Development Of Cognitive Decline Research Articles

The role of dietary fats on cognition and sarcopenia in the elderly.

To elucidate the role of dietary fats on the relationship between mild cognitive impairment and sarcopenia and help identifying and preventing the decline of cognitive and muscle function in elderly individuals. The study conducted involving a group of 1812 individuals between the ages of 61 and 92. Body composition and BMR were assessed by bioelectrical impedance analysis. Cognitive function and dietary nutrition were evaluated by neuropsychological assessments and questionnaire of food intake frequency. Lipidomics analysis was performed using UHPLC-Qtrap-MS/MS. MCI and SA are mutual influencing factors, lower intake of MUFA, PUFA and higher intake of fat was associated with cognitive dysfunction and/or SA (p < 0.05). PUFA was important for MCI combined with SA (Compared with Q1, Q4 OR: 0.176, 95%CI: 0.058,0.533). Lipidomics analysis revealed that triacylglycerol (TAG) contain more carbon chains with saturated double bonds may be closely related to cognitive impairment and the progression of SA (p < 0.05). While, DAG with carbon chains of unsaturated double bonds is opposite. Insufficient intake of unsaturated fatty acids was associated with the development of cognitive decline and the progression of SA. MUFA affecting muscle health, fats and PUFA has a greater impact on MCI combined with SA. Less MUFA intake and increasing saturated double-bonded fatty acid intake might be the key factors on promoting cognitive impairment and SA in the elderly. They have the potential to serve as prospective biomarkers indicating a higher risk of cognitive decline and/or SA in the elderly population.

Association of glycogen synthase kinase-3β with cognitive impairment in type 2 diabetes patients: a six-year follow-up study.

Our previous multicenter case-control study showed that aging, up-regulation of platelet glycogen synthase kinase-3β (GSK-3β), impaired olfactory function, and ApoE ϵ4 genotype were associated with cognitive decline in type 2 diabetes mellitus (T2DM) patients. However, the causal relationship between these biomarkers and the development of cognitive decline in T2DM patients remains unclear. To further investigate this potential relationship, we designed a 6-year follow-up study in 273 T2DM patients with normal cognitive in our previous study. Baseline characteristics of the study population were compared between T2DM patients with and without incident mild cognitive impairment (MCI). We utilized Cox proportional hazard regression models to assess the risk of cognitive impairment associated with various baseline biomarkers. Receiver operating characteristic curves (ROC) were performed to evaluate the diagnostic accuracy of these biomarkers in predicting cognitive impairment. During a median follow-up time of 6 years (with a range of 4 to 9 years), 40 patients (16.13%) with T2DM developed MCI. Participants who developed incident MCI were more likely to be older, have a lower education level, have more diabetic complications, a higher percentage of ApoE ϵ4 allele and a higher level of platelet GSK-3β activity (rGSK-3β) at baseline (P<0.05). In the longitudinal follow-up, individuals with higher levels of rGSK-3β were more likely to develop incident MCI, with an adjusted hazard ratio (HR) of 1.60 (95% confidence interval [CI] 1.05, 2.46), even after controlling for potential confounders. The AUC of the combination of age, rGSK-3β and ApoEϵ4 allele predicted for incident MCI was 0.71. Platelet GSK-3β activity could be a useful biomarker to predict cognitive decline, suggesting the feasibility of identifying vulnerable population and implementing early prevention for dementia.

A pilot study of longitudinal changes in neurocognition, white matter hyperintensities, and cortical thickness in atrial fibrillation patients following catheter ablation vs medical management

BackgroundCerebral microembolization and atrophy complicate atrial fibrillation (AF). ObjectivesWe aimed to compare changes in neuroimaging findings between AF patients treated with catheter ablation and those treated with medical therapy. MethodsIn this pilot study, we evaluated differences in the change in regional white matter hyperintensity burden (WMHb) and cognitive function from baseline to 6-weeks and 1-year in patients treated with AF ablation (ABL, n=12) and patients treated with medical management alone (MM, n=11). Change in cortical thickness in Alzheimer’s Disease (AD)-risk, aging-associated or shared AD-risk/aging regions was also compared between groups. ResultsThe mean age was 69.7±5.0, 78% of patients were male, 39% had persistent AF, and all received oral anticoagulation. There were no significant differences between groups in the change in cognitive function. At 6-weeks, there were no significant differences in periventricular WMHb changes between groups (0.00 vs. 0.04; p=0.12), but changes in attention/concentration were inversely correlated with periventricular (p=0.01) and total WMHb (p=0.03). MM patients demonstrated significantly greater cortical thinning in AD-risk regions from baseline to 1-year (p=0.003). ConclusionsAF patients who underwent ablation demonstrated less cortical thinning in regions associated with AD risk than patients treated with medical therapy. Larger, prospective studies are needed to better understand the relationship between AF therapies and the development of cognitive decline.

