Mini-Mental State Exam Score Research Articles

Predictors of decisional capacity in AD biomarker test candidates

AbstractBackgroundDeciding to learn one’s Alzheimer’s disease (AD) biomarker status requires comprehending and deliberating about complex and nuanced information. Assessing capacity to consent to AD biomarker testing and disclosure is further complicated when candidates have cognitive impairment and present with family care partners. The objective of this analysis was to identify predictors of decisional capacity for an amyloid PET disclosure study among persons with Mild Cognitive Impairment (PwMCI) and their care partners (CPs).MethodThis investigation was a secondary analysis, using baseline data of a randomized controlled trial of amyloid PET results disclosure. Multiple linear regression modeling was used to examine predictors of decisional capacity, measured by the University of California, San Diego Brief Assessment of Capacity to Consent (UBACC). Focusing on PwMCI (n = 82), the predictor variables of interest were sociodemographic characteristics, and level of knowledge on MCI/AD and normal aging, global cognition measured by Mini Mental Status Exam (MMSE), and neuropsychological tests of language and executive functioning. Dyadic analyses were conducted with CP data (n = 82), using the Actor Partner Interdependence Model (APIM) to assess for presence of partner effects among key variables.ResultParticipants and CPs were mostly White (91.5%, 90.2%), highly educated (16.5, 15.5 years on average), with mean age 72.7 and 66.8 years, respectively. CPs tended to be female, and spouses of the participants (70.7%). MMSE scores (b = 0.215, SE = 0.082, p = 0.011) and MCI/AD knowledge scores (b = 0.241, SE = 0.101, p = 0.020) positively predicted decisional capacity for PwMCI. Dyadic analysis using APIM showed that level of MCI/AD knowledge (p = 0.019) and level of education (p<0.001) were highly correlated within the dyad. Furthermore, analyses revealed significant positive correlations for MCI/AD knowledge for actor relations for decisional capacity for both the participant (a11 = 0.328, p = 0.005) and the CP (a22 = 0.262, p = 0.025). CP’s level of MCI/AD knowledge had a negative association for partner effects for decisional capacity (p21 = ‐0.207, p = 0.043) of the PwMCI.ConclusionAssessment of decisional capacity is imperative when considering participation in AD research, including biomarker studies involving results disclosure. Our findings highlight that not only do individual characteristics put PwMCI at risk for lower decisional capacity, but dyadic effects from their CPs may also be present.

Longitudinal Locus Coeruleus Imaging across the Alzheimer’s Spectrum

AbstractBackgroundNoradrenergic neurons of the locus coeruleus (LC) may play a critical role in the pathophysiology of Alzheimer’s Disease (AD). LC imaging with MRI is a promising in vivo method to study the role of this system in AD. Here we investigate longitudinal change in LC integrity across the AD spectrum.MethodThis study included 291 participants from the TRIAD cohort at the McGill Research Center for Studies in Aging (cognitively normal: n = 166, mild cognitive impairment: n = 79, AD: n = 46). Follow‐up data was available for 123 participants. All participants underwent MR imaging including a turbo spin echo (TSE) sequence for LC imaging, tau positron emission tomography (using [18F]MK6240), and clinical and cognitive assessment including the Mini Mental State Exam (MMSE). LC signal contrast was assessed relative to a pontine reference region. Linear regression analyses related LC signal to clinical measures.ResultConsistent with prior work in an earlier version of this sample, at baseline, LC signal was reduced in tau positive participants (t(285) = ‐4.56, p<0.0001) and negatively correlated to AD severity (Braak stage: t(253) = ‐4.79, p<0.0001; MMSE score: t(254) = 4.30, p<0.0001). There was no significant change in LC signal over time (t(122) = 1.36, p = 0.18) and no significant impact of tau status on LC change (t(119) = 0.39, p = 0.70). Counterintuitively, there was evidence of increasing LC signal in the most severe participants, as those with low MMSE score (<27) showed a significant signal increase over time (t(16) = 2.16, p = 0.046). Moreover, increasing LC signal in tau positive participants was correlated to reduction in MMSE performance over time (t(35) = ‐2.13, p = 0.040). In contrast, tau negative participants showed the opposite trend (t(52) = 1.97, p = 0.054).ConclusionWhile cross‐sectional analyses found the expected negative correlation between LC signal and AD severity, longitudinal analyses obtained the surprising result that increasing signal correlated to worsening AD severity. This finding could suggest that the LC imaging sequence used (TSE) may imperfectly capture LC degeneration and signal increases could be driven by other factors occuring simultaneously with LC degeneration (perhaps elevated neuromelanin or tau deposition). Future work could determine if different types of LC sequence (TSE versus magnetization transfer) differ in their ability to capture degeneration and provide complementary information.

