Mild Cognitive Impairment Cases Research Articles

CSF synapse marker changes in predementia Alzheimer´s Disease: AMPA receptor modulators NPTX2 and NPTXR mediate cognition within A/T/N stages

AbstractBackgroundSynapse pathology has been linked to excitotoxicity and glutamate receptor dysregulation (such as AMPAR) in Alzheimer´s Disease (AD) progression. Of the core cerebrospinal fluid (CSF) AD biomarkers for amyloid, tau pathology and neurodegeneration (A/T/N), T/N status is proposed to reflect levels of neuronal plasticity, but fluid biomarkers for precision interventions in subgroups with increased excitotoxicity are lacking. Herein, we assess group differences of 19 CSF synapse markers including the AMPAR‐modulating NPTX, in both cognitively normal (CN) and Mild Cognitive Impairment (MCI) with either A+/T‐/N‐ and A+/T or N+ (A+/T/N+) as compared to CN A‐/T‐/N‐ and assess relationships with verbal memory recall and hippocampal volume.MethodsA/T/N was determined using the CSF Aβ42/40 ratio, p‐tau181 and total‐tau in predementia AD cases (n = 194) and CN participants with normal AD biomarkers (n = 145) in the Dementia Disease Initiation cohort. CSF synapse marker concentrations were determined using mass‐spectrometry (table 1) and ELISA for GAP‐43. Adjusted for age and sex, we compared marker concentrations between CN cases (A+/T‐/N‐ n = 20; A+/T/N+ n = 40) and MCI cases (A+/T‐/N‐ n = 25;A+/T/N+ n = 109) with CN A‐/T‐/N‐ (n = 145) as the reference group. Associations to verbal memory recall and brain imaging were performed in the total sample and respective A/T/N groups adjusted for covariates. Results p<.01 were considered significant.ResultsTop markers based on between‐group results are reported (Table 1 & figure 1‐2 for all markers). Compared to CN A‐/T‐/N‐, 14‐3‐3 ζ/δ concentrations were higher in all A+/T/N+ groups (p<.001), but unaltered in A+/T‐/N‐ groups. In A+/T‐/N‐, NPTX2 concentrations were lower in MCI (p<.001) but not in CN. In A+/T/N+, NPTX2 was higher in CN (p<.001) but not in MCI. 14‐3‐3 ζ/δ was associated with worse memory in the total sample (p<.001) but not in the A+ groups. Lower NPTX2 was associated with worse memory in the total sample (p<.001) and in both A+ groups (p<.01; p<001). Neither 14‐3‐3 ζ/δ nor NPTX2 were significantly associated with hippocampal volume (figure 2).ConclusionOverall, increased 14‐3‐3 ζ/δ was most closely associated with worse memory recall. Lower NPTX2 was linked to poorer cognitive status within A+ groups, suggesting links to AMPAR dysregulation and excitotoxicity.

Six‐month risk of non‐traumatic intracranial hemorrhage in cognitively impaired patients following Covid‐19 infection

AbstractBackgroundStudies suggest dementia patients have higher rates of non‐traumatic intracranial hemorrhage (nt‐ICH) compared to cognitively‐unimpaired peers. Recent studies also suggest increased risk of nt‐ICH, following infection with Covid‐19 in the general population. However, the risk of nt‐ICH following Covid‐19 infection in cognitively‐impaired individuals is currently unknown.MethodUsing US electronic health records ICD codes, we matched Alzheimer’s disease (AD), dementia, and mild cognitive impairment (MCI) cases with a history of Covid‐19 to similarly cognitively impaired controls without Covid‐19 history and examined incidence of nt‐ICH over six‐months following infection. Cases and controls were propensity score matched on age, sex, race, ethnicity, time since cognitive‐diagnosis, anticoagulant use, antiplatelet use, and 37 comorbidities. Analyses focused on the first year of the pandemic in 2020, prior to availability of at‐home tests and vaccines, to reduce misclassification bias. Individuals with prior history of nt‐ICH, traumatic ICH, or stroke were excluded to focus on incident nt‐ICH. Cox proportional hazard models compared risk between those with and without Covid‐19.ResultOur sample included 2,287 AD cases with Covid‐19 matched to 6,861 AD controls; 5,726 dementia cases matched to 17,178 dementia controls; and 807 MCI cases matched to 2,419 MCI controls. The incidence of nt‐ICH following Covid‐19, among AD cases, was 12.53/1,000 person‐years (95% CI: 7.66‐19.36) vs. 4.16/1,000 person‐years (95% CI: 2.51‐6.50) in AD patients without Covid‐19; HR = 3.1 (95% CI: 1.7, 5.8), p = 0.0004. Similarly in dementia patients, Covid‐19 increased the risk by 3.0 times (95% CI: 1.8, 4.7), p<0.0001. The incidence in dementia Covid‐19 cases was 8.48/1,000 person‐years (95% CI: 5.91, 11.80) vs. 2.97/1,000 person‐years (95% CI: 2.07, 4.13) in dementia patients without a history of Covid‐19 over the study period. The incidence in MCI patients with a history of Covid‐19 was 5.03/1,000 person‐years (95% CI: 1.37, 12.87), vs. 1.56/1,000 person‐years (95% CI: 0.32, 4.57) in MCI controls, but risk was not significantly different; HR = 3.4 (95% CI: 0.8, 15.0), p = 0.11.ConclusionAlthough nt‐ICH was rare among cognitively impaired patients following Covid‐19 infection in 2020, the risk over 6‐months in AD and dementia cases was approximately 3 times higher than controls without a history of Covid‐19.