Neurobehavioral Analysis to Assess Olfactory and Motor Dysfunction in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative condition, primarily affecting dopaminergic neurons. It is defined by motor impairments, such as bradykinesia, stiffness, resting tremor, and postural instability. The striatum, a structure essential for motor control, is impaired in function due to the significant loss of dopaminergic neurons in the substantia nigra and the development of Lewy bodies in the surviving nigral dopaminergic neurons. Olfactory impairment is one of the earliest indications of neurodegenerative disorders like PD that appear years before motor symptoms and cognitive decline development. Olfactory dysfunction is the most common nonmotor PD sign in at least 90% of cases, frequently occurring 5-10years before motor disturbances. Surprisingly, even though olfactory impairment is intimately linked to PD and is thought to be a potential biomarker, little is known about the brain process underlying this failure. Exposure to environmental toxins has been linked to olfactory dysfunction, leading to nigral neurodegeneration and loss of motor functions. Behavioral neuroscience plays a significant role in identifying and characterizing these olfactory and motor symptoms. In preclinical research, novel treatment approaches are being evaluated in rodent models by behavioral phenotyping to ensure their efficacy. This chapter describes neurobehavioral analysis to assess olfactory and motor dysfunction in rodent models of Parkinson's disease.

Longitudinal sleep instability predicts cognitive decline and is associated with increased MRI‐visible perivascular space burden

AbstractBackgroundAlthough emerging data suggest a direct link between sleep duration, aging, and cognitive performance, the impact of longitudinal sleep patterns have on Alzheimer’s disease‐associated pathology and cognitive decline remains unclear.MethodUtilizing longitudinal data on self‐reported sleep duration collected within the Seattle Longitudinal Study, we used a Cox proportional hazard (CPH) regression to evaluate the relationship between longitudinal sleep factors on the development of cognitive decline. Additional analysis in a sub‐cohort utilized multivariate linear regression prediction analyses to evaluate the predictive value of these longitudinal sleep factors on the incidence of developing cognitive impairment over an interval of 10 years.A cohort within the study received MRI and FLAIR neuroimaging, enabling the assessment of the impact these longitudinal sleep factors have on subcortical white matter MRI‐visible perivascular space burden (PVS). A semi‐automated segmentation algorithm accounted for PVS total burden and volume, as well as average PVS width, length, and median volume across participants, blinded by group.ResultCPH analysis found years of education (HR 1.12, 95% CI 1.02, 1.22), APOE4 status (HR 2.18, 95% CI 1.37, 3.49), higher depression scores (HR 1.08, 95% CI 1.04, 1.13), short sleep phenotype (HR 1.78, 95% CI 1.03, 3.08) and increased sleep variability (HR 3.10, 95% CI 1.66, 5.80) were significantly associated with cognitive impairment. Further, when including these factors into our linear regression prediction analyses, age (p&lt;0.0001), depression (p = 0.01) and sleep variability (p = 0.042) were significant predictors of cognitive impairment over a 10‐year period.Preliminary analysis showed significant association between high sleep variability and increased whole‐brain PVS volume (p = 0.04) and length (p = 0.03), with a significant correlation between sleep variability and median PVS volume (p = 0.04). Follow‐up analysis evaluated PVS features within the wider cohort.ConclusionThese findings suggest that variability in longitudinal self‐reported sleep duration exerts a previously unappreciated influence on downstream cognitive performance and pathological processes, potentially including glymphatic dysfunction. These findings elaborate the link between sleep instability, aging, cognitive decline and neuropathologic disease state. Future studies should evaluate these findings on an independent cohort to assess whether sleep variability of different time scales (weeks, years, decades) exerts similar effects on these outcomes.

Longitudinal sleep instability predicts cognitive decline and is associated with increased MRI‐visible perivascular space burden

