Optimal cutoff scores of the Montreal Cognitive Assessment to detect mild cognitive impairment and dementia in Costa Rican older adults.

BACKGROUND: The burden of Alzheimer's disease and related dementias (AD/ADRD) in Costa Rica is expected to become one of the highest in the region. Early detection will help optimize resources and improve primary care interventions. The Montreal Cognitive Assessment (MoCA) has shown good sensitivity for detecting mild cognitive impairment (MCI), but specificity varies depending on the population. This motivated the analysis of different cutoffs to minimize false-positive classifications in a Costa Rican sample for its use in clinical settings. METHODS: Data was analyzed from 516 memory clinic outpatients (148 cognitively normal, 260 MCI, 108 mild AD/ADRD; mean age 66.3 ± 10.8 years) who underwent complete neurological and neuropsychological assessment and were diagnosed by consensus. Optimal MoCA cutoff scores were identified using a multiple cutoff approach. RESULTS: Overall, a cutoff score of ≥ 23 showed better accuracy to distinguish between normal cognition (NC) and MCI (sensitivity 73%, specificity 83%). When analyzed by educational levels, a cutoff score of ≥ 21 showed better accuracy for ≤ 6 years (sensitivity 80%, specificity 76%), ≥23 for 7-12 years (sensitivity 86%, specificity 76%) and ≥ 24 for > 12 years (sensitivity 70%, specificity 85%). For distinguishing MCI from mild AD/ADRD, the optimal overall cutoff score was ≥ 15 (sensitivity 66%, specificity 85%). When stratified by years of education, cutoff scores of ≥ 14 showed better accuracy for ≤ 6 years (sensitivity 70%, specificity 88%), ≥15 for 7-12 years (sensitivity 46%, specificity 95%) and ≥ 17 for > 12 years (sensitivity 67%, specificity 93%). CONCLUSIONS: A MoCA cutoff score of ≥ 23 in the Costa Rican population showed better diagnostic accuracy for detecting MCI and may reduce the false positive rate. Our findings may be helpful for primary care clinical settings and further referral criteria.

Risk factors and cognitive domain markers of progression in subjective cognitive decline.

We evaluated risk factor differences and cognitive domain markers associated with progression in subjects with subjective cognitive decline (SCD) at baseline from the NYU Alzheimer Disease Research Center. We included SCD non-decliners (n = 27), who remained stable, and decliners (n = 24), who progressed to mild cognitive impairment or worse, between the second to sixth yearly follow-up visits. Adjusted mixed-effects models examined group differences and associations between demographic, APOE status, psychometric test performance and comorbidities with longitudinal-decline. Overall, mean (SD) age was 67.4 (9.2) and total follow-up time was 5.1 (1.8) years. Lower education (14.9 (3.2) vs. 17.3 (2.1)), Hispanic ethnicity (50.0% vs. 11.0%), and hypercholesterolemia (aOR: 6.67), p ≤ 0.05 for all, were risk factors for progression in SCD, whereas APOE status was not. Notably, SCD decliners were at increased risk for both amnestic and non-amnestic cognitive-decline with psychometric changes in memory, executive, and language domains (p < 0.001 for all). These findings inform further work on SCD outcomes and related biomarkers, as well as preventive studies that target modifiable risk factors for SCD progression.

Cell type-specific impact of aging and Alzheimer disease on hippocampal CA1 perforant path input.

The perforant path (PP) carries direct inputs from entorhinal cortex to CA1 pyramidal neurons (PNs), with an impact dependent on PN position across transverse (CA1a-CA1c) and radial (superficial/deep) axes. It remains unclear how aging and Alzheimer disease (AD) affect PP input, despite its critical role in memory and early AD. Applying ex vivo recordings and two-photon microscopy in slices from mice up to 30 months old, we interrogated PP responses across PN subpopulations and compared them to Schaffer collateral and intrinsic excitability changes. We found that aging uniquely impacts PP excitatory responses, abolishing transverse and radial differences via a mechanism independent of presynaptic and membrane excitability change. This is amplified in aged 3xTg-AD mice, with further weakening of PP inputs to CA1a superficial PNs associated with distal dendritic spine loss. This demonstrates a unique feature of aging-related circuit dysfunction, with mechanistic implications related to memory impairment and synaptic vulnerability.