APOE4 Carrier Status Modifies Alzheimer’s Disease Plasma Biomarker Concentrations in Healthy Adults Over 85 Years Old

AbstractBackgroundMany blood‐based biomarkers have been thoroughly investigated in the context of Alzheimer’s disease (AD) and other dementias. However, few studies have examined these biomarkers in healthy seniors in the absence of dementia or other age associated morbidities. Investigating biomarkers in a healthy geriatric population allows for the identification of novel biological associations that might otherwise be masked by presence of disease. This study will investigate the effect of APOE genotype on plasma biomarkers of AD to determine whether carrying the APOE4 allele, which increases risk of AD, modifies biomarker concentrations in healthy seniors. Plasma biomarkers analyzed include: amyloid beta 42/40 (Aβ42/40), phosphorylated tau‐181 (p‐tau‐181), neurofilament light (NF‐L), and glial fibrillary acidic protein (GFAP).Methods370 plasma specimens from the Super Seniors study, which enrolled participants ≥85 years old who have never been diagnosed dementia, cancer, diabetes, cardiovascular or major pulmonary disease; were used. Biomarkers were analysed on the Quanterix Simoa HD‐X analyzer using commercial Neurology 4‐plex E and p‐tau‐181 assays. Group comparisons were performed using a Mann‐Whitney test for continuous variables and a Fisher’s exact test for categorical variables. The association between APOE genotype and biomarker concentration was analyzed using multivariable linear regression.Results80 (22%) participants were APOE4 carriers (E3E4 N = 71, E4E4 N = 3, E2E4 N = 6) and 290 (73%) were non‐carriers (E2E2 N = 3, E2E3 N = 58, E3E3 N = 229). No significant differences were found between APOE4 carriers and non‐carriers in age (p = 0.3215), sex (p>0.9999), or mini mental state exam scores (p = 0.1327). In APOE4 carriers, Aβ42/40 is lower (0.0596 vs 0.0618 pg/ml, p = 0.0462), and p‐tau‐181 (3.24 vs 2.78 pg/ml, p = 0.0069) and GFAP (196 vs 172 pg/ml, p = 0.0474) are higher than in non‐APOE4 carriers. NF‐L had no significant difference between carrier status (p = 0.1188). After adjusting for age and sex, p‐tau‐181 remains significantly associated with APOE4 carrier status (β = 0.066, p = 0.0112), while Aβ42/40 and GFAP no longer have significant associations.Conclusionsp‐tau‐181 concentration is associated with APOE4 genotype in healthy seniors, making it an important variable to account for in future analysis.

Microglial activation interacts with amyloid‐β to drive longitudinal tau tangle accumulation and cognitive decline

