reduced in cerebral cortex and cerebellum regions. Multimodal molecular imaging results suggested Tau protein deposition in the corresponding brain regions without Aß pathology changes. These pathological changes may indicate a role of WFS1 in neuronal vulnerability to tau pathology associated with neurodegeneration and ischemia-induced damage.

High levels of kappa free light chain synthesis predict cognitive decline in relapsing-remitting multiple sclerosis.

Background: Evolving evidence suggests that measurement of cerebrospinal fluid (CSF) kappa free light chain (KFLC) synthesis has high diagnostic sensitivity and specificity for multiple sclerosis (MS), but its prognostic ability is less investigated. The usefulness of KFLC in predicting cognitive impairment (CI) is still unknown. Methods: In a monocentric longitudinal retrospecitve cohort study, KFLC-index ([CSF KFLC/serum KFLC]/[CSF albumin/serum albumin]) measured by latex-enhanced immunonephelometry was prospectively determined as part of the diagnostic workup in patients with early relapsing-remitting MS (RRMS, n=77). The ability of KFLC-index to predict information processing speed (IPS) worsening as assessed with the symbol digit modalities test (SDMT) was investigated in univariable and multivariable models. Results: In patients with KFLC-index>100 (n=31), 11 subjects (35.5%) showed reduced SDMT scores by ≥8 points at follow-up (mean follow-up time 7.3 ± 2.6 years), compared with their baseline scores (p=0.01). Baseline KFLC-index>100 was strongly associated with a higher hazard of SDMT score reduction at follow-up (adjusted hazard ratio 10.5, 95% confidence interval 2.2-50.8, p=0.003; median time to SDMT reduction 7 years). Conclusion: Intrathecal KFLC synthesis has become an attractive diagnostic tool for MS. We show for the first time that in a real-world setting of early RRMS, KFLC-index predicted cognitive decline. Whether this predictive ability of KFLC-index also concerns other cognitive domains than IPS, warrants further investigations.

Women in the field of multiple sclerosis: How they contributed to paradigm shifts.

History is full of women who made enormous contributions to science. While there is little to no imbalance at the early career stage, a decreasing proportion of women is found as seniority increases. In the multiple sclerosis (MS) field, 44% of first authors and only 35% of senior authors were female. So, in this review, we highlight ground-breaking research done by women in the field of MS, focusing mostly on their work as principal investigators. MS is an autoimmune disorder of the central nervous system (CNS), with evident paradigm shifts in the understating of its pathophysiology. It is known that the immune system becomes overactivated and attacks myelin sheath surrounding axons. The resulting demyelination disrupts the communication signals to and from the CNS, which causes unpredictable symptoms, depending on the neurons that are affected. Classically, MS was reported to cause mostly physical and motor disabilities. However, it is now recognized that cognitive impairment affects more than 50% of the MS patients. Another shifting paradigm was the involvement of gray matter in MS pathology, formerly considered to be a white matter disease. Additionally, the identification of different T cell immune subsets and the mechanisms underlying the involvement of B cells and peripheral macrophages provided a better understanding of the immunopathophysiological processes present in MS. Relevantly, the gut-brain axis, recognized as a bi-directional communication system between the CNS and the gut, was found to be crucial in MS. Indeed, gut microbiota influences not only different susceptibilities to MS pathology, but it can also be modulated in order to positively act in MS course. Also, after the identification of the first microRNA in 1993, the role of microRNAs has been investigated in MS, either as potential biomarkers or therapeutic agents. Finally, concerning MS therapeutical approaches, remyelination-based studies have arisen on the spotlight aiming to repair myelin loss/neuronal connectivity. Altogether, here we emphasize the new insights of remarkable women that have voiced the impact of cognitive impairment, white and gray matter pathology, immune response, and that of the CNS-peripheral interplay on MS diagnosis, progression, and/or therapy efficacy, leading to huge breakthroughs in the MS field.

Low Serum Superoxide Dismutase Is Associated With a High Risk of Cognitive Impairment After Mild Acute Ischemic Stroke.