Incidence of Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) in the United States Medicare population

AbstractBackgroundAlzheimer’s disease (AD) is a chronic, neurodegenerative condition. Mild cognitive impairment (MCI) is characterized by cognitive decline, without dementia. We aimed to estimate the incidence of AD and MCI among Medicare beneficiaries.MethodPatients were identified from the US Center for Medicare and Medicaid Services (CMS) database using International Classification of Diseases (ICD) codes for AD (331.0, G30.9, G30.8, or G30.1,) and MCI (331.83 or G31.84). Both AD and MCI were identified using the search rule of 2 ICD codes ≥30 days apart ≤365 days from both Medicare fee‐for‐service (FFS: 2008‐2018) and Medicare Advantage (MA: 2015‐2018). US regions were derived using zip codes and categorized by National Center for Chronic Disease Prevention/Health Promotion regions. Yearly incidence was defined as the number of new cases of AD or MCI in each year divided by the population at risk in the year. Confidence intervals were not reported due to small intervals.ResultThe incidence of AD and MCI per 10,000 person‐years was 82.9 and 4.9, 80.3 and 7.4, 74.5 and 9.3, 69.8 and 10.9, 65.3 and 13.4, 62.8 and 15.8, 60.7 and 17.4, 65.5 and 20.7, 61.4 and 22.4, 56.0 and 22.9, and 52.2 and 23.2 spanning from 2008 through 2018, respectively. In 2018, the incidence of AD and MCI per 10,000 person‐years by demographic subgroups was: 43 and 21 for men and 59 and 25 for women; 16 and 10 among those aged 65‐69 years, 30 and 18 for ages 70‐74 years, 58 and 30 for ages 75‐79, 102 and 44 for ages 80‐84, 176 and 57 for age ≥85 years old; 56 and 26 for Whites, 38 and 13 for Blacks, and 43 and 15 for Asians. The incidence of AD and MCI per 10,000 person‐years in 2018 was highest in the US Northeast, especially in New Hampshire (77 and 39), Vermont (74 and 47), and New Jersey (73 and 33).ConclusionAmong Medicare beneficiaries from 2008 to 2018, AD incidence generally decreased while MCI increased. Women, older age, White race, and Northeast region were associated with higher incidence of AD and MCI in 2018.

Occurrence of sleep disorders, anxiety, and depression among patients with mild cognitive impairment and Alzheimer’s disease in diverse populations: A large nationwide electronic health record cohort study

AbstractBackgroundPatients affected with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) often experience anxiety, depression, and sleep disturbances. Some of the published studies reported a higher incidence of these disorders in minority populations. The objectives of this study were to characterize the occurrence of sleep disorders, anxiety, and depression among patients with MCI and/or AD, stratified by gender, age and race/ethnicity in the United States clinical practice setting.MethodA retrospective cohort study was conducted using electronic health records and insurance claims from the Optum® Market Clarity database containing data from more than 63 million people in the US insured through Medicare, Medicaid, and other insurance providers. The study included patients diagnosed, utilizing ICD diagnosis codes, with MCI and/or AD between January 2017 and September 2021. Prevalence of depression, anxiety, and sleep disorders, as well as associated medication prescriptions, were identified in the 12 months before and after MCI and/or AD diagnoses. The occurrence of these diagnoses and prescriptions was evaluated stratified by gender, age, and race/ethnicity.ResultA total of 197,346 patients were diagnosed with MCI (56.9% female, mean age of 70.0 [SD 14.8]) and 144,321 with AD (63.9% female, mean age of 79.3 [SD 8.2]) at the baseline. Overall, a large proportion of MCI and AD cases had depression (pre‐MCI diagnosis: 40.3%; post‐MCI diagnosis: 44.8%; pre‐AD diagnosis: 32.2%; post‐AD diagnosis: 38.3%), anxiety (pre‐MCI diagnosis: 36.2%; post‐MCI diagnosis: 40.2%; pre‐AD diagnosis: 26.4%; post‐AD diagnosis: 31.5%), and sleep disorders (pre‐MCI diagnosis: 36.2%; post‐MCI diagnosis: 39.3%; pre‐AD diagnosis: 23.2%; post‐AD diagnosis: 25.4%). Occurrences of depression and anxiety were highest among females. Among individuals with MCI and/or AD, the gap between the proportion experiencing depression and the proportion prescribed an antidepressant was greatest for African American males and females. This was not observed for anxiety and anti‐anxiety medications.ConclusionA large proportion of individuals with MCI and/or AD also had depression, anxiety, and sleep issues. Further understanding of the populations with these comorbidities and their associated prescriptions by different ages, sex, and races/ethnicities is important when supporting patients with MCI and AD.