AbstractBackgroundActivation of microglial cells in the brain, more commonly known as neuroinflammation, has often been linked to the pathophysiology of Alzheimer’s disease (AD). However, how microglial activation is associated with longitudinal tau tangle accumulation and consequent cognitive decline is poorly understood. Here, we aimed to investigate whether baseline microglial activation impacts tau tangle deposition and cognitive decline in individuals across the AD continuum.MethodWe assessed 92 individuals from the TRIAD cohort (57 cognitively unimpaired and 35 cognitively impaired) with available baseline [11C]PBR28‐PET, a measure of microglial activation and [18F]NAV4694 Aß‐PET, and longitudinal [18F]MK6240 Tau‐PET (mean follow‐up time = 1.93 years) and Mini‐Mental State Exam (MMSE) (mean follow‐up time = 1.84 years). We performed voxel‐wise associations using linear regressions accounting for age and sex and adjusted for multiple comparisons using Random Field Theory (RFT) (p < 0.05). We used the cuneus and superior temporal cortex as a composite ROI for [11C]PBR28‐PET and Aß‐PET since these regions showed a higher association with longitudinal tau accumulation in the temporal meta‐ROI.ResultVoxel‐wise analysis showed that baseline levels of [11C]PBR28‐PET alone are not sufficient to predict longitudinal tau tangle accumulation (Fig. 1a). However, the interaction between [11C]PBR28‐PET levels and Aß burden predicted an increased accumulation of tau tangle, mainly in the cuneus, inferior frontal and lateral occipital regions (Fig. 1b).Individuals with higher baseline [11C]PBR28‐PET and Aß‐PET levels present higher rates of longitudinal tau accumulation in the temporal meta‐ROI (ß = 0.36, t = 3.46, p = 0.0009; Fig. 1c). Similarly, while [11C]PBR28‐PET levels alone did not correlate with longitudinal changes in MMSE score (ß = ‐0.17, t = ‐1.69, p = 0.10), a significant interaction between [11C]PBR28‐PET and Aß‐PET levels on MMSE annual decline was observed (ß = ‐0.24, t = ‐2.25, p = 0.028; Fig. 1d).ConclusionWe found that baseline levels of microglial activation was associated with longitudinal tau tangle accumulation and cognitive decline in individuals across the AD continuum in the presence of Aß burden. Our results indicate that microglial activation might act potentiating the deleterious effects of Aß on forthcoming tau tangle deposition.

Alzheimer’s Disease (AD): Vitamin B12 deficiency is associated with lower Mini‐Mental State Exam (MMSE) scores

AbstractBackgroundAlzheimer’s Disease (AD) is the leading cause of dementia in the elderly and several lines of evidence indicate that B12 hypovitaminosis is linked to AD. The biochemical pathways involved in AD that are affected by vitamin B12 are APP processing, Aβ fibrillization, Aβ‐induced oxidative damage as well as tau hyperphosphorylation and tau aggregation.Method103 outpatients with the diagnosis of AD conforming to criteria proposed by NINCDS‐ADRDA (2011), followed‐up at a public university hospital, had their vitamin B12 levels assessed and MMSE scores evaluated.Result91 patients (88,35%) presented vitamin B12 normal range (200 – 800 pg/mL) and 12 patients (11,65%) presented vitamin B12 deficiency (≤ 200 pg/mL). From the normal range group, 13 patients (14,29%) presented severe cognitive impairment (MMSE < 10), 33 patients (36,26%) presented moderate cognitive impairment (MMSE = 10 – 20) and 45 patients (49,45%) presented mild cognitive impairment (MMSE > 20). From the deficiency group, 2 patients (16,8%) presented severe cognitive impairment, 5 patients (41,6%) presented moderate cognitive impairment and 5 patients (41,6%) presented mild cognitive impairment. Both groups, vitamin B12 normal range and deficiency, had on average the same educational level: 2,91 and 3,42 years, respectively.ConclusionIn this sample of patients with AD, B12 hypovitaminosis is associated with lower MMSE scores when compared to vitamin B12 normal range.

