Subjective Cognitive Decline Plus and Longitudinal Assessment and Risk for Cognitive Impairment.

Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting. Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults. Design, Setting, and Participants: The Framingham Heart Study, a community-based prospective cohort study, assessed SCD between 2005 and 2019, with up to 12 years of follow-up. Participants 60 years and older with normal cognition at analytic baseline were included. Cox proportional hazards (CPH) models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS), excluding the APOE region. Data were analyzed from May 2021 to November 2023. Exposure: SCD was assessed longitudinally using a single question and considered present if endorsed at the last cognitively normal visit. It was treated as a time-varying variable, beginning at the first of consecutive, cognitively normal visits, including the last, at which it was endorsed. Main Outcomes and Measures: Consensus-diagnosed MCI, AD, and all-cause dementia. Results: This study included 3585 participants (mean [SD] baseline age, 68.0 [7.7] years; 1975 female [55.1%]). A total of 1596 participants (44.5%) had SCD, and 770 (21.5%) were carriers of APOE ε4. APOE ε4 and tertiles of AD PRS status did not significantly differ between the SCD and non-SCD groups. MCI, AD, and all-cause dementia were diagnosed in 236 participants (6.6%), 73 participants (2.0%), and 89 participants (2.5%), respectively, during follow-up. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all-cause dementia by 6.9 years. SCD was significantly associated with survival time to MCI (hazard ratio [HR], 1.57; 95% CI, 1.22-2.03; P <.001), AD (HR, 2.98; 95% CI, 1.89-4.70; P <.001), and all-cause dementia (HR, 2.14; 95% CI, 1.44-3.18; P <.001). After adjustment for APOE and AD PRS, the hazards of SCD were largely unchanged. Conclusions and Relevance: Results of this cohort study suggest that in a community setting, SCD reflecting SCD+ features was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. SCD may be an independent risk factor for AD and other dementias beyond the risk incurred by APOE ε4 and AD PRS.

Neutrophil-to-lymphocyte ratio and longitudinal cognitive performance in Parkinson's disease.

OBJECTIVE: Previous studies have suggested a link between peripheral inflammation and cognitive outcomes in the general population and individuals with Parkinson's disease (PD). We sought to test the association between peripheral inflammation, measured by the neutrophil-to-lymphocyte ratio (NLR), cognitive performance, and mild cognitive impairment (MCI) status in individuals with PD. METHODS: A retrospective, longitudinal analysis was carried out using data from the Parkinson's Progression Markers Initiative (PPMI), including 422 participants with PD followed over 5 years. Cognitive performance was assessed using a neuropsychological battery including the Montreal Cognitive Assessment (MoCA) and tests of verbal learning, visuospatial function, processing speed, and executive function. Mixed-effect regression models were used to analyze the association between NLR, cognitive performance, and MCI status, controlling for age, sex, education, APOE genotype, and motor severity. RESULTS: There was a negative association between NLR and MoCA, even after adjusting for covariates (b = -0.12, p = 0.033). MoCA scores for individuals in the high NLR category exhibited a more rapid decline over time compared to the low NLR group (b = -0.16, p = 0.012). Increased NLR was associated with decreased performance across all cognitive domains. However, NLR was not associated with MCI status over 5 years of follow-up. INTERPRETATION: This study demonstrates a link between elevated NLR and cognitive performance in PD, but not with MCI status over 5 years. This suggests that NLR is more strongly associated with day-to-day cognitive performance than with incident MCI, but this requires further study in more heterogeneous cohorts.

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer's disease in the Framingham Heart Study.

Aim: Endothelial dysfunction has been associated with both cerebrovascular pathology and Alzheimer's disease (AD). However, the connection between circulating endothelial cells and the risk of AD remains uncertain. The objective was to leverage data from the Framingham Heart Study to investigate various circulating endothelial subtypes and their potential correlations with the risk of AD. Methods: The study conducted data analyses using Cox proportional hazard regression and linear regression methods. Additionally, genome-wide association study (GWAS) was carried out to further explore the data. Results: Among the eleven distinct circulating endothelial subtypes, only circulating endothelial progenitor cells (EPCs) expressing CD34+CD133+ were found to be negatively and dose-dependently associated with reduced AD risk. This association persisted even after adjusting for age, sex, years of education, apolipoprotein E (APOE) ε4 status, and various vascular diseases. Particularly noteworthy was the significant association observed in individuals with hypertension and cerebral microbleeds. Consistently, positive associations were identified between CD34+CD133+ EPCs and specific brain regions, such as higher proportions of circulating CD34+CD133+ cells correlating with increased volumes of white matter and the hippocampus. Additionally, a GWAS study unveiled that CD34+CD133+ cells influenced AD risk specifically in individuals with homozygous genotypes for variants in two stem cell-related genes: kirre like nephrin family adhesion molecule 3 (KIRREL3, rs580382 CC and rs4144611 TT) and exocyst complex component 6B (EXOC6B, rs61619102 CC). Conclusions: The findings suggest that circulating CD34+CD133+ EPCs possess a protective effect and may offer a new therapeutic avenue for AD, especially in individuals with vascular pathology and those carrying specific genotypes of KIRREL3 and EXOC6B genes.