Identification of leukocyte surface biomarkers associated with late‐onset Alzheimer’s disease

AbstractBackgroundAltered innate immunity has been long associated with late‐onset Alzheimer’s disease (AD) and its associated blood‐based biomarkers are important for AD diagnosis and prognosis.MethodWe collected 38 participants from the AIBL study, including 22 cognitive normal (CN) individuals with negative amyloid burden (Centiloid [CL] < 15), 5 CN individuals with positive amyloid burden (CL > 15), and 11 mild cognitive impairment (MCI) and AD cases. A total of 17 leukocyte surface antigens were examined by flow cytometry immunophenotyping and compared between healthy controls (CN Ab ‐ve), pre‐clinical patients (CN Ab +ve), and clinical cases (MCI & AD), including CD36, MerTK, Clec7a, RAGE, Tyro3, CR1 (CD35), CX3CR1, CCR2, Axl, LILRB2, LILRB3, LILRB4, PILRA, and P2×7.ResultWe identified leukocyte surface markers differentially expressed between HC, pre‐clinical patients, and clinical cases. Mean fluorescence intensities of CD85d and CD85k were significantly reduced in pre‐clinical patients and cases compared with HC, implicating CD85d and CD85k downregulation in AD pathogenesis. Significant upregulation of RAGE, Tyro3, CCR2, CD85a, and PILRA was also noted in cases compared with HC. Leukocyte surface expressions of RAGE, CCR2, PILRA, and CD85k were significantly associated with the Preclinical Alzheimer’s Cognitive Composite (PACC), which is one of the most accurate estimates of cognition in AD diagnosis.ConclusionOur preliminary investigations into these leukocyte markers demonstrated their dysregulations in pre‐clinical stage of AD, implicating early deficits in innate immunity, as supported by genomic studies of AD. This project will continue collecting more AIBL participants up to 200 to evaluate leukocyte surface markers more comprehensively, which would benefit AD screening and diagnosis.

A 10‐minute Digitally Administered and Scored Neuropsychological Protocol Assessing Executive Control and Episodic Memory

AbstractBackgroundDigital assessment technology provides rapid and reliable assessment of neurocognitive abilities associated with Alzheimer’s Disease and Related Dementia (ADRD) and Mild Cognitive Impairment (MCI). Dysexecutive and amnestic impairment typify many ADRD and MCI disorders. Here, we evaluate a 10‐minute digitally administered protocol assessing these neurocognitive constructs.Method229 community dwelling participants were assessed (age = 68.32+9.85; education = 15.01+2.58, MMSE = 26.84+2.78; 144 females). Executive abilities were assessed with three trials of 5‐digits backward digit span test (BDST) and the ‘animal’ fluency test. Episodic memory was assessed with a 6‐word Philadelphia (repeatable) Verbal Learning Test (PrVLT) consisting of 2 immediate free recall (IFR) trials, delayed free recall (DFR), and delayed recognition. Traditional pencil and paper testing was not used. Data were obtained with an iPad processed using automatic speech recognition.ResultA K‐means cluster analysis (k = 3) classified participants with possible dementia (pDem = 31), MCI (n = 96), and cognitively normal (CN, n = 100; Table 1). Groups differed from each other on all three P(r)VLT parameters (p = 0.001). CN participants outperformed other groups on executive measures (p = 0.001). All between‐group analyses yielded large effect sizes (η2 = 0.277–0.642). Logistic regression analysis using P(r)VLT‐DFR, P(r)VLT‐recognition, BDST, and ‘animal’ fluency parameters classify MCI and pDem participants into their respective groups compared to CN participants (p = 0.003). For the pDem group, within‐group t‐tests found rapid forgetting (PrVLT‐DFT<PrVLT‐IFR trial 2, p = 0.013; PrVLT‐recognition<PrVLT‐DFR (p = 0.013). Additional, within‐group pDem group comparisons found no differences between P(r)VLT‐recognition and either executive tests. Within group comparisons for the MCI group found P(r)VLT delayed recognition improved compared to P(r)VLT delayed free recall (p<0.001), and worse performance on both executive measures compared to P(r)VLT‐ recognition (p = .001). All of these comparisons are consistent with a mild dysexecutive syndrome.ConclusionThe protocol described above is efficient, reliable, removes any inter‐rater reliability issues, and is able to operationally‐define dysexecutive and amnestic cognitive impairment ‐ key neurocognitive constructs related to ADRD and MCI. This 10‐minute digitally administered and automatically scored neuropsychological protocol assessing executive abilities and episodic memory could easily be deployed in clinical trials and in primary‐ and specialty‐care settings to screen for emergent cases of MCI and ADRD by efficient assessment of episodic memory and executive abilities.