The Association Between Street Network Accessibility and Cognitive Impairment

AbstractBackgroundAccess to different amenities has been hypothesised to reduce the risk of cognitive impairment in older adults. Literature in urban planning shows that a well‐connected street network enables access to amenities, however, the role of street network accessibility has not been studied extensively in relation to cognitive function. The aim of this study is to investigate the cross‐sectional relationship between street network accessibility and cognitive impairment in older people in England, UK.MethodThe baseline data from the Cognitive Function and Ageing Study (CFAS) II (2008‐2011), a cohort study of people aged 65+ across three areas in England, was used (N = 7485) excluding 144 housebound participants. Cognitive impairment was defined by the Mini Mental State Exam (MMSE) score: mild‐severe (MMSE<26) and moderate‐severe (MMSE<21). Using Geographical Information System (GIS) data, proximity to a main road was represented by betweenness centrality (shortest routes corresponding to high potential of through movement) of the street network, using normalised angular choice (NACH ‐ range of 0‐1.5, with 0.9+ meaning a main road). Mean NACH was calculated within 300m walk of participants’ postcode centroid and categorised into tertiles (low = NACH<0.8, medium = NACH 0.8‐0.9, high = NACH>0.9). Logistic regression was used to investigate the relationship between proximity to a main road, the risk of mild‐severe and moderate‐severe cognitive impairment adjusting for age, sex, education, and area deprivation.ResultThe prevalence was 24% for mild‐severe cognitive impairment and 7.3% for moderate‐severe cognitive impairment. Compared to those living at low proximity from a main road, those who lived at medium (OR 0.817 95% CI [0.716, 0.932]) and high proximity (OR 0.756 95% CI [0.662, 0.863]) had lower risk of mild‐severe cognitive impairment. The adjusted associations remained similar (OR 0.771 95% CI [0.671, 0.886] for medium proximity, OR 0.755 95% CI [0.656, 0.869] for high proximity). Proximity to a main road was not associated with moderate‐severe cognitive impairment.ConclusionThe results suggest evidence for the role of proximity to a main road in reducing the risk of mild‐severe cognitive impairment in non‐housebound individuals, but not moderate‐severe cognitive impairment. More research is needed on other aspects of street network accessibility.

Involvement of single nucleotide polymorphisms of junction adhesion molecule with small vessel vascular dementia.

It is now recognized that blood brain barrier (BBB) leakage occurs in cerebral small vascular disease (CSVD) and plays a significant role in the pathophysiology of vascular dementia. We hypothesized that genetic polymorphisms of junctional adhesion molecule-A (JAM-A) (which may result in compromised structure of tight junction proteins that form the BBB) in combination with cerebrovascular risk factors hypertension, lipid disorders, and type 2 diabetes may result in BBB leakage and increase the individual's risk of CSVD-related dementia. In this case-control study, 97 controls with a mean Mini-Mental State Exam (MMSE) score of 29 and 38 CSVD-related vascular dementia participants (mean MMSE score of 19) were recruited. Bloods were collected for the analysis of two common single nucleotide polymorphisms (SNPs) of the JAM-A genotypes rs790056 and rs2481084 using real-time polymerase chain reaction (PCR) assay. Medical history of hypertension, hyperlipidemia, and diabetes was collected for all participants. Polymorphisms of genotype JAM-A SNP rs790056 showed statistically significant result when the subgroup with hyperlipidemia was analyzed (OR = 3.130, p = 0.042 for TC + CC genotypes with hyperlipidaemia vs controls). Similar result was found with diabetes (OR = 4.670, p = 0.031 for TC + CC genotypes vs controls). No significant result was found with hypertension. Borderline results of statistical significance were found for JAM-A SNP rs2481084 with hyperlipidemia (OR = 3.210, p = 0.054 for TC + CC genotypes vs controls) and with diabetes (OR = 3.620, p = 0.069 for TC + CC genotypes vs controls) but not for hypertension. The borderline results might have been due to lack of statistical power because of small sample size. These results lend further support that cerebrovascular risk factors interact with genetic polymorphisms of BBB proteins to increase the risk of vascular dementia.

Neuronal pentraxin‐2 by Simoa ‐ a potential synaptic biomarker in Alzheimer’s disease