Maximizing utility of neuropsychological measures in sex-specific predictive models of incident Alzheimer's disease in the Framingham Heart Study.

INTRODUCTION: Sex differences in neuropsychological (NP) test performance might have important implications for the diagnosis of Alzheimer's disease (AD). This study investigates sex differences in neuropsychological performance among individuals without dementia at baseline. METHODS: Neuropsychological assessment data, both standard test scores and process coded responses, from Framingham Heart Study participants were analyzed for sex differences using regression model and Cox proportional hazards model. Optimal NP profiles were identified by machine learning methods for men and women. RESULTS: Sex differences were observed in both summary scores and composite process scores of NP tests in terms of adjusted means and their associations with AD incidence. The optimal NP profiles for men and women have 10 and 8 measures, respectively, and achieve 0.76 mean area under the curve for AD prediction. DISCUSSION: These results suggest that NP tests can be leveraged for developing more sensitive, sex-specific indices for the diagnosis of AD.

Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer's Disease.

Cerebrovascular damage coexists with Alzheimer's disease (AD) pathology and increases AD risk. However, it is unclear whether endothelial progenitor cells reduce AD risk via cerebrovascular repair. By using the Framingham Heart Study (FHS) offspring cohort, which includes data on different progenitor cells, the incidence of AD dementia, peripheral and cerebrovascular pathologies, and genetic data (n = 1,566), we found that elevated numbers of circulating endothelial progenitor cells with CD34+CD133+ co-expressions had a dose-dependent association with decreased AD risk (HR = 0.67, 95% CI: 0.46-0.96, p = 0.03) after adjusting for age, sex, years of education, and APOE ε4. With stratification, this relationship was only significant among those individuals who had vascular pathologies, especially hypertension (HTN) and cerebral microbleeds (CMB), but not among those individuals who had neither peripheral nor central vascular pathologies. We applied a genome-wide association study (GWAS) and found that the number of CD34+CD133+ cells impacted AD risk depending on the homozygous genotypes of two genes: KIRREL3 rs580382 CC carriers (HR = 0.31, 95% CI: 0.17-0.57, p<0.001), KIRREL3 rs4144611 TT carriers (HR = 0.29, 95% CI: 0.15-0.57, p<0.001), and EXOC6B rs61619102 CC carriers (HR = 0.49, 95% CI: 0.31-0.75, p<0.001) after adjusting for confounders. In contrast, the relationship did not exist in their counterpart genotypes, e.g. KIRREL3 TT/CT or GG/GT carriers and EXOC6B GG/GC carriers. Our findings suggest that circulating CD34+CD133+ endothelial progenitor cells can be therapeutic in reducing AD risk in the presence of cerebrovascular pathology, especially in KIRREL3 and EXOC6B genotype carriers.

Examination of potentially modifiable dementia risk factors across the adult life course: The Framingham Heart Study.

INTRODUCTION: We examined for associations between potentially modifiable risk factors across the adult life course and incident dementia. METHODS: Participants from the Framingham Heart Study were included (n = 4015). Potential modifiable risk factors included education, alcohol intake, smoking, body mass index (BMI), physical activity, social network, diabetes, and hypertension. Cox models were used to examine associations between each factor and incident dementia, stratified by early adult life (33-44 years), midlife (45-65 years), and late life (66-80 years). RESULTS: Increased dementia risk was associated with diabetes (hazard ratio [HR] = 1.62; 95% confidence interval [CI] = 1.07-2.46) and physical inactivity (HR = 1.57; 95% CI = 1.12-2.20) in midlife, and with obesity (HR = 1.76; 95% CI = 1.08-2.87) in late life. Having multiple potential modifiable risk factors in midlife and late life was associated with greater risk. DISCUSSION: Potentially modifiable risk factors individually have limited impact on dementia risk in this population across the adult life course, although in combination they may have a synergistic effect. HIGHLIGHTS: Diabetes and physical inactivity in midlife is associated with increased dementia risk. Obesity in late life is associated with increased dementia risk. Having more potentially modifiable risk factors in midlife and late life is associated with greater dementia risk.