A 10‐minute Digitally Administered and Scored Neuropsychological Protocol Assessing Executive Control and Episodic Memory

AbstractBackgroundDigital assessment technology provides rapid and reliable assessment of neurocognitive abilities associated with Alzheimer’s Disease and Related Dementia (ADRD) and Mild Cognitive Impairment (MCI). Dysexecutive and amnestic impairment typify many ADRD and MCI disorders. Here, we evaluate a 10‐minute digitally administered protocol assessing these neurocognitive constructs.Method229 community dwelling participants were assessed (age = 68.32+9.85; education = 15.01+2.58, MMSE = 26.84+2.78; 144 females). Executive abilities were assessed with three trials of 5‐digits backward digit span test (BDST) and the ‘animal’ fluency test. Episodic memory was assessed with a 6‐word Philadelphia (repeatable) Verbal Learning Test (PrVLT) consisting of 2 immediate free recall (IFR) trials, delayed free recall (DFR), and delayed recognition. Traditional pencil and paper testing was not used. Data were obtained with an iPad processed using automatic speech recognition.ResultA K‐means cluster analysis (k = 3) classified participants with possible dementia (pDem = 31), MCI (n = 96), and cognitively normal (CN, n = 100; Table 1). Groups differed from each other on all three P(r)VLT parameters (p = 0.001). CN participants outperformed other groups on executive measures (p = 0.001). All between‐group analyses yielded large effect sizes (η2 = 0.277–0.642). Logistic regression analysis using P(r)VLT‐DFR, P(r)VLT‐recognition, BDST, and ‘animal’ fluency parameters classify MCI and pDem participants into their respective groups compared to CN participants (p = 0.003). For the pDem group, within‐group t‐tests found rapid forgetting (PrVLT‐DFT<PrVLT‐IFR trial 2, p = 0.013; PrVLT‐recognition<PrVLT‐DFR (p = 0.013). Additional, within‐group pDem group comparisons found no differences between P(r)VLT‐recognition and either executive tests. Within group comparisons for the MCI group found P(r)VLT delayed recognition improved compared to P(r)VLT delayed free recall (p<0.001), and worse performance on both executive measures compared to P(r)VLT‐ recognition (p = .001). All of these comparisons are consistent with a mild dysexecutive syndrome.ConclusionThe protocol described above is efficient, reliable, removes any inter‐rater reliability issues, and is able to operationally‐define dysexecutive and amnestic cognitive impairment ‐ key neurocognitive constructs related to ADRD and MCI. This 10‐minute digitally administered and automatically scored neuropsychological protocol assessing executive abilities and episodic memory could easily be deployed in clinical trials and in primary‐ and specialty‐care settings to screen for emergent cases of MCI and ADRD by efficient assessment of episodic memory and executive abilities.

Diagnosis patterns among diverse populations with mild cognitive impairment and Alzheimer’s disease: A large nationwide electronic health record cohort study

AbstractBackgroundWith recent advances and emerging research on diagnostic biomarkers and evolving diagnostic criteria, practitioners managing patients with cognitive complaints operate within a complex, changing environment. Although some evidence is available on the importance of prompt diagnosis, little information exists on the diagnostic process used in real‐world settings among diverse populations. This study’s objective was to characterize diagnosis patterns among adults with mild cognitive impairment (MCI), Alzheimer’s disease (AD), and/or dementia in the United States, and stratify by gender, age and race/ethnicity.MethodThis retrospective observational cohort study utilized the Optum® Market Clarity database from January 1, 2017–September 30, 2021. Eligible individuals had ≥1 diagnosis of MCI, AD, and/or dementia in their electronic health records or ≥2 diagnosis codes separated by ≥30 days in claims data, had ≥12 months of continuous enrollment before the cohort entry date, and had ≥1 day of continuous healthcare plan enrollment after the index date. Demographic information and the occurrence of diagnostic tests were also obtained from electronic medical records and insurance claims. Descriptive statistics were calculated and stratified by demographic factors.ResultA total of 179,419 newly diagnosed MCI cases, 81,267 AD cases, and 338,739 dementia cases were identified. The mean age at MCI, AD, or dementia diagnosis was similar overall for males and females. Among Caucasians, the mean age of MCI diagnosis was 70.5±14.8 for females and 69.8±14.5 for males. Among African Americans, the mean age at MCI diagnosis was 66.3±15.4 for females and 63.6±16.1 for males. PET scans and CSF biomarker screening occurred less often than MRI and CT (MCI: PET 0.6%, CSF 1.6%, MRI 16.6%, CT 17.5%; AD: PET 0.5%; CSF 0.9%; MRI 9.0%; CT 18.4%; dementia: PET 0.2%; CSF 1.6%; MRI 9.5%; CT 25.9%).ConclusionThe mean age at MCI, AD, and dementia diagnosis varied by demographic groups. The diagnosis of MCI, AD, and dementia remains largely clinical, with low use of brain imaging or CSF biomarkers. This knowledge of the patient populations and diagnostic experiences in a real‐world setting allows for greater understanding and growth to improve diagnosis across diverse groups and lead to faster support.