Background: Post-stroke cognitive impairment (PSCI) is a common complication after stroke, but effective therapy is limited. Identifying potential risk factors for effective intervention is warranted. We investigated whether serum superoxide dismutase (SOD) levels were related to cognitive impairment after mild acute ischemic stroke (AIS) by using a prospective cohort design. Methods: A total of 187 patients diagnosed with mild AIS (National Institutes of Health Stroke Scale ≤ 8) were recruited. Serum SOD, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin-6 (IL-6) levels were measured, and cognitive assessments (Mini-Mental State Examination, MMSE; Montreal Cognitive Assessment, MoCA) were performed in the early phase (within 2 weeks). These indexes and assessments were repeated at 3 months after onset. MoCA < 22 was defined as early cognitive impairment (CI-E) within 2 weeks and late cognitive impairment (CI-L) at 3 months after stroke. Results: In a survey, 105 of 187 (56.1%) patients were identified as CI-E after mild AIS. Lower serum SOD associated with higher inflammatory biomarkers (ESR, CRP, and IL-6) and worse cognitive scores was observed in CI-E patients. In a survey, 39 of 103 (37.9%) stroke patients who completed the 3-month follow-up were identified as CI-L. Serum SOD was consistently lower in CI-L patients at baseline and 3 months and positively associated with cognitive scores. In adjusted analyses, low serum SOD at baseline was independently associated with high risks of CI-E and CI-L, with odds ratios (ORs) of 0.64 and 0.33 per standard deviation increase in serum SOD, respectively. Multiple-adjusted spline regression models showed linear associations between serum SOD and CI-E (P = 0.044 for linearity) and CI-L (P = 0.006 for linearity). Moreover, 35.2% (19/54) of CI-E patients cognitively recovered during the 3-month follow-up. In multivariable analysis, SOD was identified as a protective factor for cognitive recovery after stroke (OR 1.04, 95% CI: 1.01-1.08, P = 0.024). Conclusion: We demonstrate that low serum SOD is associated with a high risk of cognitive impairment after mild AIS, indicating SOD may be a potential modifiable factor for PSCI.

Brain Structural and Functional Changes in Cognitive Impairment Due to Alzheimer's Disease.

Cognitive neuropsychology seeks a potential alignment between structural and functional brain features to explain physiological or pathological processes, such as Alzheimer's disease (AD). Several structural and functional brain changes occurring during the disease, including cognitive impairment, are found at the end of the patient's life, but we need to know more about what happens before its onset. In order to do that, we need earlier biomarkers at preclinical stages, defined by those biomarkers, to prevent the cognitive impairment. In this minireview, we have tried to describe the structural and functional changes found at different stages during AD, focusing on those features taking place before clinical diagnosis.

Higher Serum Soluble TREM2 as a Potential Indicative Biomarker for Cognitive Impairment in Inadequately Controlled Type 2 Diabetes Without Obesity: The DOR-KyotoJ-1.

Objective: Type 2 diabetes is a risk factor for dementia. We investigated whether serum levels of soluble triggering receptor expressed on myeloid cell 2 (sTREM2), a soluble form of the cell surface receptor TREM2, were predictive of cognitive impairment in type 2 diabetes without obesity. Methods: A total of 166 Japanese patients with type 2 diabetes without obesity were followed-up for 2 years. We measured clinical parameters, assessed cognitive function using the mini-mental state examination (MMSE), quantified and divided serum sTREM2 levels into quartiles, and examined the longitudinal associations. Results: During the follow-up, HbA1c levels were elevated in 98 patients and decreased in 68 patients. In the HbA1c-elevated group, higher sTREM2 levels at baseline showed a significant association with a greater tendency for reduction in MMSE scores (P for trend = 0.015), whereas they were not significantly associated with other examined parameters. In the HbA1c-decreased group, there was no significant association between sTREM2 levels at baseline and changes in MMSE scores, but higher sTREM2 levels at baseline were significantly associated with a greater tendency for reduction in waist circumference (P for trend = 0.027), homeostasis model assessment of insulin resistance (P for trend = 0.039), and sTREM2 levels (P for trend = 0.023). Conclusions: Glycemic control is suggested to be important in preventing cognitive impairment in patients with type 2 diabetes without obesity. Higher serum sTREM2 levels would be a predictive marker for cognitive impairment in inadequately controlled type 2 diabetes without obesity.

