Normal Cognition Participants Research Articles

I‐CONECT Intervention Effects on Weekly Time Spent Outside of Home and Social Contacts among Socially Isolated Older Adults with Normal Cognition and Mild Cognitive Impairment

AbstractBackgroundSocial isolation has been linked to an increased risk of cognitive decline and incident dementia. Socially isolated individuals tend to lack access to cognitively stimulating activities. This may adversely impact their cognitive health. The Internet‐Based Conversational Engagement Clinical Trial (I‐CONECT) was designed to deliver online conversation sessions to socially isolated older adults to slow cognitive decline and ultimately delay the onset of dementia. The current study examined the intervention effects on participants’ weekly time spent out‐of‐home and their social interaction with family and friends as clinically meaningful functional outcomes.MethodsIntervention group engaged in 30‐minutes video chat 4 times/week and 10‐minute weekly phone calls, while control group received only 10‐minute weekly phone calls over 48 weeks. In each call, we asked participants to report time spent out‐of‐home and whether they contacted family or friends during the week (yes/no). Linear mixed‐effect models were run for time spent out‐of‐home, and mixed‐effect models with a logistic link were performed for contact with family and friends. The intervention effect was modeled by including an interaction term of time (in weeks) and group assignments. We ran analyses separately for participants with normal cognition (NC) and mild cognitive impairments (MCI). All models controlled for age, sex, race, education, and a pre vs. post COVID‐19 pandemic indicator.ResultsAs weeks passed, participants (N = 155, mean age 81, 72.3% female, 17.53% African American, 51.95% MCI) in both groups reported spending more time out of home, indicated by a significant time main effect (B = , p<.001). Among NC participants, the intervention group had a steeper increase in their reported time spent out‐of‐home compared to the control group (B = , p = .016). Among MCI participants, the intervention group had an increased likelihood of contacting friends over time (OR = 1.013, p = .001), while the intervention effect on contact with family was not significant for either the NC or MCI group.ConclusionPreviously we reported the I‐CONECT intervention positively affected cognitive functions. The current results suggest the translational effects of I‐CONECT to functional outcomes beyond cognitive test scores, activating weekly activities among socially isolated older adults. The intervention provides a remote social interaction platform that brings cognitive stimulation to at‐risk populations.

Further along the Alzheimer’s disease continuum: associations between mild behavioral impairment with hippocampal and entorhinal volume and incident cognitive decline

AbstractBackgroundMild behavioral impairment (MBI) identifies a high‐risk group for Alzheimer’s disease and related dementias (ADRD), leveraging the risk associated with later‐life emergent and persistent neuropsychiatric symptoms (NPS). MBI may act as a complementary behavioral analog to later‐life emergent cognitive symptoms (mild cognitive impairment, MCI). These constructs are not mutually exclusive and can co‐occur. We characterized the relationship between MBI, grey matter volume in the hippocampus and entorhinal cortex, and incident cognitive decline in older adults with normal cognition (NC) and MCI.MethodSeven‐hundred‐forty‐two participants were included from the National Alzheimer’s Coordinating Center Uniform Dataset. The Normative Morphometry Image Statistics tool was used to generate estimates of grey matter volume for the bilateral hippocampi and entorhinal cortices, normalized by age, sex, total intracranial volume, and image quality. NPS were evaluated using the informant‐rated Neuropsychiatric Inventory Questionnaire, from which MBI scores were derived based on a published algorithm. Associations between MBI status and the regions‐of‐interest were modelled separately in NC and MCI using multivariable linear regressions, adjusting for education and clinical‐MRI visit interval time. Associations between MBI status and incident cognitive decline were modelled using Cox proportional hazards regressions.ResultParticipant characteristics are summarized in Table 1. As per Figures 1 and 2, NC participants with MBI had lower grey matter volume in the bilateral hippocampi (B = ‐0.40, 95%CI:[‐0.66, ‐0.15], p = .004), and a greater hazard of incident MCI or dementia, than those without MBI (HR = 3.34, 95%CI:[2.04, 5.48), p<.001). NC MBI+ participants also had lower grey matter volume in the bilateral entorhinal cortices compared to NC MBI‐ participants, although not statistically significant (B = ‐0.13, 95%CI:[‐0.35, ‐0.08], p = .22). In MCI, participants with MBI had lower grey matter volume bilaterally in both the hippocampus (B = ‐0.46, 95%CI:[‐0.80, ‐0.12], p = .01) and entorhinal cortex (B = ‐0.42, 95%CI:[‐0.76, ‐0.12], p = .009), and had greater progression‐rates to dementia (HR = 4.13, 95%CI:[2.45, 6.94), p<.001), than those without MBI.ConclusionOur findings suggest that evaluating dementia‐free older adults for MBI status in conjunction with cognitive status identifies a group further along the ADRD continuum than those without MBI, who have greater baseline atrophy in key ADRD regions and greater progression rates to later cognitive stages.