AbstractBackgroundAlthough emerging data suggest a direct link between sleep duration, aging, and cognitive performance, the impact of longitudinal sleep patterns have on Alzheimer’s disease‐associated pathology and cognitive decline remains unclear.MethodUtilizing longitudinal data on self‐reported sleep duration collected within the Seattle Longitudinal Study, we used a Cox proportional hazard (CPH) regression to evaluate the relationship between longitudinal sleep factors on the development of cognitive decline. Additional analysis in a sub‐cohort utilized multivariate linear regression prediction analyses to evaluate the predictive value of these longitudinal sleep factors on the incidence of developing cognitive impairment over an interval of 10 years. A cohort within the study received MRI and FLAIR neuroimaging, enabling the assessment of the impact these longitudinal sleep factors have on subcortical white matter MRI‐visible perivascular space burden (PVS). A semi‐automated segmentation algorithm accounted for PVS total burden and volume, as well as average PVS width, length, and median volume across participants, blinded by group.ResultCPH analysis found years of education (HR 1.12, 95% CI 1.02, 1.22), APOE4 status (HR 2.18, 95% CI 1.37, 3.49), higher depression scores (HR 1.08, 95% CI 1.04, 1.13), short sleep phenotype (HR 1.78, 95% CI 1.03, 3.08) and increased sleep variability (HR 3.10, 95% CI 1.66, 5.80) were significantly associated with cognitive impairment. Further, when including these factors into our linear regression prediction analyses, age (p&lt;0.0001), depression (p = 0.01) and sleep variability (p = 0.042) were significant predictors of cognitive impairment over a 10‐year period. Preliminary analysis showed significant association between high sleep variability and increased whole‐brain PVS volume (p = 0.04) and length (p = 0.03), with a significant correlation between sleep variability and median PVS volume (p = 0.04). Follow‐up analysis evaluated PVS features within the wider cohort.ConclusionThese findings suggest that variability in longitudinal self‐reported sleep duration exerts a previously unappreciated influence on downstream cognitive performance and pathological processes, potentially including glymphatic dysfunction. These findings elaborate the link between sleep instability, aging, cognitive decline and neuropathologic disease state. Future studies should evaluate these findings on an independent cohort to assess whether sleep variability of different time scales (weeks, years, decades) exerts similar effects on these outcomes.

Tributyrin oral administration significantly attenuates the loss of intestinal butyrate‐producing bacteria and the ensuing cognitive dysfunction associated with Alzheimer’s Disease pathogenesis in 3xTg‐AD mice

AbstractBackgroundAlzheimer’s Disease (AD) development is linked to the loss of overall gut microbial diversity. However, the specific alterations are only beginning to be examined. In this regard, decreases in intestinal butyrate‐producing bacteria have been indicated by pre‐clinical and clinical studies in AD. The current work, employing the 3xTg‐AD mouse model examined the causal association of loss of butyrate‐producing bacterial communities with cognitive dysfunction associated with AD pathogenesis.MethodCecal samples from tributyrin (TB) treated and untreated female 3xTg‐AD mice were used to perform metataxonomic analysis by sequencing the 16S rRNA gene (V4 region) on a large‐scale Illumina MiSeq platform. Inferred metagenomics analysis was performed using the PICRUSt2 pipeline. TB treatment (oral gavage, 2mg/kg, twice a week) was initiated at 6‐months of age until 17‐months. Spatial and short‐term memory functions were tested using the Y‐maze and Novel Object Recognition Test (NORT).ResultMetataxonomic analysis showed an age‐dependent, significant decline in alpha diversity represented by measures of OTUs, Chao‐1 and Shannon Index from 2‐ to 18‐months. Additionally, age‐dependent changes in gut microbial composition were demonstrated by a significant decrease in the Firmicutes‐to‐Bacteroidota (F/B) ratio. Further analysis of specific features of the gut microbiome demonstrated an age‐dependent decrease in total butyrate‐producing families within the Firmicutes phylum; particularly, a significant loss of critical butyrate producing family Ruminococcacea was identified. Predictive functional analysis using PICRUSt2 also showed a significant reduction in the abundance of specific bacterial genes involved in butyrate synthesis. Importantly, these age‐dependent markers of gut microbial dysbiosis coincided with diminished measures of spatial and short‐term memory. Notably, administration of TB, a butyrate pro‐drug, significantly attenuated the age‐dependent (i) decline in gut microbial diversity &amp; butyrate‐producing bacteria and (ii) loss of spatial and short‐term memory.ConclusionThe findings from this study identify that decline in total butyrate‐producing families is a key pathogenic feature of AD‐associated microbial dysbiosis and cognitive dysfunction. Importantly, these findings have the potential to inform the development of treatment strategies targeting gut microbial dysbiosis using TB, to prevent onset and development of cognitive decline in AD.