Intrinsic network changes associated with cognitive impairment in patients with hearing loss and tinnitus: a resting-state functional magnetic resonance imaging study.

Background: Hearing loss and tinnitus often occur concurrently and play a vital role in the development and progression of cognitive impairment (CI). However, the exact mechanism remains unclear. This study aimed to investigate the changes in intrinsic brain connectivity in patients with hearing loss and tinnitus accompanied by CI. Methods: A total of 24 hearing loss and tinnitus patients with CI, 23 hearing loss and tinnitus patients with cognitive normality (CN), and 20 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Resting-state networks (RSNs) were identified and intrinsic functional connectivity (FC) values were measured using independent component analysis (ICA). FC values within the RSNs were measured and correlations between altered RSNs and clinical characteristics were evaluated using Pearson correlation analysis. Results: No significant difference was found in the disease duration or Tinnitus Handicap Inventory (THI) scores between the CI and CN groups. Eleven RSNs differed significantly among the 3 groups. Compared with the CN group, the CI group exhibited higher FC in the right supramarginal and left middle temporal gyri within the auditory network (AN), the left inferior parietal, but supramarginal and angular gyrus (IPL) gyrus within the right frontoparietal network (RFPN), the right middle occipital gyrus (R_MOG) and left superior frontal gyrus (L_SFG) within the dorsal attention network (DAN), the right middle frontal gyrus (R_MFG) within the executive control network (ECN), the right cuneus (R_cuneus) within the visual network (VN), and the left inferior frontal gyrus within the salience network (SAN), as well as lower FC in the right superior temporal gyrus (R_STG) within the AN and the left FPN (LFPN) and the right superior frontal gyrus (R_SFG) within the LFPN. Montreal Cognitive Assessment (MoCA) scores were negatively correlated with the FC values of the R_MFG and positively correlated with the FC values of the R_STG and R_SFG. Conclusions: Aberrant intrinsic FC was observed in the R_MFG within the ECN, the R_STG within the AN, and the R_SFG within the LFPN in hearing loss and tinnitus patients, which may be a biomarker for the severity of CI in hearing loss and tinnitus patients.

Visual Search in Naturalistic Scenes Reveals Impaired Cognitive Processing Speed in Multiple Sclerosis.

BACKGROUND: Standardized neuropsychological testing serves to quantify cognitive impairment in multiple sclerosis (MS) patients. However, the exact mechanism underlying the translation of cognitive dysfunction into difficulties in everyday tasks has remained unclear. To answer this question, we tested if MS patients with intact vs. impaired information processing speed measured by the Symbol Digit Modalities Test (SDMT) differ in their visual search behavior during ecologically valid tasks reflecting everyday activities. METHODS: Forty-three patients with relapsing-remitting MS enrolled in an eye-tracking experiment consisting of a visual search task with naturalistic images. Patients were grouped into "impaired" and "unimpaired" according to their SDMT performance. Reaction time, accuracy and eye-tracking parameters were measured. RESULTS: The groups did not differ regarding age, gender, and visual acuity. Patients with impaired SDMT (cut-off SDMT-z-score < -1.5) performance needed more time to find and fixate the target (q = 0.006). They spent less time fixating the target (q = 0.042). Impaired patients had slower reaction times and were less accurate (both q = 0.0495) even after controlling for patients' upper extremity function. Exploratory analysis revealed that unimpaired patients had higher accuracy than impaired patients particularly when the announced target was in unexpected location (p = 0.037). Correlational analysis suggested that SDMT performance is inversely linked to the time to first fixation of the target only if the announced target was in its expected location (r = -0.498, p = 0.003 vs. r = -0.212, p = 0.229). CONCLUSION: Dysfunctional visual search behavior may be one of the mechanisms translating cognitive deficits into difficulties in everyday tasks in MS patients. Our results suggest that cognitively impaired patients search their visual environment less efficiently and this is particularly evident when top-down processes have to be employed.