AbstractBackgroundSynaptic dysfunction and degeneration are believed to be among the earliest and most reliable indicators of cognitive impairment in neurodegenerative disorders, including Alzheimer’s disease (AD). Discovering and verifying novel biomarkers that can quantify synaptic degeneration and serve as prognostic indicators would be valuable to track cognitive decline in clinical and drug trial settings. By using mass spectrometry, we have studied a panel of 17 synaptic proteins as potential biomarkers for AD and a broad range of neurodegenerative disorders. Of these proteins, neuronal pentraxin‐2 (NPTX2) has shown great promise as a synaptic biomarker, showing a decrease in symptomatic disease. Therefore, we aimed to develop a Single molecule array (Simoa) for NXPT2, a method more suited for routine clinical assessment than mass spectrometry‐based workflows.MethodWe developed an in‐house NPTX2 Simoa assay on the HD‐X platform (Quanterix) with paramagnetic beads coupled with a rabbit monoclonal capture antibody (EPR24020‐38, Abcam) and biotinylated rabbit monoclonal detector antibody (EPR15618, Abcam), both specifically targeting NPTX2. Full‐length recombinant NPTX2 (7816‐NP‐050, Biotechne) was used as the calibrator. Using the assay, we analyzed 55 healthy controls (78.0 (6.5 SD) years) and 54 AD patients (73.5 (7.0 SD) years) using 2 uL cerebrospinal fluid (CSF) in the BioFINDER pilot study. Group comparisons were performed using the Wilcoxon rank sum test and linear models adjusted for age and sex were used to assess associations of NPTX2 protein levels with cognitive function (mini mental status exam (MMSE)) and with neuroimaging, e.g., Aβ‐PET, tau‐PET (temporal ROI, Braak I‐IV) as well as cortical thickness in an AD signature composed of temporal regions in the AD group.ResultCSF NPTX2 concentration was found to be lower in AD compared with controls (p = 0.017, Figure). Lower NPTX2 concentration was associated with greater tau PET SUVR (β(SD) = ‐0.25(0.079), p‐value = 0.0027) and cortical thickness atrophy (β(SD) = 0.075(0.024), p‐value = 0.0034)) but not with amyloid‐β PET SUVR. Lower NPTX2 concentration was also associated with lower MMSE score (β(SD) = 2.62 (0.75), p‐value = 0.0010).ConclusionWe have successfully developed a Simoa assay of a novel CSF biomarker, NPTX2. This semi‐automated method allows for large‐scale evaluation of NPTX2, a leading candidate for synaptic degeneration in neurodegenerative disorders.

A Randomized, Double‐blind, Sham‐controlled, Adaptive‐Design Pivotal Trial of Sensory Stimulation in Subjects with Alzheimer’s Disease

AbstractBackgroundIn three prospective clinical trials (Overture: NCT03556280, Etude: NCT03661034, Flicker: NCT03543878) non‐invasive, visual and auditory gamma (40 Hz) sensory stimulation diminished Alzheimer’s disease (AD) symptoms, including a reduction in decline in cognitive and functional symptoms. These trials initiated the design of the Cognito Therapeutics sponsored Hope pivotal trial which examines the safety and efficacy of Cognito Therapeutics’ Sensory Stimulation System.MethodThe US‐based multicenter Hope trial will randomize (1:1) approximately 500 subjects aged 50 and older diagnosed with mild to moderate AD (MMSE 15‐26) and will stratify them to active and sham in a blinded manner across MMSE score ranges: 15‐20 and 21‐26. Subjects in both study arms will self‐administer therapy via the Sensory Stimulation System for 60 minutes daily for 12 months. An interim analysis will employ the promising zone methodology, allowing the sample size to be adjusted if the effect is trending toward success, but additional subjects are needed to maintain greater than 80% power.ResultThe primary outcome measure will be the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS‐ADL) test. Changes in function and cognition will be evaluated using a combined statistical test for ADCS‐ADL and the Mini Mental State Exam (MMSE). The key secondary outcome is change in cognition using the MMSE. Other clinical efficacy assessments include instrumental activities of daily living (IADL), Zarit Burden Index (ZBI), the Clinical Dementia Rating Scale (CDR) and The Neuropsychiatric Inventory anxiety subscale (NPI – Anxiety). Key biomarker assessments include whole brain, white matter, and hippocampal volume and occipital cortical thickness. Sleep fragmentation will be assessed in a subgroup of subjects using actigraphy. Exploratory measures will include additional brain structural change, plasma biomarkers, EEG assessed coherence, and at‐home tablet‐based tasks. Safety will be evaluated via routine clinical laboratory assessments, review of adverse events, concurrent medication use, physical and neurological exams, vital signs, MRI, and a suicidality scale.ConclusionThe Hope pivotal trial is designed to demonstrate the efficacy and safety of daily in‐home gamma sensory stimulation in AD patients to support a regulatory filing with the FDA.