The Colorado Cognitive Assessment (CoCA): Development of an Advanced Neuropsychological Screening Tool.

OBJECTIVE: The Colorado Cognitive Assessment (CoCA) was designed to improve upon existing screening tests in a number of ways, including enhanced psychometric properties and minimization of bias across diverse groups. This paper describes the initial validation study of the CoCA, which seeks to describe the test; demonstrate its construct validity; measurement invariance to age, education, sex, and mood symptoms; and compare it to the Montreal Cognitive Assessment (MoCA). METHOD: Participants included 151 older adults (MAge = 71.21, SD = 8.05) who were administered the CoCA, MoCA, Judgment test from the Neuropsychological Assessment Battery (NAB), 15-item version of the Geriatric Depression Scale (GDS-15), and 10-item version of the Geriatric Anxiety Scale (GAS-10). RESULTS: A single-factor confirmatory factor analysis model of the CoCA fit the data well, CFI = 0.955; RMSEA = 0.033. The CoCA factor score reliability was .84, compared to .74 for the MoCA. The CoCA had stronger disattenuated correlations with the MoCA (r = .79) and NAB Judgment (r = .47) and weaker correlations with the GDS-15 (r = -.36) and GAS-10 (r = -.15), supporting its construct validity. Finally, when analyzed using multiple-indicators, multiple-causes (MIMIC) modeling, the CoCA showed no evidence of measurement noninvariance, unlike the MoCA. CONCLUSIONS: These results provide initial evidence to suggest that the CoCA is a valid cognitive screening tool that offers numerous advantages over the MoCA, including superior psychometric properties and measurement noninvariance. Additional validation and normative studies are warranted.

The Differential Effects of Alzheimer's Disease and Lewy Body Pathology on Cognitive Performance: a Meta-analysis.

Differential diagnosis of Alzheimer's disease (AD) from normal aging and other dementia etiologies is imperative for disease specific treatment options and long-term care planning. Neuropathological confirmation is the gold standard for neurodegenerative disease diagnosis, yet most published studies examining the use of neuropsychological tests in the differential diagnosis of dementia rely upon clinical diagnostic outcomes. The present study undertook a meta-analytic review of the literature to identify cognitive tests and domains that allow for the differentiation of individuals with AD pathology from individuals with dementia with Lewy Bodies (DLB) pathology and pathology-free individuals. A comprehensive literature search yielded 14 studies that met the inclusion criteria for the present meta-analysis. Six studies comprised 222 decedents with AD compared to 433 normal controls, and eight studies comprised 431 cases of AD compared to 155 decedents with DLB. Results revealed that the effect of having neuropathologically confirmed AD versus DLB lowered performance in the memory domain, and having DLB decreased performance in the visuospatial domain. No single test differed significantly across the AD and DLB groups. For the AD and pathology free comparison, results indicated that that AD was associated with poorer performance on the memory and language domains. With respect to specific cognitive tests, AD produced lower scores on list learning tests, category fluency, and the Digit Symbol substitution test. The limited number of studies meeting inclusion criteria warrants formulation of guidelines for reporting in clinico-pathological studies; suggested guidelines are provided.

The effectiveness and unique contribution of neuropsychological tests and the δ latent phenotype in the differential diagnosis of dementia in the uniform data set.

OBJECTIVE: Two main approaches to the interpretation of cognitive test performance have been utilized for the characterization of disease: evaluating shared variance across tests, as with measures of severity, and evaluating the unique variance across tests, as with pattern and error analysis. Both methods provide necessary information, but the unique contributions of each are rarely considered. This study compares the 2 approaches on their ability to differentially diagnose with accuracy, while controlling for the influence of other relevant demographic and risk variables. METHOD: Archival data requested from the NACC provided clinical diagnostic groups that were paired to 1 another through a genetic matching procedure. For each diagnostic pairing, 2 separate logistic regression models predicting clinical diagnosis were performed and compared on their predictive ability. The shared variance approach was represented through the latent phenotype δ, which served as the lone predictor in 1 set of models. The unique variance approach was represented through raw score values for the 12 neuropsychological test variables comprising δ, which served as the set of predictors in the second group of models. RESULTS: Examining the unique patterns of neuropsychological test performance across a battery of tests was the superior method of differentiating between competing diagnoses, and it accounted for 16-30% of the variance in diagnostic decision making. CONCLUSION: Implications for clinical practice are discussed, including test selection and interpretation. (PsycINFO Database Record

Practice Effects on Story Memory and List Learning Tests in the Neuropsychological Assessment of Older Adults.