Visual disorders and driving ability in persons with dementia: A mini review.

Background: Impaired driving ability in patients with Alzheimer's disease (AD) is associated with a decline in cognitive processes and a deterioration of their basic sensory visual functions. Although a variety of ocular abnormalities have been described in patients with AD, little is known about the impact of those visual disorders on their driving performance. Aim: Aim of this mini-review is to provide an update on the driving ability of patients with dementia and summarize the primary visual disorders affecting their driving behavior. Methods: Databases were screened for studies investigating dementia, associated visual abnormalities and driving ability. Results: There is consistent evidence that dementia affects driving ability. Patients with dementia present with a variety of visual disorders, such as visual acuity reduction, visual field defects, impaired contrast sensitivity, decline in color vision and age-related pathological changes, that may have a negative impact on their driving ability. However, there is a paucity in studies describing the impact of oculovisual decline on the driving ability of AD subjects. A bidirectional association between cognitive and visual impairment (VI) has been described. Conclusion: Given the bidirectional association between VI and dementia, vision screening and cognitive assessment of the older driver should aim to identify at-risk individuals and employ timely strategies for treatment of both cognitive and ocular problems. Future studies should characterize the basic visual sensory status of AD patients participating in driving studies, and investigate the impact of vision abnormalities on their driving performance.

Identifying different cognitive phenotypes and their relationship with disability in neuromyelitis optica spectrum disorder.

Background: The existence, frequency, and features of cognitive impairment (CI) in patients with neuromyelitis optica spectrum disorder (NMOSD) are still debated. A precise classification and characterization of cognitive phenotypes in patients with NMOSD are lacking. Methods: A total of 66 patients with NMOSD and 22 healthy controls (HCs) underwent a neuropsychological assessment. Latent profile analysis (LPA) on cognitive test z scores was used to identify cognitive phenotypes, and ANOVA was used to define the clinical features of each phenotype. Univariate and multivariate analyses were used to explore the predictors of severe CI, and a corresponding nomogram was created to visualize the predictive model. Results: LPA results suggested four distinct meaningful cognitive phenotypes in NMOSD: preserved cognition (n = 20, 30.3%), mild-attention (n = 21, 31.8%), mild-multidomain (n = 18, 27.3%), and severe-multidomain (n = 7, 10.6%). Patients with the last three phenotypes were perceived to have CI, which accounts for 67.6% of patients with NMOSD. Patients with NMOSD and worse cognitive function were older (p < 0.001) and had lower educational levels (p < 0.001), later clinical onset (p = 0.01), worse Expanded Disability Status Scale scores (p = 0.001), and poorer lower-limb motor function (Timed 25-Foot Walk, p = 0.029; 12-item Multiple Sclerosis Walking Scale [MSWS-12], p < 0.001). Deterioration of Nine-Hole Peg Test (odds ratio, OR: 1.115 [1, 1.243], p = 0.05) and MSWS-12 (OR: 1.069 [1.003, 1.139], p = 0.04) were the independent risk factors for severe cognitive dysfunction. Finally, a nomogram was built based on the entire cohort and the above factors to serve as a useful tool for clinicians to evaluate the risk of severe cognitive dysfunction. Conclusions: We introduced a classification scheme for CI and highlighted that the deterioration of upper- and lower-limb motor disability potentially predicts cognitive phenotypes in NMOSD.

Increased both cortical activation and functional connectivity after transcranial direct current stimulation in patients with post-stroke: A functional near-infrared spectroscopy study.