Effects of mammary cancer and chemotherapy on neuroimmunological markers and memory function in a preclinical mouse model

Treatment modalities for breast cancer, including cyclophosphamide chemotherapy, have been associated with the development of cognitive decline (CRCD), which is characterized by impairments in memory, concentration, attention, and executive functions. We and others have identified a link between inflammation and decreased cognitive performance in patients with breast cancer receiving chemotherapy. In order to better understand the inflammation-associated molecular changes within the brain related to tumor alone or in combination with chemotherapy, we orthotopically implanted mouse mammary tumors (E0771) into female C57BL/6 mice and administered clinically relevant doses of cyclophosphamide and doxorubicin intravenously at weekly intervals for four weeks. We measured serum cytokines and markers of neuroinflammation at 48 h and up to one month post-treatment and tested memory using a reward-based delayed spatial alternation paradigm. We found that breast tumors and chemotherapy altered systemic inflammation and neuroinflammation. We further found that the presence of tumor and chemotherapy led to a decline in memory over time at the longest delay, when memory was the most taxed, compared to shorter delay times. These findings in a clinically relevant mouse model shed light on possible biomarkers for CRCD and add to the growing evidence that anti-inflammatory strategies have the potential to mitigate cancer- or treatment-related side effects.

Immune gene co-expression signatures implicated in occurence and persistence of cognitive dysfunction in depression

Cognitive dysfunction contributes significantly to the burden caused by Major Depressive Disorder (MDD). Yet, while compelling evidence suggests that different biological processes play a part in both MDD aetiology and the development of cognitive decline more generally, we only begin to understand the molecular underpinnings of depression-related cognitive impairment. Developments in psychometric assessments, molecular high-throughput methods and systems biology derived analysis strategies advance this endeavour.Here, we aim to identify gene expression signatures associated with cognitive dysfunction and cognitive improvement following therapy using RNA sequencing to analyze the whole blood-derived transcriptome of altogether 101 MDD patients who enrolled in the CERT-D study. The mRNA(Nova)Seq based transcriptome was analyzed from whole blood taken at baseline assessment, and patients' cognitive performance was measured twice at baseline and following eight weeks of therapy by means of the THINC integrated tool. Thirty-six patients showed comparatively low cognitive performance at baseline assessment, and 32 patients showed comparatively strong cognitive improvement following therapy. Differential gene expression analysis was performed using limma to a significance threshold of 0.05 and a logFC cutoff of |1.2|. Although we observed some indications for expression differences related to low cognitive performance and cognitive therapy response, signals did not withstand adjustment for multiple testing. Applying WGCNA, we retrieved altogether 25 modules of co-expressed genes and we used a combination of correlational and linear analyses to identify modules related to baseline cognitive performance and cognitive improvement following therapy. Three immune modules reflected distinct but interrelated immune processes (the yellow module: neutrophil-mediated immunity, the darkorange module: interferon signaling, the tan module: platelet activation), and higher expression of the yellow (r = −0.21, p < .05), the dark orange (r = 0.2, p < .05), and the tan (r = −0.23, p < .05) module correlated significantly negatively with patients' cognitive baseline performance. Patients' cognitive baseline performance was a significant predictor of the darkorange module (b = −0.039, p < .05) and the tan module's expression (b = 0.02, p < .05) and was close to becoming a significant predictor of the yellow module's expression (b = −0.02, p = .05). Furthermore, patients characterized by comparatively low cognitive performance at baseline showed significantly higher expression of the tan module when compared to all other patients F(1,97) = 4.32, p < .05, η= 0.04. Following eight weeks of treatment, we observed altogether significant improvement in patients' cognitive performance (b = 0.30, p < .001), and patients with comparatively high cognitive gain showed noticeably lower, but not significantly lower F(1,98) = 3.76, p = .058, expression of a dark turquoise module, which reflects complement and B-cell-associated immune processes. Noteworthy, the relation between cognitive performance and module expression remained observable after controlling for symptom severity and BMI, which partly accounted for variance in module expression. As such, our findings provide further evidence for the involvement of immune processes in MDD related cognitive dysfunction and they suggest that different immune processes contribute to the development and long-term persistence of cognitive dysfunction in the context of depression.

Dietary Total Antioxidant Capacity and Cognitive Function in Older Adults in the United States: The NHANES 2011-2014.