Two of the most commonly used methods to assess memory functioning in studies of cognitive aging and dementia are story memory and list learning tests. We hypothesized that the most commonly used story memory test, Wechsler's Logical Memory, would generate more pronounced practice effects than a well validated but less common list learning test, the Neuropsychological Assessment Battery (NAB) List Learning test. Two hundred eighty-seven older adults, ages 51 to 100 at baseline, completed both tests as part of a larger neuropsychological test battery on an annual basis. Up to five years of recall scores from participants who were diagnosed as cognitively normal (n = 96) or with mild cognitive impairment (MCI; n = 72) or Alzheimer's disease (AD; n = 121) at their most recent visit were analyzed with linear mixed effects regression to examine the interaction between the type of test and the number of times exposed to the test. Other variables, including age at baseline, sex, education, race, time (years) since baseline, and clinical diagnosis were also entered as fixed effects predictor variables. The results indicated that both tests produced significant practice effects in controls and MCI participants; in contrast, participants with AD declined or remained stable. However, for the delayed-but not the immediate-recall condition, Logical Memory generated more pronounced practice effects than NAB List Learning (b = 0.16, p < .01 for controls). These differential practice effects were moderated by clinical diagnosis, such that controls and MCI participants-but not participants with AD-improved more on Logical Memory delayed recall than on delayed NAB List Learning delayed recall over five annual assessments. Because the Logical Memory test is ubiquitous in cognitive aging and neurodegenerative disease research, its tendency to produce marked practice effects-especially on the delayed recall condition-suggests a threat to its validity as a measure of new learning, an essential construct for dementia diagnosis.

The Role of Alzheimer's and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer's Disease.

BACKGROUND: Dementia severity can be modeled as the construct δ, representing the "cognitive correlates of functional status." OBJECTIVE: We recently validated a model for estimating δ in the National Alzheimer's Coordinating Center's Uniform Data Set; however, the association of δ with neuropathology remains untested. METHODS: We used data from 727 decedents evaluated at Alzheimer's Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants' last visit prior to death were used to estimate dementia severity (δ). RESULTS: A structural equation model using age, education, race, and apolipoprotein E (APOE) genotype (number of ɛ2 and ɛ4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more ɛ2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more ɛ4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD. CONCLUSIONS: Using δ as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity.

Reliable Change on Neuropsychological Tests in the Uniform Data Set.

Longitudinal normative data obtained from a robust elderly sample (i.e., believed to be free from neurodegenerative disease) are sparse. The purpose of the present study was to develop reliable change indices (RCIs) that can assist with interpretation of test score changes relative to a healthy sample of older adults (ages 50+). Participants were 4217 individuals who completed at least three annual evaluations at one of 34 past and present Alzheimer's Disease Centers throughout the United States. All participants were diagnosed as cognitively normal at every study visit, which ranged from three to nine approximately annual evaluations. One-year RCIs were calculated for 11 neuropsychological variables in the Uniform Data Set by regressing follow-up test scores onto baseline test scores, age, education, visit number, post-baseline assessment interval, race, and sex in a linear mixed effects regression framework. In addition, the cumulative frequency distributions of raw score changes were examined to describe the base rates of test score changes. Baseline test score, age, education, and race were robust predictors of follow-up test scores across most tests. The effects of maturation (aging) were more pronounced on tests related to attention and executive functioning, whereas practice effects were more pronounced on tests of episodic and semantic memory. Interpretation of longitudinal changes on 11 cognitive test variables can be facilitated through the use of reliable change intervals and base rates of score changes in this robust sample of older adults. A Web-based calculator is provided to assist neuropsychologists with interpretation of longitudinal change.

Regression-Based Norms for a Bi-factor Model for Scoring the Brief Test of Adult Cognition by Telephone (BTACT).

The current study developed regression-based normative adjustments for a bi-factor model of the The Brief Test of Adult Cognition by Telephone (BTACT). Archival data from the Midlife Development in the United States-II Cognitive Project were used to develop eight separate linear regression models that predicted bi-factor BTACT scores, accounting for age, education, gender, and occupation-alone and in various combinations. All regression models provided statistically significant fit to the data. A three-predictor regression model fit best and accounted for 32.8% of the variance in the global bi-factor BTACT score. The fit of the regression models was not improved by gender. Eight different regression models are presented to allow the user flexibility in applying demographic corrections to the bi-factor BTACT scores. Occupation corrections, while not widely used, may provide useful demographic adjustments for adult populations or for those individuals who have attained an occupational status not commensurate with expected educational attainment.