I‐CONECT Intervention Effects on Weekly Time Spent Outside of Home and Social Contacts among Socially Isolated Older Adults with Normal Cognition and Mild Cognitive Impairment

AbstractBackgroundSocial isolation has been linked to an increased risk of cognitive decline and incident dementia. Socially isolated individuals tend to lack access to cognitively stimulating activities. This may adversely impact their cognitive health. The Internet‐Based Conversational Engagement Clinical Trial (I‐CONECT) was designed to deliver online conversation sessions to socially isolated older adults to slow cognitive decline and ultimately delay the onset of dementia. The current study examined the intervention effects on participants’ weekly time spent out‐of‐home and their social interaction with family and friends as clinically meaningful functional outcomes.MethodIntervention group engaged in 30‐minutes video chat 4 times/week and 10‐minute weekly phone calls, while control group received only 10‐minute weekly phone calls over 48 weeks. In each call, we asked participants to report time spent out‐of‐home and whether they contacted family or friends during the week (yes/no). Linear mixed‐effect models were run for time spent out‐of‐home, and mixed‐effect models with a logistic link were performed for contact with family and friends. The intervention effect was modeled by including an interaction term of time (in weeks) and group assignments. We ran analyses separately for participants with normal cognition (NC) and mild cognitive impairments (MCI). All models controlled for age, sex, race, education, and a pre vs. post COVID‐19 pandemic indicator.ResultAs weeks passed, participants (N = 155, mean age 81, 72.3% female, 17.53% African American, 51.95% MCI) in both groups reported spending more time out of home, indicated by a significant time main effect (B = , p<.001). Among NC participants, the intervention group had a steeper increase in their reported time spent out‐of‐home compared to the control group (B = , p = .016). Among MCI participants, the intervention group had an increased likelihood of contacting friends over time (OR = 1.013, p = .001), while the intervention effect on contact with family was not significant for either the NC or MCI group.ConclusionPreviously we reported the I‐CONECT intervention positively affected cognitive functions. The current results suggest the translational effects of I‐CONECT to functional outcomes beyond cognitive test scores, activating weekly activities among socially isolated older adults. The intervention provides a remote social interaction platform that brings cognitive stimulation to at‐risk populations.

FC44: Prevalence of mental health outcomes and the impact of sex and mood or cognitive comorbidity in older adults during the COVID-19 pandemic

Introduction:Older adults are at greater risk for developing severe illness from SARS-COV2 infection and may be more vulnerable to negative mental health outcomes as a result of public health guidelines that increase social isolation. We assessed mental health outcomes in older adults with normal cognition (NC), past history of major depressive disorder (i.e., remitted; rMDD), or mild cognitive impairment (MCI) to determine the prevalence of depression, anxiety, general stress, and post-traumatic stress during the COVID-19 pandemic and the impact of diagnosis and sex.Methods:The sample included 108 older adults (37 males, mean age=72.1 years): 71 older adults with normal cognition (NC) based on normal neuropsychological test performance and no psychiatric history, 21 rMDD participants based on DSM5 criteria, and 16 MCI participants based on NIA-AA criteria. Participants completed self-report measures of depression [Patient Health Questionnaire-9 (PHQ-9)], anxiety [Patient-Reported Outcomes Measurement Information System (PROMIS)], general stress [Perceived Stress Scale (PSS)] and post-traumatic stress [Impact of Events Scale Revised (IES-R)] through video- or teleconferencing. Prevalence rates of clinically significant psychiatric symptoms were expressed as the percentage of participants with total scores that exceed the normal cut-offs. Separate MANOVAs were used to examine the effects of diagnosis and sex. Non-normally distributed data (PHQ-9 and PROMIS total scores) were rank-transformed.Results:Approximately 1/3rd of participants endorsed clinically significant symptoms based on scores exceeding the cut-off for normal: 33.7% on PHQ-9, 31.3% on PROMIS-Anxiety, 35.5% on PSS, 38.3% on IES-R. rMDD participants scored higher on all measures compared to NC participants (p’s < .005) while MCI participants scored higher on the PSS compared to NC (p=.035). Women scored higher on all measures compared to men.Conclusions:These rates of approximately 1/3rd reporting clinically significant symptoms of depression, anxiety, general stress, and post-traumatic stress are higher than those described in population surveys of older adults but are comparable to prevalence rates of psychiatric symptoms in the general adult population. The effects of diagnosis and sex indicate that older adults with previous depression or current MCI, as well as women overall, are particularly vulnerable to developing clinically significant psychiatric

Evaluation of the NIH Toolbox Odor Identification Test across normal cognition,amnestic mild cognitive impairment, and dementia due to Alzheimer's disease.