Prevalence, risk factors, and impact of anxiety in early Alzheimer disease: a retrospective study of an autopsy-confirmed cohort.

Anxiety is a neuropsychiatric symptom (NPS) of Alzheimer disease (AD) patients which has been studied primarily in prospective and retrospective studies of clinically diagnosed AD. However, this can be confounded by other primary etiologies. Moreover, anxiety has not been comprehensively studied in autopsy-confirmed AD cases across subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia stages. We conducted a retrospective longitudinal analysis of 212 participants with autopsy-confirmed AD, followed from 1986-2013 at the NYU Alzheimer's Disease Research Center with staging via the Global Deterioration Scale and NPS assessed via BEHAVE-AD. We found that anxiety varied uniquely with stage and was the most common NPS in SCD and MCI (35-40% prevalence). ApoE4 carriage associated with a higher rate of anxiety only at mild dementia. Anxiety in SCD associated with cerebral amyloid angiopathy and arteriosclerosis on brain autopsy, but there were no such associations with concomitant neuropathology at MCI and mild dementia. Anxiety associated with increased progression rate (∼2.5-fold) from SCD to MCI/dementia stages, but not from MCI to dementia. These results suggest an important relationship between anxiety and AD, especially at the preclinical stage. This warrants further study of anxiety as a possible modifiable factor of disease experience and course.

Factors Affecting Resilience and Prevention of Alzheimer's Disease and Related Dementias.

Alzheimer's disease (AD) is a devastating, age-associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid ß (Aß) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aß-targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD-related pathologies, such as NFTs, are not directly targeted. A non-mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD-related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024.

Two-Year Longitudinal Outcomes of Subjective Cognitive Decline in Hispanics Compared to Non-hispanic Whites.

BACKGROUND: Subjective cognitive decline (SCD), considered a preclinical dementia stage, is less understood in Hispanics, a high-risk group for dementia. We investigated SCD to mild cognitive impairment (MCI) progression risk, as well as baseline and longitudinal features of depressive symptoms, SCD complaints, and objective cognitive performance among Hispanics compared to non-Hispanic Whites (NHW). METHODS: Hispanic (n = 23) and NHW (n = 165) SCD participants were evaluated at baseline and 2-year follow-up. Evaluations assessed function, depressive symptoms, SCD, and objective cognitive performance. RESULTS: Hispanics were at increased risk of progression to MCI (OR: 6.10, 95% CI 1.09-34.20, P = .040). Hispanic participants endorsed more depressive symptoms at baseline (P = .048) that worsened more longitudinally (OR: 3.16, 95% CI 1.18-8.51, P = .023). Hispanic participants had increased SCD complaints on the Brief Cognitive Rating Scale (BCRS) (ß = .40 SE: .17, P = .023), and in specific BCRS domains: concentration (ß = .13, SE: .07, P = .047), past memory (ß = .13, SE: .06, P = .039) and functional abilities (ß = .10, SE: .05, P = .037). In objective cognitive performance, Hispanic ethnicity associated with decline in MMSE (ß = -.27, SE: .13, P = .039), MoCA (ß = -.80 SE: .34, P = .032), Trails A (ß = 2.75, SE: .89, P = .002), Trails B (ß = 9.18, SE: 2.71, P = .001) and Guild Paragraph Recall Delayed (ß = -.80 SE: .28, P = .005). Conclusions: Hispanic ethnicity associated with a significantly increased risk of 2-year progression of SCD to MCI compared to NHW. This increased risk associated with increased depressive symptoms, distinctive SCD features, and elevated amnestic and non-amnestic objective cognitive decline. This supports further research to refine the assessment of preclinical dementia in this high-risk group.

The relationship between anxiety and levels of Alzheimer's disease plasma biomarkers.

Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with CSF/PET biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/Aß42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.

Drivers of Memory Loss Underreport in Mild Cognitive Impairment Due to Alzheimer Versus Vascular Disease.