Background: Previous studies have shown that cognitive impairment is common after stroke. Transcranial direct current stimulation (tDCS) is a promising tool for rehabilitating cognitive impairment. This study aimed to investigate the effects of tDCS on the rehabilitation of cognitive impairment in patients with stroke. Methods: Twenty-two mild-moderate post-stroke patients with cognitive impairments were treated with 14 tDCS sessions. A total of 14 healthy individuals were included in the control group. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Cortical activation was assessed using functional near-infrared spectroscopy (fNIRS) during the verbal fluency task (VFT). Results: The cognitive function of patients with stroke, as assessed by the MMSE and MoCA scores, was lower than that of healthy individuals but improved after tDCS. The cortical activation of patients with stroke was lower than that of healthy individuals in the left superior temporal cortex (lSTC), right superior temporal cortex (rSTC), right dorsolateral prefrontal cortex (rDLPFC), right ventrolateral prefrontal cortex (rVLPFC), and left ventrolateral prefrontal cortex (lVLPFC) cortical regions. Cortical activation increased in the lSTC cortex after tDCS. The functional connectivity (FC) between the cerebral hemispheres of patients with stroke was lower than that of healthy individuals but increased after tDCS. Conclusion: The cognitive and brain functions of patients with mild-to-moderate stroke were damaged but recovered to a degree after tDCS. Increased cortical activation and increased FC between the bilateral cerebral hemispheres measured by fNIRS are promising biomarkers to assess the effectiveness of tDCS in stroke.

SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET/fMRI assessment of target engagement.

Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit. Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80 mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [11C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives. Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy. Conclusion: Single oral doses of SDI-118 up to 80 mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05486195.

Asymptomatic Carotid Disease and Cognitive Impairment: What Is the Evidence?

The development of cognitive dysfunction and dementia is a complex, multifactorial process. One of the contributors to various types of cognitive dysfunction is carotid atherosclerosis which can frequently be seen in asymptomatic individuals. There are a number of different manifestations of asymptomatic carotid atherosclerosis including arterial stiffness, carotid intima-media thickening, flow-limiting stenosis, and complex, atherosclerotic plaque. Each of these forms of atherosclerosis may contribute to cerebral parenchymal damage, contributing to cognitive dysfunction. In this review article, we will discuss each of these forms of carotid atherosclerosis, present the potential mechanistic underpinnings behind an association, and then review the scientific evidence supporting potential associations to cognitive dysfunction and dementia.

Neurodegeneration Over 3 Years Following Ischaemic Stroke: Findings From the Cognition and Neocortical Volume After Stroke Study.

Background: Stroke survivors are at high risk of dementia, associated with increasing age and vascular burden and with pre-existing cognitive impairment, older age. Brain atrophy patterns are recognised as signatures of neurodegenerative conditions, but the natural history of brain atrophy after stroke remains poorly described. We sought to determine whether stroke survivors who were cognitively normal at time of stroke had greater total brain (TBV) and hippocampal volume (HV) loss over 3 years than controls. We examined whether stroke survivors who were cognitively impaired (CI) at 3 months following their stroke had greater brain volume loss than cognitively normal (CN) stroke participants over the next 3 years. Methods: Cognition And Neocortical Volume After Stroke (CANVAS) study is a multi-centre cohort study of first-ever or recurrent adult ischaemic stroke participants compared to age- and sex-matched community controls. Participants were followed with MRI and cognitive assessments over 3 years and were free of a history of cognitive impairment or decline at inclusion. Our primary outcome measure was TBV change between 3 months and 3 years; secondary outcomes were TBV and HV change comparing CI and CN participants. We investigated associations between group status and brain volume change using a baseline-volume adjusted linear regression model with robust standard error. Results: Ninety-three stroke (26 women, 66.7 ± 12 years) and 39 control participants (15 women, 68.7 ± 7 years) were available at 3 years. TBV loss in stroke patients was greater than controls: stroke mean (M) = 20.3 cm3 ± SD 14.8 cm3; controls M = 14.2 cm3 ± SD 13.2 cm3; [adjusted mean difference 7.88 95%CI (2.84, 12.91) p-value = 0.002]. TBV decline was greater in those stroke participants who were cognitively impaired (M = 30.7 cm3; SD = 14.2 cm3) at 3 months (M = 19.6 cm3; SD = 13.8 cm3); [adjusted mean difference 10.42; 95%CI (3.04, 17.80), p-value = 0.006]. No statistically significant differences in HV change were observed. Conclusions: Ischaemic stroke survivors exhibit greater neurodegeneration compared to stroke-free controls. Brain atrophy is greater in stroke participants who were cognitively impaired early after their stroke. Early cognitive impairment was associated greater subsequent atrophy, reflecting the combined impacts of stroke and vascular brain burden. Atrophy rates could serve as a useful biomarker for trials testing interventions to reduce post-stroke secondary neurodegeneration. Clinical Trail Registration: http://www.clinicaltrials.gov, identifier: NCT02205424.