Oxidative stress level takes part in the development of cognitive decline. However, the association between total antioxidant capacity (TAC) from diet and cognitive function is controversial. The aim of this study was to investigate the relationship between TAC and the cognitive function of older adults in the U.S. A cross-sectional study. National Health and Nutrition Examination Surveys database. 2712 older adults aged over 60 years. TAC was calculated from 8 antioxidative vitamins based on the reference values for vitamin C equivalent antioxidant capacity obtained from individuals' 24 h dietary recall. Four memory-related assessments were employed [Immediate Recall test (IRT), Delayed Recall test (DRT), Animal Fluency test (AFT), and Digit Symbol Substitution test (DSST)]. Among the 2712 participants, the median age was 68 years, and 50.4% were women. Participants in the group with higher TAC levels had relatively higher IRT, AFT and DSST scores (P=0.025, P=0.008, P<0.001, respectively). In adjusted weighted linear regression, log-transformed TAC was positively associated with AFT (β=1.10, 95%CI: 0.51, 1.70) and DSST (β=2.81, 95%CI: 1.16, 4.45). Compared with the first quartile, the participants in the second (Q2 vs. Q1, OR=0.66, 95%CI: 0.43,1.02) and fourth quartile (Q4 vs. Q1, OR=0.47, 95%CI:0.28, 0.78) of log-transformed TAC showed a decreased risk of impaired cognitive function (ICF) after adjusting for confounders. The dose-response analysis indicated a gradual descent in the risk of ICF as TAC increases. Diabetes mellitus (DM) mediated part of the effect of TAC on ICF. The relationship between TAC and ICF was more pronounced in subjects with DM (Q4 vs Q1, OR=0.36, 95%CI:0.17, 0.74). Our findings support that higher dietary antioxidant potential was related to a decreased risk of cognitive dysfunction, particularly in the subjects with DM who may have oxidative injury. DM was one of the factors mediating the effect of TAC on ICF.

Adrenergic regulation of astroglial aerobic glycolysis and lipid metabolism: Towards a noradrenergic hypothesis of neurodegeneration

Ageing is a key factor in the development of cognitive decline and dementia, an increasing and challenging problem of the modern world. The most commonly diagnosed cognitive decline is related to Alzheimer's disease (AD), the pathophysiology of which is poorly understood. Several hypotheses have been proposed. The cholinergic hypothesis is the oldest, however, recently the noradrenergic system has been considered to have a role as well. The aim of this review is to provide evidence that supports the view that an impaired noradrenergic system is causally linked to AD. Although dementia is associated with neurodegeneration and loss of neurons, this likely develops due to a primary failure of homeostatic cells, astrocytes, abundant and heterogeneous neuroglial cells in the central nervous system (CNS). The many functions that astrocytes provide to maintain the viability of neural networks include the control of ionic balance, neurotransmitter turnover, synaptic connectivity and energy balance. This latter function is regulated by noradrenaline, released from the axon varicosities of neurons arising from the locus coeruleus (LC), the primary site of noradrenaline release in the CNS. The demise of the LC is linked to AD, whereby a hypometabolic CNS state is observed clinically. This is likely due to impaired release of noradrenaline in the AD brain during states of arousal, attention and awareness. These functions controlled by the LC are needed for learning and memory formation and require activation of the energy metabolism. In this review, we address first the process of neurodegeneration and cognitive decline, highlighting the function of astrocytes. Cholinergic and/or noradrenergic deficits lead to impaired astroglial function. Then, we focus on adrenergic control of astroglial aerobic glycolysis and lipid droplet metabolism, which play a protective role but also promote neurodegeneration under some circumstances, supporting the noradrenergic hypothesis of cognitive decline. We conclude that targeting astroglial metabolism, glycolysis and/or mitochondrial processes may lead to important new developments in the future when searching for medicines to prevent or even halt cognitive decline.

The Confusion Surrounding Androgen Deprivation Therapy and Cognitive Dysfunction

There are varied associations that have been identified between the use of androgen deprivation therapy (ADT) and the development of cognitive decline. We highlight the first studies to evaluate chronic use of ADT, other systemic treatments for prostate cancer, and genetic polymorphisms in this context.

Disentangling the relationship of subjective cognitive decline and depressive symptoms in the development of cognitive decline and dementia.

Subjective cognitive decline (SCD) and depressive symptoms (DS) frequently co-occur prior to dementia. However, the temporal sequence of their emergence and their combined prognostic value for cognitive decline and dementia is unclear. Temporal relationships of SCD, DS and memory decline were examined by latent difference score modeling in a high-aged, population-based cohort (N = 3217) and validated using Cox-regression of dementia-conversion. In 334 cognitively unimpaired SCD-patients from memory-clinics, we examined the association of DS with cognitive decline and with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. In the population-based cohort, SCD preceded DS. High DS were associated with increased risk of dementia conversion in individuals with SCD. In SCD-patients from memory-clinics, high DS were associated with greater cognitive decline. CSF Aß42 predicted increasing DS. SCD typically precedes DS in the evolution to dementia. SCD-patients from memory-clinics with DS may constitute a high-risk group for cognitive decline. Subjective cognitive decline (SCD) precedes depressive symptoms (DS) as memory declines. Emerging or persistent DS after SCD reports predict dementia. In SCD patients, more amyloid pathology relates to increasing DS. SCD patients with DS are at high risk for symptomatic progression.

Is Matrix Metalloproteinase-9 Associated with Post-Stroke Cognitive Impairment or Dementia?