Olfactory decline is associated with cognitive decline in aging, amnestic mild cognitive impairment (aMCI), and amnestic dementia associated with Alzheimer's disease neuropathology (ADd). The National Institutes of Health Toolbox Odor Identification Test (NIHTB-OIT) may distinguish between these clinical categories. We compared NIHTB-OIT scores across normal cognition (NC), aMCI, and ADd participants (N=389,≥65 years) and between participants positive versus negative for AD biomarkers and the APOE ε4 allele. NIHTB-OIT scores decreased with age (p<0.001) and were lower for aMCI (p<0.001) and ADd (p<0.001) compared to NC participants, correcting for age and sex. The NIHTB-OIT detects aMCI (ADd) versus NC participants with 49.4% (56.5%) sensitivity and 88.8% (89.5%) specificity. NIHTB-OIT scores were lower for participants with positive AD biomarkers (p<0.005), but did not differ based on the APOE ε4 allele (p>0.05). The NIHTB-OIT distinguishes clinically aMCI and ADd participants from NC participants. National Institutes of Health Toolbox Odor Identification Test (NIHTB-OIT) discriminated normal controls from mild cognitive impairment. NIHTB-OIT discriminated normal controls from Alzheimer's disease dementia. Rate of olfactory decline with age was similar across all diagnostic categories. NIHTB-OIT scores were lower in participants with positive Alzheimer's biomarker tests. NIHTB-OIT scores did not differ based on APOE genotype.

Intrasession Repeatability of OCT Angiography Parameters in Neurodegenerative Disease.

To assess the intrasession repeatability of macular OCT angiography (OCTA) parameters in Alzheimer's disease (AD), mild cognitive impairment (MCI), Parkinson's disease (PD), and normal cognition (NC). Cross sectional study. Patients with a clinical diagnosis of AD, PD, MCI, or NC were imaged. Images with poor quality and of those with diabetes mellitus, glaucoma, or vitreoretinal disease were excluded from analysis. All participants were imaged using the Zeiss Cirrus HD-5000 with AngioPlex (Carl Zeiss Meditec, Software Version 11.0.0.29946) and repeat OCTA images were obtained for both eyes. Perfusion density (PFD), vessel density (VD), and Foveal avascular zone (FAZ) area were measured from 3×3 mm and 6×6 mm OCTA images centered on the fovea using an ETDRS grid overlay. Intraclass correlation coefficients were used to quantify repeatability of PFD, VD, and FAZ area measurements obtained from imaging. 3×3 mm scans of 22 AD, 40 MCI, 21 PD, and 26 NC participants and 6×6 mm scans of 29 AD, 44 MCI, 29 PD, and 30 NC participants were analyzed. Repeatability values ranged from 0.64 (0.49-0.82) for 6×6 mm PFD in AD participants to 0.87 (0.67-0.92) for 3×3 mm PFD in AD participants. No significant differences were observed in repeatability between NC participants and those with neurodegenerative disease. Overall, similar OCTA repeatability was observed between NC participants and those with neurodegeneration. Regardless of diagnostic group, macular OCTA metrics demonstrated moderate to good repeatability. The authors have no proprietary or commercial interest in any materials discussed in this article.

Cortical Iron Accumulation as an Imaging Marker for Neurodegeneration in Clinical Cognitive Impairment Spectrum: A Quantitative Susceptibility Mapping Study.

Cortical iron deposition has recently been shown to occur in Alzheimer's disease (AD). In this study, we aimed to evaluate how cortical gray matter iron, measured using quantitative susceptibility mapping (QSM), differs in the clinical cognitive impairment spectrum. This retrospective study evaluated 73 participants (mean age ± standard deviation, 66.7 ± 7.6 years; 52 females and 21 males) with normal cognition (NC), 158 patients with mild cognitive impairment (MCI), and 48 patients with AD dementia. The participants underwent brain magnetic resonance imaging using a three-dimensional multi-dynamic multi-echo sequence on a 3-T scanner. We employed a deep neural network (QSMnet+) and used automatic segmentation software based on FreeSurfer v6.0 to extract anatomical labels and volumes of interest in the cortex. We used analysis of covariance to investigate the differences in susceptibility among the clinical diagnostic groups in each brain region. Multivariable linear regression analysis was performed to study the association between susceptibility values and cognitive scores including the Mini-Mental State Examination (MMSE). Among the three groups, the frontal (P < 0.001), temporal (P = 0.004), parietal (P = 0.001), occipital (P < 0.001), and cingulate cortices (P < 0.001) showed a higher mean susceptibility in patients with MCI and AD than in NC subjects. In the combined MCI and AD group, the mean susceptibility in the cingulate cortex (β = -216.21, P = 0.019) and insular cortex (β = -276.65, P = 0.001) were significant independent predictors of MMSE scores after correcting for age, sex, education, regional volume, and APOE4 carrier status. Iron deposition in the cortex, as measured by QSMnet+, was higher in patients with AD and MCI than in NC participants. Iron deposition in the cingulate and insular cortices may be an early imaging marker of cognitive impairment related neurodegeneration.