55 Tracking Cognitive Change in Huntington’s Disease with the Mini Mental State Exam and the Montreal Cognitive Assessment

Objective:To assess the utility of the Mini Mental State Exam (MMSE) and Montreal Cognitive Assessment (MoCA) for tracking cognitive changes Huntington’s Disease.Participants and Methods:Currently, the most frequently used brief assessment of global cognitive functioning is the MMSE. Although the MMSE is helpful for distinguishing individuals without significant cognitive impairment from those with dementia, it is not particularly sensitive to more subtle cognitive deficits. The MoCA is another brief cognitive screening tool that has been shown to be more sensitive to mild impairment and may have greater usefulness in subcortical dementias because of its more extensive assessment of executive function. Although the MoCA appears to have high sensitivity and specificity in a variety of neurological populations, there is currently little known about its efficacy in tracking cognitive decline in individuals with HD. We used a mixed effects model to analyze MMSE and MoCA scores collected prospectively during 5 years of follow-up for 163 patients with HD seen at one academic HDSA Center of Excellence. Baseline mean age for the HD cohort was 51.35 years, mean education 14.46 years, and a mean CAG repeat length 43.95. Mean follow-up time was 3.33 years.Results:Mean MMSE and MoCA scores at baseline were 25.13 (SD=1.66) and 22.76 (SD=3.70) respectively. At baseline, age and gender were not associated with MMSE and MoCA scores, while years of education were. Neither age nor gender predicted rate of decline for the MoCA while years of education predicted rate of decline for the MMSE. For the MMSE, each year of education predicted on average 0.51 points higher score at enrollment; for the MoCA, each year of education predicted on average 0.79 points higher score at enrollment. The mean rates of decline on the MMSE was 0.48 points per year (p<.001) while that on the MoCA was only 0.31 points annually (p<.001) in the first five years of observation.Conclusions:The MMSE and MoCA decline significantly over time in an unselected HD population. The smaller rate of decline in the MoCA may be due, in part, to the greater variability in baseline, MoCA (SD=3.70) vs MMSE (SD=1.66) scores in our HD cohort. Unlike cortical dementias, such as Alzheimer’s disease (AD), where declines of 2-3 points per year have been described for the MMSE and MoCA, much lower annual rates of decline have been reported in subcortical dementias such as Parkinson’s disease. To our knowledge, this is the first report of rate of cognitive decline on the MMSE and MoCA in HD: such information is vital for adequately preparing patients and families for future needs, in addition to planning for interventional/treatment trials in HD.

79 Brief Subjective Memory Screener Predicts Memory Dysfunction

Objective:Alzheimer’s disease (AD) is expected to affect over 7 million older Americans by 2025. Development of fast and inexpensive screening measures for routine screening is critical for identifying those suffering from the earliest stages of AD including Mild Cognitive Impairment (MCI) and Subjective Cognitive Decline (SCD). Here we assess the validity and utility of a brief, 5-item SCD screener and its associations with neuropsychological performance as compared to an existing objective cognitive screener, the Mini Mental Status Exam (MMSE).Participants and Methods:Development: A brief, 5-item SCD questionnaire was developed based on a more extensive 20-item version previously validated (Chapman et al. 2021). Participants: 27 cognitively diverse (MCI and cognitively normal) community dwelling older adults were recruited for this study. Mean age: 71.9 ± 7. Inclusion criteria include memory concerns. Exclusion criteria include no previous diagnoses of neurodegenerative diseases and/or major stroke. Administration: Participants completed a brief, 5-item SCD screener along with cognitive testing including the MMSE and a clinically validated list-learning test, the Selective Reminding Test (SRT). Statistical Methods: Spearman 2-tailed correlations were conducted to assess the relationship between the two screening measures, and their relationships to the SRT. Outcome measures on the SRT included total recall (max: 72) and delayed recall (max: 12). All cognitive measures were demographically adjusted with normative data.Results:The mean total for the SCD screener was 2.1 ±1.1, and the mean MMSE score was 29.2 ± 1.2. The SCD screener was associated with MMSE scores (r= -.39, p= .043), SRT Total Recall (r= -.43, p= .024) and Delayed Recall (r=-.42, p=.031) measures. MMSE scores did not associate with either SRT outcome (p>.05).Conclusions:Results support the utility and validity of a brief subjective cognitive decline screener for identifying those who may be experiencing memory dysfunction. The brief SCD screener outperformed the MMSE, an existing and widely used objective screening measure. Associations between the SCD screener and SRT outcomes support the validity and utility of the brief screener and recapitulate previous findings with the more extensive version of the SCD questionnaire (Chapman et al. 2021). Ongoing research is focusing on the utility of the screener in frontline clinical settings and translation of the screener into Spanish.