Matrix metalloproteinase-9 (MMP-9) is a significant protease required for synaptic plasticity, learning, and memory. Yet, the role of MMP-9 in the occurrence and development of cognitive decline after ischemic stroke is not fully understood. In this study, we used clinical data experiments to further investigate whether MMP-9 and genetic polymorphism are associated with post-stroke cognitive impairment or dementia (PSCID). A total of 148 patients with PSCID confirmed by the Montreal Cognitive Assessment (MoCA) 3 months after onset (PSCID group) were included in the study. The MMP-9 rs3918242 polymorphisms were analyzed using polymerase chain reaction coupled with restriction fragment length polymorphism, and the serum level of MMP-9 was measured using enzyme-linked immunosorbent assay (ELISA). The same manipulations have been done on 169 ischemic stroke patients without cognitive impairment (NCI group) and 150 normal controls (NC group). The expression level of serum MMP-9 in the PSCID group and NCI group was higher compared to the NC group, and the levels in the PSCID group were higher than that in the NCI group (all p < 0.05). Diabetes mellitus, hyperhomocysteinemia, and increased serum MMP-9 levels were the main risk factors of cognitive impairment after ischemic stroke. The serum level of MMP-9 was negatively correlated with the MoCA score, including visual-spatial executive, naming, attention, language, and delayed recall. Genetic polymorphism showed that TC genotype with MMP-9 rs3918242 and CC genotype were associated with a significantly increased risk of PSCID; moreover, the TC genotype significantly increased the risk of cognitive impairment. In the TCCC genotype of MMP-9 rs3918242, diabetes mellitus and hyperhomocysteinemia were associated with the increased risk of PSCID; also, hyperhomocysteinemia could increase the risk of cognitive impairment. MMP-9 level and MMP-9 rs3918242 polymorphism have an important role in the occurrence and development of post-stroke cognitive impairment or dementia (PSCID).

Clinical reasoning of occupational therapists in selecting activities together with older adults with dementia to postpone further development of cognitive decline

Background Research suggests that participation in activities has the potential to prevent or delay the development of later-life cognitive decline and dementia. This area is unexplored within occupational therapy. Aim To explore and describe the clinical reasoning of occupational therapists in selecting activities together with older adults with dementia to participate in, with the goal to postpone further development of cognitive decline in a sample from the German part of Switzerland. Methods A constructivist grounded theory approach was used. Six in-depth, semi-structured interviews with occupational therapists working in geriatric units in the German part of Switzerland were conducted. Results Three main categories were identified: (i) from the discovery of ‘who the older adult is’ to the discovery of ‘meaningful activities’, (ii) reflecting on occupational therapists’ individuality, and (iii) matching the activity to older adults’ skills. A core category was developed: Pursuing active participation through meaningful and chosen activities. Conclusions The study suggests that to pursue enabling active participation in activities among older adults with dementia, and promoting the quality of participation, occupational therapists must consider the identified elements that are important in selecting the activities which might be used to postpone cognitive decline in each individual.

The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex.

Parkinson’s disease (PD) is a complex pathology causing a plethora of non-motor symptoms besides classical motor impairments, including cognitive disturbances. Recent studies in the PD human brain have reported microgliosis in limbic and neocortical structures, suggesting a role for neuroinflammation in the development of cognitive decline. Yet, the mechanism underlying the cognitive pathology is under investigated, mainly for the lack of a valid preclinical neuropathological model reproducing the disease’s motor and non-motor aspects. Here, we show that the bilateral intracerebral infusion of pre-formed human alpha synuclein oligomers (H-αSynOs) within the substantia nigra pars compacta (SNpc) offers a valid model for studying the cognitive symptoms of PD, which adds to the classical motor aspects previously described in the same model. Indeed, H-αSynOs-infused rats displayed memory deficits in the two-trial recognition task in a Y maze and the novel object recognition (NOR) test performed three months after the oligomer infusion. In the anterior cingulate cortex (ACC) of H-αSynOs-infused rats the in vivo electrophysiological activity was altered and the expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) and the AMPA receptor subunit GluR1 were decreased. The histological analysis of the brain of cognitively impaired rats showed a neuroinflammatory response in cognition-related regions such as the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. We found an increased GFAP reactivity and the acquisition of a proinflammatory phenotype by microglia, as indicated by the increased levels of microglial Tumor Necrosis Factor alpha (TNF-α) as compared to vehicle-infused rats. Moreover, diffused deposits of phospho-alpha synuclein (p-αSyn) and Lewy neurite-like aggregates were found in the SNpc and striatum, suggesting the spreading of toxic protein within anatomically interconnected areas. Altogether, we present a neuropathological rat model of PD that is relevant for the study of cognitive dysfunction featuring the disease. The intranigral infusion of toxic oligomeric species of alpha-synuclein (α-Syn) induced spreading and neuroinflammation in distant cognition-relevant regions, which may drive the altered neuronal activity underlying cognitive deficits.