Patients with Alzheimer's disease have an increased removal rate of soluble beta-amyloid-42.

Senile plaques, which are mostly composed of beta-amyloid peptide, are the main signature of Alzheimer's disease (AD). Two main forms of beta-amyloid in humans are 40 and 42-amino acid, long; the latter is considered more relevant to AD etiology. The concentration of soluble beta-amyloid-42 (Aβ42) in cerebrospinal fluid (CSF-Aβ42) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-Aβ42 levels compared to individuals with normal cognition (NC), even after accounting for this correlation. The goal of this study was to infer deviations of Aβ42 metabolism parameters that underlie this difference using data from the Alzheimer's Disease Neuroimaging Initiative cohort. Aβ42 is released to the interstitial fluid (ISF) by cells and is removed by several processes. First, growth of insoluble fibrils by aggregation decreases the concentration of soluble beta-amyloid in the ISF. Second, Aβ42 is physically transferred from the brain to the CSF and removed with the CSF flow. Finally, there is an intratissue removal of Aβ42 ending in proteolysis, which can occur either in the ISF or inside the cells after the peptide is endocytosed. Unlike aggregation, which preserves the peptide in the brain, transfer to the CSF and intratissue proteolysis together represent amyloid removal. Using a kinetic model of Aβ42 turnover, we found that compared to NC subjects, AD patients had dramatically increased rates of amyloid removal. A group with late-onset mild cognitive impairment (LMCI) also exhibited a higher rate of amyloid removal; however, this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group. We hypothesize that increased amyloid removal is mediated by Aβ42 cellular uptake; this is because CSF flow is not increased in AD patients, while most proteases are intracellular. Aβ cytotoxicity depends on both the amount of beta-amyloid internalized by cells and its intracellular conversion into toxic products. We speculate that AD and LMCI are associated with increased cellular amyloid uptake, which leads to faster disease progression. The early-onset MCI (EMCI) patients do not differ from the NC participants in terms of cellular amyloid uptake. Therefore, EMCI may be mediated by the increased production of toxic amyloid metabolites.

Associations Between the Digital Clock Drawing Test and Brain Volume: Large Community-Based Prospective Cohort (Framingham Heart Study).

BackgroundThe digital Clock Drawing Test (dCDT) has been recently used as a more objective tool to assess cognition. However, the association between digitally obtained clock drawing features and structural neuroimaging measures has not been assessed in large population-based studies.ObjectiveWe aimed to investigate the association between dCDT features and brain volume.MethodsThis study included participants from the Framingham Heart Study who had both a dCDT and magnetic resonance imaging (MRI) scan, and were free of dementia or stroke. Linear regression models were used to assess the association between 18 dCDT composite scores (derived from 105 dCDT raw features) and brain MRI measures, including total cerebral brain volume (TCBV), cerebral white matter volume, cerebral gray matter volume, hippocampal volume, and white matter hyperintensity (WMH) volume. Classification models were also built from clinical risk factors, dCDT composite scores, and MRI measures to distinguish people with mild cognitive impairment (MCI) from those whose cognition was intact.ResultsA total of 1656 participants were included in this study (mean age 61 years, SD 13 years; 50.9% women), with 23 participants diagnosed with MCI. All dCDT composite scores were associated with TCBV after adjusting for multiple testing (P value <.05/18). Eleven dCDT composite scores were associated with cerebral white matter volume, but only 1 dCDT composite score was associated with cerebral gray matter volume. None of the dCDT composite scores was associated with hippocampal volume or WMH volume. The classification model for differentiating MCI and normal cognition participants, which incorporated age, sex, education, MRI measures, and dCDT composite scores, showed an area under the curve of 0.897.ConclusionsdCDT composite scores were significantly associated with multiple brain MRI measures in a large community-based cohort. The dCDT has the potential to be used as a cognitive assessment tool in the clinical diagnosis of MCI.

Structural brain characteristics and gene co-expression analysis: A study with outcome label from normal cognition to mild cognitive impairment

BackgroundLongitudinal studies reported that some elderly people with normal cognition (NC) converted to mild cognitive impairment (MCI), and some remained normal state (NC_S). The underlying factor for this difference conversion of NC is worthy of exploration MethodsEighty-three NC participants were tracked for eight years. Thirty participants transitioned from NC to MCI (NC_MCI). The remaining 53 participants retained an NC_S. The structural brain features and genetic expression of the 83 NC participants were obtained. We applied weighted gene co-expression network analysis (WGCNA) to inquire into the co-expression network of those. Mediator effect analysis of regulatory roles was conducted to inquire into the associations between brain measures, expression values, and clinical scores. ResultsThe main results are: 1) 20 brain features and 740 gene expression had significant differences between the two groups, 2) one module including 187 genes had the most correlation with cortical thickness of left superior temporal sulcus (L.STS), 3) NFKBIA and RARA genes were the top two genes that made the greatest contribution to L.STS thickness, and 4) mediating effect was found between the L.STS thickness, the NFKBIA and RARA expression levels, and clinical scores. ConclusionOur results provide a theoretical foundation based on gene expression and brain imaging for the factors of NC with different outcomes.