The δ latent dementia phenotype in the uniform data set: Cross-validation and extension.

OBJECTIVE: Royall and colleagues identified a latent dementia phenotype, "δ", reflecting the "cognitive correlates of functional status." We sought to cross-validate and extend these findings in a large clinical case series of adults with and without dementia. METHOD: A confirmatory factor analysis (CFA) model for δ was fit to National Alzheimer's Coordinating Center data (n = 26,068). Factor scores derived from δ were compared with the Clinical Dementia Rating Sum of Boxes (CDR-SB) and to clinically diagnosed dementia. A longitudinal parallel-process growth model compared changes in δ with changes in CDR-SB over 6 annual evaluations. RESULTS: The CFA model fit well; CFI = 0.971, RMSEA = 0.070. Factor scores derived from δ discriminated between demented and nondemented participants with an area under the curve of .96. The growth model also fit well, CFI = 0.969, RMSEA = 0.032. CONCLUSIONS: The δ construct represents a novel approach to measuring dementia-related changes and has potential to improve cognitive assessment of neurodegenerative diseases.

Capgras syndrome in Dementia with Lewy Bodies.

BACKGROUND: Capgras syndrome is characterized by the recurrent, transient belief that a person has been replaced by an identical imposter. We reviewed clinical characteristics of Dementia with Lewy Bodies (DLB) patients with Capgras syndrome compared to those without Capgras. METHODS: We identified 55 consecutive DLB patients (11 cases with Capgras syndrome (DLB-C) and 44 cases without evidence of Capgras (DLB). Semi-structured interviews with the patient and an informant, neurological exams, and neuropsychological testing were performed. Caregivers were assessed for caregiver burden and depression. Primary comparisons were made between DLB-C and DLB. Exploratory analyses using stepwise logistic regression and bootstrap analyses were performed to determine clinical features associated with Capgras. RESULTS: DLB-C patients experienced more visual hallucinations and self-reported anxiety, had higher scores on the Neuropsychiatric Inventory, and were less likely to be treated with cholinesterase inhibitors at time of initial evaluation. Extrapyramidal symptoms and depression were not associated with Capgras. Caregivers of DLB-C patients had higher caregiver burden. DLB-C was associated with self-reported anxiety (OR = 10.9; 95% CI = 2.6-47.6). In a bootstrap analysis, clinical findings that were predictors of Capgras included visual hallucinations (log(OR) = 18.3; 95% CI = 17.9-19.3) and anxiety (log(OR) = 2.9; 95% CI = 0.31-20.2). CONCLUSIONS: Our study suggests that Capgras syndrome is common in DLB and usually occurs in the presence of anxiety and visual hallucinations, suggesting related etiopathogenesis. Early appreciation of Capgras syndrome may afford the opportunity to alleviate caregiver burden and improve patient and caregiver outcomes.

Nitric oxide is elicited and inhibits viral replication in pigs infected with porcine respiratory coronavirus but not porcine reproductive and respiratory syndrome virus.

There is little information on the role of nitric oxide (NO) in innate immunity to respiratory coronavirus (CoV) infections. We examined NO levels by Greiss assay in bronchoalveolar lavage (BAL) of pigs infected with either porcine respiratory coronavirus (PRCV) or porcine reproductive and respiratory syndrome virus (PRRSV), a member of Nidovirales, like CoV. The antiviral effects of NO on these two viruses were tested in an in vitro system using a NO donor, S-nitroso-N-acetylpenicillamine (SNAP). We detected a large increase in NO levels in BAL fluids of PRCV-infected pigs, but not in PRRSV-infected pigs. Pulmonary epithelial cell necrosis induced by PRCV coincided with increased NO. Moreover, NO levels in cell culture medium of PRRSV-infected alveolar macrophages (AMs) did not differ from that of mock-infected AMs. Antiviral assays showed that NO significantly inhibited PRCV replication in swine testicular (ST) cells, whereas PRRSV was not susceptible to NO based on the conditions tested. Our study suggests that unlike PRRSV which induces apoptosis in AMs, respiratory CoVs such as PRCV that infect pulmonary epithelial cells and cause cytolysis, induce NO production in the respiratory tract. Thus, NO may play a role in innate immunity to respiratory CoV infections by inhibiting viral replication.