BACKGROUND: We examined drivers of self and study partner reports of memory loss in mild cognitive impairment (MCI) from Alzheimer (AD-MCI) and vascular disease (Va-MCI). METHODS: We performed retrospective cross-sectional analyses of participants with AD-MCI (n=2874) and Va-MCI (n=376) from the National Alzheimer Coordinating Center data set. Statistical analysis utilized 2-sided t test or the Fisher exact test. RESULTS: Compared with AD-MCI, Va-MCI subjects (24.5% vs. 19.7%, P =0.031) and study partners (31.4% vs. 21.6%, P <0.0001) were more likely to deny memory loss. Black/African Americans were disproportionately represented in the group denying memory loss in AD-MCI (20.0% vs. 13.2%, P <0.0001) and Va-MCI (33.7% vs. 18.0%, P =0.0022). Study partners of participants with these features also disproportionately denied memory loss: female (AD-MCI: 60.1% vs. 51.7%, P =0.0002; Va-MCI: 70.3% vs. 52.3%, P =0.0011), Black/African American (AD-MCI: 23.5% vs. 11.98%, P <0.0001; Va-MCI: 48.8% vs. 26.5%, P =0.0002), and <16 years of education (AD-MCI only: 33.9% vs. 16.3%, P =0.0262). In AD-MCI and Va-MCI, participants with anxiety were disproportionately represented in the group endorsing memory loss (AD: 28.2% vs. 17.4%, P <0.0001; Va: 31.5% vs. 16.1%, P =0.0071), with analogous results with depression. CONCLUSION: The findings would suggest extra vigilance in interview-based MCI detection of persons at-risk for self-based or informant-based misreport.

Diffusion imaging markers of accelerated aging of the lower cingulum in subjective cognitive decline.

Introduction: Alzheimer's Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent. Methods: To better characterize the microstructure of this region, we applied DTI to cognitively normal participants in the Cam-CAN database over the age of 55 with cognitive testing and diffusion MRI available (N = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus. Results: SCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD. Discussion: The diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition.

Sensitivity of unconstrained quantitative magnetization transfer MRI to Amyloid burden in preclinical Alzheimer's disease.

Magnetization transfer MRI is sensitive to semi-solid macromolecules, including amyloid beta, and has previously been used to discriminate Alzheimer's disease (AD) patients from controls. Here, we fit an unconstrained 2-pool quantitative MT (qMT) model, i.e., without constraints on the longitudinal relaxation rate R 1 s of semi-solids, and investigate the sensitivity of the estimated parameters to amyloid accumulation in preclinical subjects. We scanned 15 cognitively normal volunteers, of which 9 were amyloid positive by [18F]Florbetaben PET. A 12 min hybrid-state qMT scan with an effective resolution of 1.24 mm isotropic and whole-brain coverage was acquired to estimate the unconstrained 2-pool qMT parameters. Group comparisons and correlations with Florbetaben PET standardized uptake value ratios were analyzed at the lobar level. We find that the exchange rate and semi-solid pool's R 1 s were sensitive to the amyloid concentration, while morphometric measures of cortical thickness derived from structural MRI were not. Changes in the exchange rate are consistent with previous reports in clinical AD, while changes in R 1 s have not been reported previously as its value is typically constrained in the literature. Our results demonstrate that qMT MRI may be a promising surrogate marker of amyloid beta without the need for contrast agents or radiotracers.

Predicting Risk of Alzheimer's Diseases and Related Dementias with AI Foundation Model on Electronic Health Records.

Early identification of Alzheimer's disease (AD) and AD-related dementias (ADRD) has high clinical significance, both because of the potential to slow decline through initiating FDA-approved therapies and managing modifiable risk factors, and to help persons living with dementia and their families to plan before cognitive loss makes doing so challenging. However, substantial racial and ethnic disparities in early diagnosis currently lead to additional inequities in care, urging accurate and inclusive risk assessment programs. In this study, we trained an artificial intelligence foundation model to represent the electronic health records (EHR) data with a vast cohort of 1.2 million patients within a large health system. Building upon this foundation EHR model, we developed a predictive Transformer model, named TRADE, capable of identifying risks for AD/ADRD and mild cognitive impairment (MCI), by analyzing the past sequential visit records. Amongst individuals 65 and older, our model was able to generate risk predictions for various future timeframes. On the held-out validation set, our model achieved an area under the receiver operating characteristic (AUROC) of 0.772 (95% CI: 0.770, 0.773) for identifying the AD/ADRD/MCI risks in 1 year, and AUROC of 0.735 (95% CI: 0.734, 0.736) in 5 years. The positive predictive values (PPV) in 5 years among individuals with top 1% and 5% highest estimated risks were 39.2% and 27.8%, respectively. These results demonstrate significant improvements upon the current EHR-based AD/ADRD/MCI risk assessment models, paving the way for better prognosis and management of AD/ADRD/MCI at scale.