Prevalence of mental health outcomes and effects of sex and mood or cognitive comorbidity in older adults during the COVID-19 pandemic

IntroductionOlder adults are at greater risk for developing severe illness from SARS-COV2 infection and may be more vulnerable to negative mental health outcomes as a result of public health guidelines that increase social isolation. In the current study, we assessed mental health outcomes in a cohort of older adults with normal cognition (NC), past history of major depressive disorder (i.e., remitted; rMDD), or mild cognitive impairment (MCI) to determine the prevalence of clinically significant symptoms of depression, anxiety, general stress, and post-traumatic stress. Additionally, we assessed the effects of mood or cognitive diagnosis and sex on symptom severity. Based on the pre-pandemic literature, we predicted that the presence of rMDD or MCI diagnosis would be associated with increased severity of psychiatric symptoms during the COVID-19 pandemic. We also predicted that women would experience greater severity of psychiatric symptoms compared to men.MethodsThe study included 108 older adults (37 males, mean age=72.1 years) who were participating in existing longitudinal studies. The sample included 71 older adults with normal cognition (NC) based on normal neuropsychological test performance and who were free of lifetime history of psychiatric illness, 21 rMDD participants based on DSM5 criteria, and 16 MCI participants based on the presence of memory concerns, impaired performance on neuropsychological assessments, and intact functional independence. Participants completed self-report measures of depression, anxiety, and stress through video- or teleconferencing with a research assistant. Measures included the Patient Health Questionnaire-9 (PHQ-9) to assess depression, the Patient-Reported Outcomes Measurement Information System (PROMIS) to measure anxiety, the Perceived Stress Scale (PSS) to measure stress, and the Impact of Events Scale-Revised (IES-R) to assess post-traumatic stress symptoms. Prevalence rates of clinically significant psychiatric symptoms were expressed as the percentage of participants with total scores that exceed the normal cut-offs for each respective measure. Separate MANOVAs were used to examine the effects of diagnosis and sex. Non-normally distributed data (PHQ-9 and PROMIS total scores) were rank-transformed and entered into MANOVA.ResultsWithin the sample of 108 participants, 33.7% exceeded the normal cut-off on the PHQ-9, 31.3% had clinically significant anxiety symptoms on the PROMIS-Anxiety, 35.5% had clinically significant stress scores on the PSS, and 38.3% had clinically significant post-traumatic stress scores on the IES-R. MANOVA showed statistically significant effects of diagnosis on all measures: PHQ-9 [F(2,90)=5.380, p=.006], PROMIS-Anxiety [F(2,90)=11.687, p<.001], PSS [F(2,90)=8.480, p<.001], and IES-R [F(2,90)=5.027, p=.009]. MDD participants scored higher on all measures compared to NC participants: PHQ-9 (p=.005), PROMIS-Anxiety (p<.001), PSS (p<.001), and IES-R (p=.004). In addition, MCI participants scored higher on the PSS compared to NC participants (p=.035). MANOVA showed significant effects of sex on all measures: PHQ-9 [F(1,91)=7.046, p=.009], PROMIS-Anxiety [F(1,91)=8.623, p=.004], PSS [F(1,91)=12.553, p<.001], and IES-R [F(1,91)=10.529, p=.002] such that women scored higher on all measures compared to men.ConclusionsOverall, over one-third of study participants reported clinically significant symptoms of depression, anxiety, general stress, and post-traumatic stress during the COVID-19 pandemic. These rates are higher than those described in population studies of older adults based on anonymous online surveys, which are reported to be 24.9% for depression, 19.4% for anxiety, 10.3% for stress, and 28.3% for post-traumatic stress; but are comparable to the prevalence rates of psychiatric symptoms in the general adult population. As predicted, presence of rMDD increased the severity of all psychiatric symptoms. However, MCI was also associated with increased stress compared to those with normal cognition, despite absence of current or past psychiatric illness. These findings suggest that older adults with previous depression or current MCI, as well as women overall, are particularly vulnerable to developing clinically significant psychiatric symptomatology during the COVID-19 pandemic. Limitations of the current study are the inclusion of participants in existing studies, as opposed to sampling from the general population and the relatively small sample size. Nevertheless, the current findings suggest that some clinical populations, including those with rMDD and MCI, as well as women overall, may benefit from receiving interventions for mental health during the current and future pandemics.This research was funded byThis study was funded by the Ontario Ministry of Health and Long-Term Care Alternative Funding Plan. The funders had no role in the design of the study, analysis, or preparation of the manuscript.