Genetic and Environmental Influences of Plasma Biomarkers and Their Relation to APOE status and Mild Cognitive Impairment

AbstractBackgroundBefore onset of Alzheimer’s dementia, aggregation of amyloid‐beta (Aβ) is thought to drive accumulation of Tau, followed by neurodegeneration (indexed here by neurofilament light chain [NFL]). Why or how Aβ increases Tau accumulation remains unclear. Using genetically informative twins aged 61.4 to 73.3 years, we sought to: (1) identify genetic and environmental influences on plasma Aβ (Aβ40, Aβ42, Aβ42/40), total Tau (t‐Tau), and NFL; (2) determine if their genetic and environmental influences are correlated with one another; (3) determine if Aβ40 and Aβ42 causally impact Tau levels; (4) measure associations between biomarkers and APOE‐ε4 status; and (5) measure associations between these biomarkers and mild cognitive impairment (MCI).MethodData were from 1,035 male twins in the Vietnam Era Twin Study of Aging. Average age was 67.1 years (SD = 2.6). Twin models were used to estimate heritability, genetic and environmental correlations, model the direction of causation between biomarkers, and associations with APOE‐ε4 status. Mixed effect linear regressions were applied to regress MCI on biomarkers.ResultHeritability for Aβ40, Aβ42, t‐Tau and NFL ranged from 43% to 51%, whereas Aβ42/40 heritability was not significantly different from zero. Phenotypic correlations between t‐Tau and Aβ40 (rP = 0.01) and Aβ42 (rP = 0.14) were small. Genetic correlations between t‐Tau and Aβ40 (rG = ‐0.05) and Aβ42 (rG = 0.05) were also very small. In contrast, genetic correlations between NFL and Aβ40 and Aβ42 were higher (rG ranging = 0.31‐0.37). We found no evidence to suggest that Aβ40 or Aβ42 causally impacts t‐Tau. APOE‐ε4 accounted for a significant, but very small amount of variance in Aβ40 and Aβ42. Finally, none of the biomarkers was significantly associated with MCI, which affected 15.1% of the sample.ConclusionBoth Aβ40 or Aβ42 appear heritable, but have very little phenotypic and genetic association with t‐Tau. The associations between the amyloid‐beta biomarkers and t‐Tau are mostly explained by non‐shared environmental factors, and the direction of causation is unclear. The small associations between APOE‐ε4 and the biomarkers, including their lack of association with MCI, may stem from the low sensitivity of plasma biomarkers, the relatively young age or the low proportion of MCI cases in this community‐dwelling sample.

6 Depressive Symptoms are Associated With Decline Over Time in Verbal Fluency Performance in Female but not Male Community-Dwelling Older Adults

Objective:Late-life depression is prevalent among older adults and the presence of depressive symptoms has been shown to be associated cross-sectionally with worse verbal fluency performance. There is limited and mixed evidence as to whether depressive symptoms impact change in verbal fluency performance over time, and whether gender impacts this relationship.Participants and Methods:Participants were community-dwelling older adults who were dementia-free at baseline (N = 522; M age = 75.96, SD + 6.46 years). Baseline depressive symptoms were measured using the Geriatric Depression Scale. Category fluency and letter fluency performance, using the Controlled Oral Word Association Test (COWAT), were examined annually. Linear mixed effects models stratified by gender examined whether associations between baseline depressive symptoms and changes in fluency performance over five years were different in female (n = 289) as compared to male (n = 233) participants. Sensitivity analyses excluding participants with prevalent or incident mild cognitive impairment (MCI) (n = 141), excluding participants with incident dementia (n = 28), and excluding participants with prevalent or incident MCI or incident dementia (n = 169) were run. All analyses were adjusted for age, years of education, estimated premorbid functioning, and health comorbidities.Results:Depression was minimal across participants (m = 4.72, SD + 3.96). A subset of participants (n = 44) reported “possible depression,” namely levels suggestive of subclinical depression, according to clinical cutoffs. The “possible depression” group included 31 females (10.73% of females) and 13 males (5.58% of males), and the “no depression” group included 258 females (89.27% of females) and 220 males (94.42% of males). Baseline levels of depressive symptoms suggestive of subclinical depression were associated with worse decline in category fluency performance during longitudinal follow-up in females (estimate = -0.16, p = .002) but not males (estimate = -0.03, p = .658). Results remained the same when excluding prevalent and incident MCI cases (estimate = -0.19, p = .005), excluding incident dementia cases (estimate = -0.12, p = .017), and excluding prevalent and incident MCI and incident dementia cases (estimate = -0.20, p = .004). Letter fluency performance did not decline over time and was not influenced by levels of depressive symptoms in females (estimate = -0.03, p = .502) or males (estimate = 0.05, p = .452).Conclusions:Baseline presence of depressive symptoms suggestive of subclinical depression was associated with worse decline in category fluency performance during longitudinal follow-up in female but not male participants. Letter fluency performance did not decline and was not impacted by levels of depressive symptoms. Results remained significant when accounting for covariates and potential confounders. The present study elucidated the combined influence of gender and depressive symptoms on change in fluency performance in older adults and can aid in identifying individuals who may be at a greater risk of cognitive decline.