Risk factors for cognitive impairment in patients with first-time ischemic stroke.

OBJECTIVE: To determine the risk factors for cognitive impairment (CI) in patients with first-time ischemic stroke. METHODS: The clinical data of 180 patients with ischemic stroke who were admitted to our hospital from January 2018 to December 2019 was retrospectively analyzed. Patients with MMSE score ≤24 were included into the CI group and the rest of the patients were placed into the normal group. Multivariate logistic regression was applied to describe risk factors for CI in patients with first-time ischemic stroke. RESULTS: Among the patients with first-time ischemic stroke, 96 cases (53%) developed CI, 84 cases (47%) were normal. In different subtypes of TOAST classifications, patients with large-artery atherosclerosis had the highest CI incidence (66.96%). For different infarction sites, the highest CI incidence occurred in the frontal lobe (82.35%), and the lowest was from cerebellar infarction (37.50%). The difference of CI incidences in the frontal lobe, parietal lobe, temporal lobe and occipital lobe was significant between the two groups (P<0.05). Logistic regression analysis indicated that independent risk factors for CI in patients with first ischemic stroke include age ≥60 years old, diabetes history, CRP >6.53 mg/L, Hcy >13.84 µmol/L, NIHSS score >4.37, VD <45.16 nmol/L, and the difference was statistically significant (P<0.05). CONCLUSION: The study showed a high CI incidence in patients with preexisting ischemic stroke. Age ≥60 years old, history of diabetes mellitus, CRP >6.53 mg/L, Hcy >13.84 µmol/L, NIHSS score >4.37 score, VD <45.16 nmol/L are independent risk factors for CI in patients with first-time ischemic stroke.

The Signaling and Pharmacology of the Dopamine D1 Receptor.

The dopamine D1 receptor (D1R) is a Gαs/olf-coupled GPCR that is expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, and cognitive processes. Although the D1R was initially identified as a promising drug target almost 40 years ago, the development of clinically useful ligands has until recently been hampered by a lack of suitable candidate molecules. The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders. To develop better therapeutics, advances in ligand chemistry must be matched by an expanded understanding of D1R signaling across cell populations in the brain, and in disease states. Depending on the brain region, the D1R couples primarily to either Gαs or Gαolf through which it activates a cAMP/PKA-dependent signaling cascade that can regulate neuronal excitability, stimulate gene expression, and facilitate synaptic plasticity. However, like many GPCRs, the D1R can signal through multiple downstream pathways, and specific signaling signatures may differ between cell types or be altered in disease. To guide development of improved D1R ligands, it is important to understand how signaling unfolds in specific target cells, and how this signaling affects circuit function and behavior. In this review, we provide a summary of D1R-directed signaling in various neuronal populations and describe how specific pathways have been linked to physiological and behavioral outcomes. In addition, we address the current state of D1R drug development, including the pharmacology of newly developed non-catecholamine ligands, and discuss the potential utility of D1R-agonists in Parkinson's Disease and cognitive impairment.

Prevalence and Its Associated Factors of Physical Frailty and Cognitive Impairment: Findings from the West China Health and Aging Trend Study (WCHAT).