Higher Functional Connectivity of Ventral Attention and Visual Network to Maintain Cognitive Performance in White Matter Hyperintensity.

Ventral attention network (VAN), associated with cognitive performance, is one of the functional networks that are most vulnerable in white matter hyperintensity (WMH). Considering the global interaction of networks for cognitive performance, we hypothesized that VAN-related between-network connectivity might play a role in maintaining cognition in patients with WMH. We included 139 participants for both cross-sectional and longitudinal analysis from CIRCLE study (ClinicalTrials.gov ID: NCT03542734) between January 2014 and January 2021. Differences of VAN-related between-network connectivity were compared between normal-cognition (NC) and cognitive-impairment (CI) groups cross-sectionally, and between cognitive-decline (CD) and cognitive non-decline (CND) groups longitudinally by using t-test. False Discovery Rate was used for multiple comparison correction. The relationship between the network connectivity and WMH was tested on linear and quadratic models. Subgroup analysis of different WMH burdens were performed to test the difference of network connectivity between NC and CI groups. Among VAN-related between-network connectivity, only VAN-Visual Network (VN) connectivity was higher both in NC (n = 106) and CND (n = 113) groups versus CI (n = 33) and CD groups (n = 26), respectively. There was an inverted U-shaped relation between periventricular WMH (PWMH) burden and VAN-VN connectivity. Normal-cognition participants had higher VAN-VN connectivity among high, but not low PWMH burden subgroups. These findings suggest that the VAN-VN connectivity plays an important role in maintaining cognitive performance in WMH patients. It may serve as a unique marker for cognitive prediction and a potential target for intervention to prevent cognitive decline in WMH patients.

Diet-Cognition Associations Differ in Mild Cognitive Impairment Subtypes.

Cognitive function is not generally associated with diet, and there is debate over that association. Moreover, little is known about such associations with the specific cognitive domains and subtypes of mild cognitive impairment (MCI). We analyzed data of 4309 Chinese adults aged 55 and over from the Community-based Cohort Study on Nervous System Diseases from 2018–2019. Dietary habits were assessed at inclusion using a validated semi-quantitative food frequency questionnaire. Cognitive function of the participants was measured by using the Montreal Cognitive Assessment. Analyses were performed using multiple logistic regression and quantile regression with adjustment for socio-demographic, lifestyle, and health-related factors. Compared with normal cognition participants, those with a worse cognition state were characterized as being an older age and lower economic level. After adjustment for potential factors, participants with higher consumption of rice, legumes, fresh vegetables, fresh fruit, pork, poultry, fish, and nuts tended to have higher scores of global cognitive function and domains, and to have lower odds of MCI, while those with higher consumption levels of wheat and eggs had worse cognition, compared with the corresponding bottom consumption level of each food. Participants with a medium consumption level of beef or mutton had 57% (OR: 1.57, 95%CI: 1.07–2.32) higher odds of aMCI-SD, whereas they had 50% (OR: 0.50, 95%CI: 0.34–0.73) lower odds of naMCI-MD. Similarly, the highest consumption level of dairy was positively associated with the odds of aMCI-SD (OR:1.51, 95%CI:1.00–2.29), but inversely linked to the odds of naMCI-SD (OR: 0.60, 95%CI: 0.38–0.93) and naMCI-MD (OR: 0.49, 95%CI: 0.29–0.82). Most diet global cognitive benefits were observed to be associated with the preexisting higher consumption of rice, legumes, fresh vegetables, fresh fruit, meat, and nuts. In addition, the heterogeneity of associations between the consumption of certain foods and MCI subtypes was observed among Chinese adults aged over 55 years. These cross-sectional observations require validation in prospective studies.

Discriminating subcortical ischemic vascular disease and Alzheimer's disease by diffusion kurtosis imaging in segregated thalamic regions.

Differentiating between subcortical ischemic vascular disease (SIVD), Alzheimer's disease (AD), and normal cognition (NC) remains a challenge, and reliable neuroimaging biomarkers are needed. The current study, therefore, investigated the discriminative ability of diffusion kurtosis imaging (DKI) metrics in segregated thalamic regions and compare with diffusion tensor imaging (DTI) metrics. Twenty‐three SIVD patients, 30 AD patients, and 24 NC participants underwent brain magnetic resonance imaging. The DKI metrics including mean kurtosis (MK), axial kurtosis (K axial) and radial kurtosis (K radial) and the DTI metrics including diffusivity and fractional anisotropy (FA) were measured within the whole thalamus and segregated thalamic subregions. Strategic correlations by group, thalamo‐frontal connectivity, and canonical discriminant analysis (CDA) were used to demonstrate the discriminative ability of DKI for SIVD, AD, and NC. Whole and segregated thalamus analysis suggested that DKI metrics are less affected by white matter hyperintensities compared to DTI metrics. Segregated thalamic analysis showed that MK and K radial were notably different between SIVD and AD/NC. The correlation analysis between K axial and MK showed a nonsignificant relationship in SIVD group, a trend of negative relationship in AD group, and a significant positive relationship in NC group. A wider spatial distribution of thalamo‐frontal connectivity differences across groups was shown by MK compared to FA. CDA showed a discriminant power of 97.4% correct classification using all DKI metrics. Our findings support that DKI metrics could be more sensitive than DTI metrics to reflect microstructural changes within the gray matter, hence providing complementary information for currently outlined pathogenesis of SIVD and AD.