Impact of dendritic spine loss on excitability of hippocampal CA1 pyramidal neurons: a computational study of early Alzheimer disease.

Synaptic spine loss is an early pathophysiologic hallmark of Alzheimer disease (AD) that precedes overt loss of dendritic architecture and frank neurodegeneration. While spine loss signifies a decreased engagement of postsynaptic neurons by presynaptic targets, the degree to which loss of spines and their passive components impacts the excitability of postsynaptic neurons and responses to surviving synaptic inputs is unclear. Using passive multicompartmental models of CA1 pyramidal neurons (PNs), implicated in early AD, we find that spine loss alone drives a boosting of remaining inputs to their proximal and distal dendrites, targeted by CA3 and entorhinal cortex (EC), respectively. This boosting effect is higher in distal versus proximal dendrites and can be mediated by spine loss restricted to the distal compartment, enough to impact synaptic input integration and somatodendritic backpropagation. This has particular relevance to very early stages of AD in which pathophysiology extends from EC to CA1.

Local and long-range GABAergic circuits in hippocampal area CA1 and their link to Alzheimer's disease.

GABAergic inhibitory neurons are the principal source of inhibition in the brain. Traditionally, their role in maintaining the balance of excitation-inhibition has been emphasized. Beyond homeostatic functions, recent circuit mapping and functional manipulation studies have revealed a wide range of specific roles that GABAergic circuits play in dynamically tilting excitation-inhibition coupling across spatio-temporal scales. These span from gating of compartment- and input-specific signaling, gain modulation, shaping input-output functions and synaptic plasticity, to generating signal-to-noise contrast, defining temporal windows for integration and rate codes, as well as organizing neural assemblies, and coordinating inter-regional synchrony. GABAergic circuits are thus instrumental in controlling single-neuron computations and behaviorally-linked network activity. The activity dependent modulation of sensory and mnemonic information processing by GABAergic circuits is pivotal for the formation and maintenance of episodic memories in the hippocampus. Here, we present an overview of the local and long-range GABAergic circuits that modulate the dynamics of excitation-inhibition and disinhibition in the main output area of the hippocampus CA1, which is crucial for episodic memory. Specifically, we link recent findings pertaining to GABAergic neuron molecular markers, electrophysiological properties, and synaptic wiring with their function at the circuit level. Lastly, given that area CA1 is particularly impaired during early stages of Alzheimer's disease, we emphasize how these GABAergic circuits may contribute to and be involved in the pathophysiology.

Gait dysfunction in Alzheimer disease.

Alzheimer's disease (AD) is the most common cause of age-associated dementia and will exponentially rise in prevalence in the coming decades, supporting the parallel development of the early stage detection and disease-modifying strategies. While primarily considered as a cognitive disorder, AD also features motor symptoms, primarily gait dysfunction. Such gait abnormalities can be phenotyped across classic clinical syndromes as well as by quantitative kinematic assessments to address subtle dysfunction at preclinical and prodromal stages. As such, certain measures of gait can predict the future cognitive and functional decline. Moreover, cross-sectional and longitudinal studies have associated gait abnormalities with imaging, biofluid, and genetic markers of AD across all stages. This suggests that gait assessment is an important tool in the clinical assessment of patients across the AD spectrum, especially to help identify at-risk individuals.

Impact of white matter hyperintensities on subjective cognitive decline phenotype in a diverse cohort of cognitively normal older adults.