MRI Visible Perivascular Spaces and the Risk of Incident Mild Cognitive Impairment in a Community Sample.

Magnetic resonance imaging (MRI) visible perivascular spaces (PVS) are associated with the risk of incident dementia but their association with the early stages of cognitive impairment remains equivocal. We examined the association between MRI visible PVS and the risk of incident mild cognitive impairment (MCI) in the community-based Framingham Heart Study (FHS). FHS participants aged at least 50 years free of stroke, cognitive impairment, and dementia at the time of MRI were included. PVS were rated according to severity in the basal ganglia and centrum semiovale (CSO) using established criteria. Cox regression analyses were used to relate PVS to incident MCI adjusted for demographic and cardiovascular variables. The mean age of the sample (1,314 participants) at MRI was 68 years (SD, 9; 54% women). There were 263 cases of incident MCI over a median 7.4 years follow-up (max, 19.8 years). MCI risk increased with higher PVS severity in the CSO. Relative to persons with the lowest severity rating, persons with the highest severity rating in the CSO had a higher risk of incident MCI (hazard ratio [HR] = 2.55; 95% confidence interval [CI], 1.48-4.37; p = 0.0007). In secondary analysis, this association seemed stronger in women. Risk of incident MCI was nominally higher for participants with the highest severity grade of PVS in the basal ganglia, though not statistically significant relative to the lowest grade (HR = 2.19; 95% CI, 0.78-6.14; p = 0.14). PVS burden in the CSO may be a risk marker for early cognitive impairment.

Relationship Between Dietary Patterns and Cognitive Function in Older Adults in USA

Purpose: The aim of the study was to investigate relationship between dietary patterns and cognitive function in older adults.
 Methodology: This study adopted a desk methodology. A desk study research design is commonly known as secondary data collection. This is basically collecting data from existing resources preferably because of its low cost advantage as compared to a field research. Our current study looked into already published studies and reports as the data was easily accessed through online journals and libraries.
 Findings: Dietary patterns significantly influence cognitive function in older adults. Adherence to the Mediterranean diet is associated with reduced cognitive decline risk. Nutritional components like walnuts can enhance memory and executive function. The ketogenic diet shows promise for improving cognitive function, particularly in mild cognitive impairment cases. Cultural diets impact cognitive outcomes, with traditional diets often linked to better cognitive performance. These findings highlight the crucial role of diet in preserving cognitive health in older populations and underscore the need for tailored dietary recommendations across diverse contexts.
 Unique Contribution to Theory, Practice and Policy: Mediterranean diet theory, the micronutrient-related dietary pattern theory, the dietary pattern index theory may be used to anchor future studies on relationship between dietary patterns and cognitive function in older adults. Promote community-based interventions that provide older adults with access to affordable, nutritious foods and opportunities for social engagement. Policy makers should recognize the importance of a balanced diet for cognitive health and reflect this in public health recommendations.

A microglial activity state biomarker panel differentiates FTD-granulin and Alzheimer’s disease patients from controls

BackgroundWith the emergence of microglia-modulating therapies there is an urgent need for reliable biomarkers to evaluate microglial activation states.MethodsUsing mouse models and human induced pluripotent stem cell-derived microglia (hiMGL), genetically modified to yield the most opposite homeostatic (TREM2-knockout) and disease-associated (GRN-knockout) states, we identified microglia activity-dependent markers. Non-targeted mass spectrometry was used to identify proteomic changes in microglia and cerebrospinal fluid (CSF) of Grn- and Trem2-knockout mice. Additionally, we analyzed the proteome of GRN- and TREM2-knockout hiMGL and their conditioned media. Candidate marker proteins were tested in two independent patient cohorts, the ALLFTD cohort (GRN mutation carriers versus non-carriers), as well as the proteomic data set available from the EMIF-AD MBD study.ResultsWe identified proteomic changes between the opposite activation states in mouse microglia and CSF, as well as in hiMGL cell lysates and conditioned media. For further verification, we analyzed the CSF proteome of heterozygous GRN mutation carriers suffering from frontotemporal dementia (FTD). We identified a panel of six proteins (FABP3, MDH1, GDI1, CAPG, CD44, GPNMB) as potential indicators for microglial activation. Moreover, we confirmed three of these proteins (FABP3, GDI1, MDH1) to be significantly elevated in the CSF of Alzheimer’s (AD) patients. Remarkably, each of these markers differentiated amyloid-positive cases with mild cognitive impairment (MCI) from amyloid-negative individuals.ConclusionsThe identified candidate proteins reflect microglia activity and may be relevant for monitoring the microglial response in clinical practice and clinical trials modulating microglial activity and amyloid deposition. Moreover, the finding that three of these markers differentiate amyloid-positive from amyloid-negative MCI cases in the AD cohort suggests that these proteins associate with a very early immune response to seeded amyloid. This is consistent with our previous findings in the Dominantly Inherited Alzheimer’s Disease Network (DIAN) cohort, where soluble TREM2 increases as early as 21 years before symptom onset. Moreover, in mouse models for amyloidogenesis, seeding of amyloid is limited by physiologically active microglia further supporting their early protective role. The biological functions of some of our main candidates (FABP3, CD44, GPNMB) also further emphasize that lipid dysmetabolism may be a common feature of neurodegenerative disorders.