Brain expression of the vascular endothelial growth factor gene family in cognitive aging and alzheimer\u2019s disease

Vascular endothelial growth factor (VEGF) is associated with the clinical manifestation of Alzheimer’s disease (AD). However, the role of the VEGF gene family in neuroprotection is complex due to the number of biological pathways they regulate. This study explored associations between brain expression of VEGF genes with cognitive performance and AD pathology. Genetic, cognitive, and neuropathology data were acquired from the Religious Orders Study and Rush Memory and Aging Project. Expression of ten VEGF ligand and receptor genes was quantified using RNA sequencing of prefrontal cortex tissue. Global cognitive composite scores were calculated from 17 neuropsychological tests. β-amyloid and tau burden were measured at autopsy. Participants (n = 531) included individuals with normal cognition (n = 180), mild cognitive impairment (n = 148), or AD dementia (n = 203). Mean age at death was 89 years and 37% were male. Higher prefrontal cortex expression of VEGFB, FLT4, FLT1, and PGF was associated with worse cognitive trajectories (p ≤ 0.01). Increased expression of VEGFB and FLT4 was also associated with lower cognition scores at the last visit before death (p ≤ 0.01). VEGFB, FLT4, and FLT1 were upregulated among AD dementia compared with normal cognition participants (p ≤ 0.03). All four genes associated with cognition related to elevated β-amyloid (p ≤ 0.01) and/or tau burden (p ≤ 0.03). VEGF ligand and receptor genes, specifically genes relevant to FLT4 and FLT1 receptor signaling, are associated with cognition, longitudinal cognitive decline, and AD neuropathology. Future work should confirm these observations at the protein level to better understand how changes in VEGF transcription and translation relate to neurodegenerative disease.

¹⁸F]THK5351 PET Imaging in Patients with Mild Cognitive Impairment.

Background and PurposeMild cognitive impairment (MCI) is a condition with diverse clinical outcomes and subgroups. Here we investigated the topographic distribution of tau in vivo using the positron emission tomography (PET) tracer [18F]THK5351 in MCI subgroups.MethodsThis study included 96 participants comprising 38 with amnestic MCI (aMCI), 21 with nonamnestic MCI (naMCI), and 37 with normal cognition (NC) who underwent 3.0-T MRI, [18F]THK5351 PET, and detailed neuropsychological tests. [18F]flutemetamol PET was also performed in 62 participants. The aMCI patients were further divided into three groups: 1) verbal-aMCI, only verbal memory impairment; 2) visual-aMCI, only visual memory impairment; and 3) both-aMCI, both visual and verbal memory impairment. Voxel-wise statistical analysis and region-of-interest -based analyses were performed to evaluate the retention of [18F]THK5351 in the MCI subgroups. Subgroup analysis of amyloid-positive and -negative MCI patients was also performed. Correlations between [18F]THK5351 retention and different neuropsychological tests were evaluated using statistical parametric mapping analyses.Results[18F]THK5351 retention in the lateral temporal, mesial temporal, parietal, frontal, posterior cingulate cortices and precuneus was significantly greater in aMCI patients than in NC subjects, whereas it did not differ significantly between naMCI and NC participants. [18F] THK5351 retention was greater in the both-aMCI group than in the verbal-aMCI and visualaMCI groups, and greater in amyloid-positive than amyloid-negative MCI patients. The cognitive function scores were significantly correlated with cortical [18F]THK5351 retention.Conclusions[18F]THK5351 PET might be useful for identifying distinct topographic patterns of [18F]THK5351 retention in subgroups of MCI patients who are at greater risk of the progression to Alzheimer's dementia.

Tau positron emission tomography using [18F]THK5351 and cerebral glucose hypometabolism in Alzheimer's disease

This study aims to evaluate the clinical validity of [18F]THK5351 positron emission tomography (PET) for the assessment of disease progression and symptoms in Alzheimer's disease (AD). Fifty-one patients with AD dementia, 30 patients with amnestic mild cognitive impairment (aMCI), and 43 controls with normal cognition (NC) were included. All subjects underwent [18F]THK5351 PET, 3.0-T magnetic resonance imaging, and detailed neuropsychological tests. Regions of interest and voxel-based statistical analyses were performed. In patients with AD dementia, [18F]THK5351 retention was greater in most association cortices as well as the limbic area compared to NC or aMCI participants. Patients with aMCI also showed higher THK5351 retention in those areas compared to NC. [18F]THK5351 retention significantly correlated with neuropsychological test results. Negative correlations between [18F]THK5351 and [18F] fluorodeoxyglucose were observed in AD dementia and aMCI groups. Mirror images of [18F]THK5351 retention and glucose hypometabolism in [18F] fluorodeoxyglucose were noticeable in the focal variants of AD. [18F]THK5351 PET reflects disease severity and symptoms in AD. Our results suggest [18F]THK5351 is reflective of tau-related AD pathology.