OBJECTIVES: Subjective cognitive decline (SCD) is a preclinical stage of AD. White matter hyperintensities (WMH), an MRI marker of cerebral small vessel disease, associate with AD biomarkers and progression. The impact of WMH on SCD phenotype is unclear. METHODS/DESIGN: A retrospective, cross-sectional analysis was conducted on a diverse cohort with SCD evaluated at the NYU Alzheimer's Disease Research Center between January 2017 and November 2021 (n = 234). The cohort was dichotomized into none-to-mild (n = 202) and moderate-to-severe (n = 32) WMH. Differences in SCD and neurocognitive assessments were evaluated via Wilcoxon or Fisher exact tests, with p-values adjusted for demographics using multivariable logistic regression. RESULTS: Moderate-to-severe WMH participants reported more difficulty with decision making on the Cognitive Change Index (1.5 SD 0.7 vs. 1.2 SD 0.5, p = 0.0187) and worse short-term memory (2.2 SD 0.4 vs. 1.9 SD 0.3, p = 0.0049) and higher SCD burden (9.5 SD 1.6 vs. 8.7 SD 1.7, p = 0.0411) on the Brief Cognitive Rating Scale. Moderate-to-severe WMH participants scored lower on the Mini-Mental State Examination (28.0 SD 1.6 vs. 28.5 SD 1.9, p = 0.0491), and on delayed paragraph (7.2 SD 2.0 vs. 8.8 SD 2.9, p = 0.0222) and designs recall (4.5 SD 2.3 vs. 6.1 SD 2.5, p = 0.0373) of the Guild Memory Test. CONCLUSIONS: In SCD, WMH impact overall symptom severity, specifically in executive and memory domains, as well as objective performance on global and domain-specific tests in verbal memory and visual working/associative memory.

On gaps of clinical diagnosis of dementia subtypes: A study of Alzheimer's disease and Lewy body disease.

Introduction: Alzheimer's disease (AD) and Lewy body disease (LBD) are the two most common neurodegenerative dementias and can occur in combination (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation of these subtypes could be difficult. However, it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectra and demographic variables. We aimed to compare clinical diagnosis and post-mortem autopsy-confirmed pathological results to assess the clinical subtype diagnosis quality across these factors. Methods: We studied data of 1,920 participants recorded by the National Alzheimer's Coordinating Center from 2005 to 2019. Selection criteria included autopsy-based neuropathological assessments for AD and LBD, and the initial visit with Clinical Dementia Rating (CDR) stage of normal, mild cognitive impairment, or mild dementia. Longitudinally, we analyzed the first visit at each subsequent CDR stage. This analysis included positive predictive values, specificity, sensitivity and false negative rates of clinical diagnosis, as well as disparities by sex, race, age, and education. If autopsy-confirmed AD and/or LBD was missed in the clinic, the alternative clinical diagnosis was analyzed. Findings: In our findings, clinical diagnosis of AD+LBD had poor sensitivities. Over 61% of participants with autopsy-confirmed AD+LBD were diagnosed clinically as AD. Clinical diagnosis of AD had a low sensitivity at the early dementia stage and low specificities at all stages. Among participants diagnosed as AD in the clinic, over 32% had concurrent LBD neuropathology at autopsy. Among participants diagnosed as LBD, 32% to 54% revealed concurrent autopsy-confirmed AD pathology. When three subtypes were missed by clinicians, "No cognitive impairment" and "primary progressive aphasia or behavioral variant frontotemporal dementia" were the leading primary etiologic clinical diagnoses. With increasing dementia stages, the clinical diagnosis accuracy of black participants became significantly worse than other races, and diagnosis quality significantly improved for males but not females. Discussion: These findings demonstrate that clinical diagnosis of AD, LBD, and AD+LBD are inaccurate and suffer from significant disparities on race and sex. They provide important implications for clinical management, anticipatory guidance, trial enrollment and applicability of potential therapies for AD, and promote research into better biomarker-based assessment of LBD pathology.

Vigorous, regular physical exercise may slow disease progression in Alzheimer's disease.

INTRODUCTION: Mild to moderate exercise may decrease Alzheimer's disease (AD) risk, but the effects of vigorous, regular physical exercise remain unclear. METHODS: Two patients with initial diagnoses of amnestic mild cognitive impairment (MCI) demonstrated positive AD biomarkers throughout 16 and 8 years of follow-up, with final diagnoses of mild AD and amnestic MCI, respectively. RESULTS: Patient 1 was diagnosed with amnestic MCI at age 64. Neuropsychological testing, magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), amyloid imaging PET, and cerebrospinal fluid (CSF) biomarkers during follow-ups remained consistent with AD. By age 80, progression was minimal with Montreal Cognitive Assessment (MoCA) 26 of 30. Patient 2 was diagnosed with amnestic MCI at age 72. Neuropsychological testing, MRI, FDG-PET, and amyloid imaging PET during follow-ups remained consistent with AD. At age 80, MoCA was 27 of 30 with no clinical progression. Both patients regularly performed vigorous, regular exercise that increased after retirement/work reduction. DISCUSSION: Vigorous, regular exercise may slow disease progression in biomarker-positive amnestic MCI and mild AD.