Plasma MIA, CRP, and Albumin Predict Cognitive Decline in Parkinson's Disease.

Using a multi-cohort, discovery-replication-validation design, we sought new plasma biomarkers that predict which individuals with Parkinson's disease (PD) will experience cognitive decline. In 108 discovery cohort PD individuals and 83 replication cohort PD individuals, we measured 940 plasma proteins on an aptamer-based platform. Using proteins associated with subsequent cognitive decline in both cohorts, we trained a logistic regression model to predict which patients with PD showed fast (>=1 point drop/year on Montreal Cognitive Assessment [MoCA]) versus slow (< 1 point drop/year on MoCA) cognitive decline in the discovery cohort, testing it in the replication cohort. We developed alternate assays for the top 3 proteins and confirmed their ability to predict cognitive decline - defined by change in MoCA or development of incident mild cognitive impairment (MCI) or dementia - in a validation cohort of 118 individuals with PD. We investigated the top plasma biomarker for causal influence by Mendelian randomization (MR). A model with only 3 proteins (melanoma inhibitory activity protein [MIA], C-reactive protein [CRP], and albumin) separated fast versus slow cognitive decline subgroups with an area under the curve (AUC) of 0.80 in the validation cohort. The individuals with PD in the validation cohort in the top quartile of risk for cognitive decline based on this model were 4.4 times more likely to develop incident MCI or dementia than those in the lowest quartile. Genotypes at MIA single nucleotide polymorphism (SNP) rs2233154 associated with MIA levels and cognitive decline, providing evidence for MIA's causal influence. An easily obtained plasma-based predictor identifies individuals with PD at risk for cognitive decline. MIA may participate causally in development of cognitive decline. ANN NEUROL 2022;92:255-269.

0644 Longitudinal sleep instability contributes to cognitive decline and Alzheimer’s pathology: Findings from the Seattle Longitudinal Study

Abstract Introduction Although emerging data suggest a link between sleep duration, aging, and dementia diagnosis, the impact of longitudinal patterns of sleep behavior on Alzheimer’s disease-associated pathology and cognitive decline remains unclear. Methods Utilizing longitudinal data on self-reported sleep duration collected within the Seattle Longitudinal Study (n=535 subjects, age 75.18 +/- 11.6 years), we first used a Cox proportional hazard (CPH) regression model to evaluate the overall effect of mean sleep duration, longitudinal changes in sleep duration, and variability in sleep duration on the development of cognitive decline, including APOE4 genotype, sex, years of education, and depression as covariates within the model. In a secondary study, within the subset of subjects for whom postmortem histopathological assessment has been conducted (n=105 subjects, age 86.6 +/- 8.0 years), we used supervised machine learning to predict Alzheimer’s pathology, measured by CERAD neuritic plaque score and Braak stage. Results Multivariable CPH regression analysis demonstrated that there was a significant association between cognitive decline risk and APOE status (hazard ratio 2.28, 95% CI 1.41-3.69, p&amp;lt;0.005), depression (hazard ratio 1.09, 95% CI 1.04-1.14, p&amp;lt;0.005), sleep stability (hazard ratio 2.78, 95% CI 1.43-5.43, p&amp;lt;0.005), and sleep restlessness (hazard ratio 0.70, 95% CI 0.51-0.97, p&amp;lt;0.03). Notably, sleep variability across time and not median sleep duration was significantly associated with cognitive impairment. Adding these sleep parameters to the model improved model performance (base model concordance = 0.66, model including sleep = 0.72). Sleep parameters also improved performance on models predicting Alzheimer’s disease-associated pathology. Conclusion While these findings support a mixed effect of sleep duration on cognitive decline and the development of Alzheimer’s-associated neuropathology, they further suggest that variability in longitudinal sleep duration may exert a previously unappreciated influence on these pathological processes. Future studies should seek to replicate these findings in an independent cohort and to assess whether sleep variability of different time scales (weeks, years, decades) exerts similar effects on these outcomes. Support (If Any)

Middle‐Aged and Older Adults with Greater White Matter Hyperintensity Burden Display Attenuated Blood Pressure and Cerebral Blood Velocity Responses During Orthostatic Tilt