Adverse vascular risk is related to cognitive decline in older adults.

Cardiovascular disease (CVD) and related risk factors are associated with Alzheimer's disease (AD). This association is less well-defined in normal cognition (NC) or prodromal AD (mild cognitive impairment, MCI). Cross-sectionally and longitudinally relate a vascular risk index to cognitive outcomes among elders free of clinical dementia. 3,117 MCI (74 ± 8 years, 56% female) and 6,603 NC participants (72 ± 8 years, 68% female) were drawn from the National Alzheimer's Coordinating Center. A composite measure of vascular risk was defined using the Framingham Stroke Risk Profile (FSRP) score (i.e., age, systolic blood pressure, anti-hypertensive medication, diabetes, cigarette smoking, CVD history, atrial fibrillation). Ordinary linear regressions and generalized linear mixed models related baseline FSRP to cross-sectional and longitudinal cognitive outcomes, separately for NC and MCI, adjusting for age, gender, race, education, and follow-up time (in longitudinal models). In NC participants, increasing FSRP was related to worse baseline global cognition, information processing speed, and sequencing abilities (p-values <0.0001) and a worse longitudinal trajectory on all cognitive measures (p-values <0.0001). In MCI, increasing FSRP correlated with worse longitudinal delayed memory (p = 0.004). In secondary models using an age-excluded FSRP score, associations persisted in NC participants for global cognition, naming, information processing speed, and sequencing abilities. An adverse vascular risk profile is associated with worse cognitive trajectory, especially global cognition, naming, and information processing speed, among NC elders. Future studies are needed to understand how effective management of CVD and related risk factors can modify cognitive decline to identify the ideal timeframe for primary prevention implementation.

A-28 * Vascular Risk and Cognitive Decline in Older Adults with and without Mild Cognitive Impairment (MCI)

Objective: Vascular risk factors are associated with increased risk for cognitive decline and clinical Alzheimer's disease (AD). The purpose of this study was to examine whether worse vascular health status would be associated with a decline in cognitive performance in older adults with normal cognition (NC) or mild cognitive impairment (MCI) at baseline. Method: Participants were drawn from the National Alzheimer's Coordinating Center Uniform Dataset, and included 5893 NC (72 ± 8 years, 69% female) and 2769 MCI (74 ± 8 years, 55% female). Vascular Health was defined using the Framingham Stroke Risk Profile score (based on age, systolic blood pressure, anti-hypertensive medication usage, diabetes, cigarette smoking, CVD history, atrial fibrillation). Cognitive performance was assessed using a comprehensive neuropsychological protocol (Mini-Mental State Examination, Digit Span, Trail Making Test Parts A & B, Digit Symbol, Boston Naming Test-30 Item, Animal Naming, Vegetable Naming, Logical Memory Immediate & Delayed Recall). Ordinary linear regressions and generalized linear mixed models related baseline FSRP to longitudinal cognitive outcomes separately for NC and MCI participants. Results: Mean follow-up time was 2.7 ± 2.3 years for NC participants and 2.0 ± 2.0 years for MCI participants. Increasing FSRP was related to worse longitudinal trajectory on all cognitive measures in NC participants (all p-values < .0001). Higher FSRP was only related to worse longitudinal delayed memory in MCI participants (p = 0.003). Conclusion(s): Our results suggest that poorer vascular health is related to worse cognitive trajectory among NC elders and worse delayed memory trajectory in MCI. Future studies are needed to understand how effective management of vascular risk factors affects cognitive progression.

Cognition in MCI and Alzheimer’s Disease: Baseline Data from a Longitudinal Study of the NTB

Baseline data are summarized from a study examining the psychometric properties of the Neuropsychological Test Battery (NTB) and its subtests, and correlating the NTB with other cognitive and functional assessments. A multicenter, longitudinal, non-interventional study included mild to moderate Alzheimer’s disease (AD, n = 196), mild cognitive impairment (MCI, n = 70), or normal cognition participants (NC, n = 75). The NTB, other cognitive assessment tools, functional/behavioral questionnaires, and health outcome assessments were administered. At baseline composite NTB, NTB memory, and NTB executive function z-scores were significantly lower for participants with AD compared with MCI, and for participants with MCI compared with NC. The composite NTB z-score had high test–retest reliability between screening and baseline. The results of this study suggest that NTB exhibits good reliability in patients with mild to moderate AD and MCI.