Cognitive Trajectories in Preclinical and Prodromal Alzheimer's Disease Related to Amyloid Status and Brain Atrophy: A Bayesian Approach.

Cognitive decline is a key outcome of clinical studies in Alzheimer's disease (AD). To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid.

Red Blood Cell Fatty Acid Profiles Are Significantly Altered in South Australian Mild Cognitive Impairment and Alzheimer's Disease Cases Compared to Matched Controls.

Nutritional imbalances have been associated with a higher risk for cognitive impairment. This study determined the red blood cell (RBC) fatty acid profile of newly diagnosed mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients compared to age and gender-matched controls. There was a significant increase in palmitic acid (p < 0.00001) for both MCI and AD groups. Saturated fatty acids were significantly elevated in the MCI group, including stearic acid (p = 0.0001), arachidic acid (p = 0.003), behenic acid (p = 0.0002), tricosanoic acid (p = 0.007) and lignoceric acid (p = 0.001). n-6 polyunsaturated fatty acids (PUFAs) were significantly reduced in MCI, including linoleic acid (p = 0.001), γ-linolenic acid (p = 0.03), eicosatrienoic acid (p = 0.009) and arachidonic acid (p < 0.00004). The n-3 PUFAs, α-linolenic acid and docosahexaenoic acid, were both significantly reduced in MCI and AD (p = 0.0005 and p = 0.00003). A positive correlation was evident between the Mini-Mental State Examination score and nervonic acid in MCI (r = 0.54, p = 0.01) and a negative correlation with γ-linolenic acid in AD (r = -0.43, p = 0.05). Differences in fatty acid profiles may prove useful as potential biomarkers reflecting increased risk for dementia.

Unbiased classification of the elderly human brain proteome resolves distinct clinical and pathophysiological subtypes of cognitive impairment

Cognitive impairment in the elderly features complex molecular pathophysiology extending beyond the hallmark pathologies of traditional disease classification. Molecular subtyping using large-scale -omic strategies can help resolve this biological heterogeneity. Using quantitative mass spectrometry, we measured ∼8000 proteins across >600 dorsolateral prefrontal cortex tissues with clinical diagnoses of no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia. Unbiased classification of MCI and AD cases based on individual proteomic profiles resolved three classes with expression differences across numerous cell types and biological ontologies. Two classes displayed molecular signatures atypical of AD neurodegeneration, such as elevated synaptic and decreased inflammatory markers. In one class, these atypical proteomic features were associated with clinical and pathological hallmarks of cognitive resilience. We were able to replicate these classes and their clinicopathological phenotypes across two additional tissue cohorts. These results promise to better define the molecular heterogeneity of cognitive impairment and meaningfully impact its diagnostic and therapeutic precision.

Association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus: A prospective study of the Hong Kong Diabetes Register

AimsTo examine the risk association of insomnia with incident chronic cognitive impairment in older adults with type 2 diabetes mellitus (T2D). MethodsBetween July 2010 and June 2015, patients with T2D aged ≥60 years enrolled in the Hong Kong Diabetes Register completed the Insomnia Severity Index (ISI) questionnaire. Patients were considered having insomnia if they had ISI score > 14. We prospectively followed up the cohort and censored outcome through reviewing diagnoses and clinical notes entered by attending physicians in electronic medical record to identify incident cases of mild cognitive impairment and dementia. ResultsAfter excluding shift workers and those with established chronic cognitive impairment at baseline, we included 986 patients with T2D in this study (58.3 % men, mean age ± standard deviation: 62.5 ± 2.6 years, disease duration of diabetes: 10.7 ± 8.2 years, HbA1c: 7.4 ± 1.3 %, insulin users: 28.7 %, insomnia: 9.1 %). After a median follow-up of 7.6 (interquartile range = 2.0) years, 41 (4.2 %) developed chronic cognitive impairment. Using Cox regression analysis, insomnia (hazard ratio, HR 2.909, p = 0.012) and HbA1c ≥ 7 % (HR 2.300, p = 0.038) were positively associated with incident chronic cognitive impairment while insulin use (HR 0.309, p = 0.028) showed negative association. ConclusionsInsomnia, suboptimal glycemic control and non-insulin use are independent risk factors for incident chronic cognitive impairment in older adults with T2D.