Cerebral autoregulation (CA) is the process by which the brain maintains adequate blood flow despite sudden changes to perfusion pressure. White matter hyperintensities (WMH) are associated with increased risk of cerebrovascular disease and dementia. This study investigated whether dynamic CA is reduced in cognitively unimpaired middle‐aged and older adults. Additionally, we evaluated dynamic CA and cerebrovascular responses at rest and in response to orthostatic tilt. We hypothesized that CA would be impaired during orthostatic tilt and that diminished blood pressure and cerebral artery blood velocity changes would be associated with greater WMH fraction. We studied 33 middle‐aged and older adults (age = 63 ± 4 y). Intracranial volume (ICV) and WMH lesion volume were measured using a T1 and FLAIR scan, respectively, on a 3T MRI scanner. WMH fraction was calculated as the cube root of (WMH lesion volume/ICV) *100. CA was measured using middle cerebral artery blood velocity (MCAv) from transcranial Doppler ultrasound and beat‐to‐beat mean arterial pressure (MAP) from a finger cuff. Five minutes of data were collected at rest and during 60º orthostatic tilt. Transfer function analysis was used to quantify dynamic CA and reported as gain and phase at low frequency (LF) (0.07‐0.20 Hz). MCAv, MAP and cerebrovascular resistance index (CVRi; calculated as MAP/MCAv) were used to quantify the cerebrovascular response to orthostatic tilt. LF gain was greater at baseline compared to 60º tilt (0.52 cm/s/mmHg vs 0.46 cm/s/mmHg, p &lt; 0.05); however, there were no differences in LF phase between baseline and 60º tilt (29.70 degrees vs 29.42 degrees, p = 0.95). During 60º tilt, MAP and MCAv decreased compared to baseline (MAP: 106 mmHg vs 101 mmHg, p = 0.02; MCAv: 59 cm/s vs 53 cm/s, p &lt; .01). CVRi was higher at 60º tilt compared with baseline (1.90 mmHg/cm/s vs 2.02 mmHg/cm/s, p &lt; 0.01). There were significant inverse associations between the percent change from baseline to 60º tilt in MAP (r = ‐0.4, p = 0.03), MCAv (r = ‐0.39, p = 0.03), but not CVRi (r = 0.13, p = 0.50), and WMH fraction. There were no associations at baseline or 60º tilt between gain (Baseline: r = ‐0.18, p = 0.33; 60º: r = ‐0.31, p = 0.09) or phase (Baseline: r = 0.07, p = 0.71; 60º: r = ‐0.29, p = 0.12) and WMH fraction. Our results indicate that dynamic CA is preserved in cognitively unimpaired adults during tilt. However, individuals with diminished MAP and MCAv responses to orthostatic tilt displayed greater WMH fraction. Future studies are needed to investigate the relationship between blood pressure and cerebral blood flow in individuals with cognitive impairment to further understand the role of cerebral blood flow regulation in the development of cognitive decline.

TLR4 mutation protects neurovascular function and cognitive decline in high-fat diet-fed mice

BackgroundMetabolic syndrome (MS) is defined as a low-grade proinflammatory state in which abnormal metabolic and cardiovascular factors increase the risk of developing cardiovascular disease and neuroinflammation. Events, such as the accumulation of visceral adipose tissue, increased plasma concentrations of free fatty acids, tissue hypoxia, and sympathetic hyperactivity in MS may contribute to the direct or indirect activation of Toll-like receptors (TLRs), specifically TLR4, which is thought to be a major component of this syndrome. Activation of the innate immune response via TLR4 may contribute to this state of chronic inflammation and may be related to the neuroinflammation and neurodegeneration observed in MS. In this study, we investigated the role of TLR4 in the brain microcirculation and in the cognitive performance of high-fat diet (HFD)-induced MS mice.MethodsWild-type (C3H/He) and TLR4 mutant (C3H/HeJ) mice were maintained under a normal diet (ND) or a HFD for 24 weeks. Intravital video-microscopy was used to investigate the functional capillary density, endothelial function, and endothelial–leukocyte interactions in the brain microcirculation. Plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), adipokines and metabolic hormones were measured with a multiplex immunoassay. Brain postsynaptic density protein-95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the vessels, microglial activation and structural capillary density were evaluated by immunohistochemistry.ResultsThe HFD-induced MS model leads to metabolic, hemodynamic, and microcirculatory alterations, as evidenced by capillary rarefaction, increased rolling and leukocyte adhesion in postcapillary venules, endothelial dysfunction, and less coverage of astrocytes in the vessels, which are directly related to cognitive decline and neuroinflammation. The same model of MS reproduced in mice deficient for TLR4 because of a genetic mutation does not generate such changes. Furthermore, the comparison of wild-type mice fed a HFD and a normolipid diet revealed differences in inflammation in the cerebral microcirculation, possibly related to lower TLR4 activation.ConclusionsOur results demonstrate that TLR4 is involved in the microvascular dysfunction and neuroinflammation associated with HFD-induced MS and possibly has a causal role in the development of cognitive decline.