OBJECTIVES: Previous literature has reported that physical frailty (PF) closely associated with cognitive impairment (CI). In this study, we aim to describe and evaluate the prevalence and associated factors with different patterns of PF and cognitive impairment. DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: Community-dwelling older adults aged ≥60 from the West China Health and Aging Trend (WCHAT) study were included in this study. MEASUREMENTS: Participants were assessed the PF and cognitive impairment. PF was assessed using the physical phenotype as defined by Fried's criteria. Cognitive impairment was identified using the Short Portable Mental Status Questionnaire (SPMSQ). According different patterns of PF and cognitive impairment, participants were divided into 4 groups: not-PF and cognitive intact ( "neither" group), not-PF and cognitive impairment ("CI only" group), PF and cognitive intact ("PF only" group), and PF and cognitive impairment ("both" group). Multinomial logistic regression was used to explore the association between medical conditions and different patterns of PF and cognitive impairment after adjusting the demographic characteristics. RESULTS: Among 4,103 participants (age 67.8 + 5.9 years, female 58.3%), 78.8%, 3.9%, 14.5% and 2.9% were "neither", "PF only", "CI only", and "both", respectively. The prevalence of "PF only", "CI only" and "both" were associated with age, lower education level and single status. In addition, there was substantial ethnicity heterogeneity in the prevalence of different patterns of PF and cognitive impairment. Comparing with "neither", PF and/or cognitive impairment had higher association with depression, ADLs impairment, and malnutrition. Of note, obesity was only significantly associated with "PF only", but not associated with "CI only" or "both". CONCLUSIONS: We found the substantial demographic and medical conditions disparities in different patterns of PF and cognitive impairment. Further research should focus on the efficient and practical screen to predict the risk of "PF only", "CI only" and "both".

Psychosocial Impact of COVID-19 Nursing Home Restrictions on Visitors of Residents With Cognitive Impairment: A Cross-Sectional Study as Part of the Engaging Remotely in Care (ERiC) Project.

Background: COVID-19 has disproportionately affected older people. Visiting restrictions introduced since the start of the pandemic in residential care facilities (RCFs) may impact negatively on visitors including close family, friends, and guardians. We examined the effects of COVID-19 visiting restrictions on measures of perceived loneliness, well-being, and carer quality of life (QoL) amongst visitors of residents with and without cognitive impairment (CI) in Irish RCFs. Methods: We created a cross-sectional online survey. Loneliness was measured with the UCLA brief loneliness scale, psychological well-being with the WHO-5 Well-being Index and carer QoL with the Adult Carer QoL Questionnaire (support for caring subscale). Satisfaction with care ("increased/same" and "decreased") was measured. A history of CI was reported by respondents. Sampling was by convenience with the link circulated through university mail lists and targeted social media accounts for 2 weeks in June 2020. Results: In all, 225 responses were included of which 202 noted whether residents had reported CI. Most of the 202 identified themselves as immediate family (91%) and as female (82%). The majority (67%) were aged between 45 and 64 years. Most (80%) reported that their resident had CI. Approximately one-third indicated reduced satisfaction (27%) or that restrictions had impaired communication with nursing home staff (38%). Median loneliness scores were 4/9, well-being scores 60/100 and carer QoL scores 10/15. Visitors of those with CI reported significantly lower well-being (p = 0.006) but no difference in loneliness (p = 0.114) or QoL (p = 0.305). Reported CI (p = 0.04) remained an independent predictors of lower WHO-5 scores, after adjusting for age, sex, RCF location, and dementia stage (advanced), satisfaction with care (reduced), and perception of staff support measured on the Adult Carer QoL Questionnaire. Conclusion: This survey suggests that many RCF visitors experienced low psychosocial and emotional well-being during the COVID-19 lockdown. Visitors of residents with CI report significantly poorer well-being as measured by the WHO-5 than those without. Additional research is required to understand the importance of disrupted caregiving roles resulting from visiting restrictions on well-being, particularly on visitors of residents with CI and how RCFs and their staff can support visitors to mitigate these.