Graph Theoretical Measures for Alzheimer’s, MCI, and Normal Controls: A Comparative Study Using MRI Data

Background The Graph theory provides the platform that could be used to model complex brain networks mathematically, and it could play a significant role in the diagnosis of various neurodegenerative diseases such as Alzheimer’s. Purpose The main aim of our study is to perform a comparative analysis in terms of various graph theoretic measures of structural brain networks. In particular, the paper evaluates graph theoretical measures by first forming graphs using magnetic resonance imaging (MRI) data. Method In this paper, we study and evaluate graph theoretical measures using MRI data, namely characteristic path length, global efficiency, strength, and clustering coefficient, in a cohort of normal controls ( N = 30), a cohort of mild cognitive impairment (MCI) ( N = 30), and a cohort of Alzheimer’s disease (AD) ( N = 30). In our work, MRI data is preprocessed and cortical thickness is extracted for each brain region. The connectivity matrix is obtained, and thus a graph is formed. We have also performed receiver operating characteristic (ROC) and area under the ROC analyses of all graph theoretical measures to better elucidate and validate the results. Results It is observed that these measures may be used to differentiate Alzheimer’s from normal. In our study, we observed that a very random and disrupted network is obtained in the case of Alzheimer’s in comparison with the normal and MCI cases. The other observations in terms of graph theoretic measures are an increase in characteristic path length, a decrease in global efficiency, a decrease in strength, and a reduction in values of the clustering coefficient in the case of Alzheimer’s. Conclusion The findings suggest that graph theoretical measures and alterations in network topology could be used as quantitative biomarkers of AD.

Investigating the relationship between allocentric spatial working memory and biomarker status in preclinical and prodromal Alzheimer’s disease

The 4 Mountain Test (4MT) is a test of allocentric spatial working memory and has been proposed as an earlier marker of predementia Alzheimer’s disease (AD) than episodic verbal memory. We here compare the 4MT to the CERAD word list memory recall in both cognitively normal (CN) and mild cognitive impairment (MCI) cases with or without cerebrospinal fluid markers (CSF) of Alzheimer’s disease pathology. Linear regression was used to assess the influence of CSF determined Aβ-plaque (Aβ-/+) or neurofibrillary tau tangles (Tau-/+) on 4MT and CERAD recall performance. Analyses were performed in the full sample and the CN and MCI sub-samples. Pearson correlations were calculated to examine the relationship between 4MT and tests of psychomotor speed, verbal memory, cognitive flexibility, verbal fluency, and visuo-spatial perception. Analyses showed no significant differences in 4MT scores between Aβ-/Aβ+, nor Tau-/Tau + participants, irrespective of cognitive status. In contrast, CERAD recall scores were lower in both Aβ+ compared to Aβ- (p<.01), and Tau + compared to Tau- participants (p<.01) in the full sample analyses. There were no significant differences in CERAD recall performance between Aβ- vs. Aβ+ and Tau- vs. to Tau + in the in CN/MCI sub-samples. 4MT scores were significantly correlated with tests of psychomotor speed, cognitive flexibility, and visuo-spatial perception in the full sample analyses. In conclusion, the CERAD recall outperformed the 4MT as a cognitive marker of CSF determined AD pathology. This suggests that allocentric working memory, as measured by the 4MT, may not be used as an early marker of predementia AD.

Holistic Approach Toward Senile Dementia with &lt;i&gt;Ayurveda&lt;/i&gt; – A Case Report

Neurological problems are a burning issue in today’s Era. The brain is that vital organ which makes humans unique from other living beings. It is the site of all the intellectual powers humans have. Memory is an important aspect of this intellectual property. It gives us protection from harmful things. Here is a case of mild cognitive impairment. The patient, 68 years old came with his son to OPD with loss of memory for 2 years. He used to forget his meals, and juices from taking on time. He used to forget the flame of burners. He used to repeat the same phrases after a fraction of the time. The patient had taken many medicines, but the condition got worse. He felt sleepy and drowsy all day. The patient was well-oriented to time and place. The Mini-mental scale examination score of this patient was 22. This patient was treated with a holistic approach. Holistic means to treat all aspects of the patient. The patient was advised to take internal medicine (Shatavari Ghanavati), meditation, counselling, and diet. The internal medication was given for three months. Counselling was done every fortnight. The patient was advised to do meditation on a daily basis. Some food regimes were advised to the patient. Then after the complete course of medicine. The Mini-mental scale examination was performed, and the score was 25 which was satisfactory for that patient. The herbal medicine along with other aspects of surviving healthy life helped this patient to live normally.