H - 45 Preliminary Teleneuropsychological Normative Data for the Mini Mental State Examination for Puerto Rican Adults.

Established guidelines for teleneuropsychology (TeleNP) indicate that normative studies are warranted for future regular use of TeleNP practice (Bilder et al., 2020). Consequently, this study aims to explore the impact of demographic factors to provide preliminary normative data for the Mini Mental State Exam (MMSE) via TeleNP for Spanish-speaking Puerto Ricans. A TeleNP version of the MMSE was administered as part of a larger neuropsychological battery to 102 cognitively healthy Puerto Ricans (69% female) between 55-78years old, 4-23years of education (Age: M = 63.2, SD = 6.1; Education: M = 16.3, SD = 3.5) and residing on the island. A thorough neurological/psychiatric history and the CERAD Wordlist were used to exclude (< 2 SD; 1 removed case) any dementia-suspicious case. Multiple regression analysis was used to clarify if age, education, or sex significantly predicted MMSE total score. Normative data was generated and stratified by statistically significant demographics. Frequency of the most missed item was reviewed. Age and education explained 26% of the variance of the MMSE score (p < 0.001). The total sample had an average raw score of M = 29.08 (SD = 1.16). Normative scores are presented according to age and education level. Most frequently missed item was delayed recall (35%; ≤2/3). This study provides preliminary normative data for cognitively healthy and community-dwelling Puerto Rican adults, which can improve diagnostic accuracy and reduce rates of false negatives while providing clinicians a TeleNP-appropriate screening tool. Future research with the MMSE via TeleNP should include a larger sample, including a clinical population.

Multifactorial assessment of Parkinson's disease course and outcomes using trajectory modeling in a multiethnic, multisite cohort - extension of the LONG-PD study.

The severity, progression, and outcomes of motor and non-motor symptoms in Parkinson's disease (PD) are quite variable. Following PD cohorts holds promise for identifying predictors of disease severity and progression. PD patients (N = 871) were enrolled at five sites. Enrollment occurred within 5 years of initial motor symptom onset. Disease progression was assessed annually for 2-to-10 years after onset. Group-based trajectory modeling was used to identify groups differing in disease progression. Models were developed for UPDRS-III scores, UPDRS-III tremor and bradykinesia-rigidity subscores, Hoehn & Yahr (H&Y) stage, Mini-Mental Status Exam (MMSE) scores, and UPDRS-III, H&Y and MMSE scores considered together. Predictors of trajectory-group membership were modeled simultaneously with the trajectories. Kaplan-Meier survival analysis evaluated survival free of PD outcomes. The best fitting models identified three groups. One showed a relatively benign, slowly progressing trajectory (Group 1), a second showed a moderate, intermediately progressing trajectory (Group 2), and a third showed a more severe, rapidly progressing trajectory (Group 3). Stable trajectory-group membership occurred relatively early in the disease course, 5 years after initial motor symptom. Predictors of intermediate and more severe trajectory-group membership varied across the single variable models and the multivariable model jointly considering UPDRS-III, H&Y and MMSE scores. In the multivariable model, membership in Group 2 (28.4% of patients), relative to Group 1 (50.5%), was associated with male sex, younger age-at-onset, fewer education-years, pesticide exposure, absence of reported head injury, and akinetic/rigid subtype at initial presentation. Membership in Group 3 (21.3%), relative to Group 1, was associated with older age-at-onset, fewer education-years, pesticide exposure, and the absence of a tremor-predominant subtype at initial presentation. Persistent freezing, persistent falls, and cognitive impairment occurred earliest and more frequently in Group 3, later and less frequently in Group 2, and latest and least frequently in Group 1. Furthermore, autonomic complications, dysphagia, and psychosis occurred more frequently in Groups 2 and 3 than in Group 1. Modeling disease course using multiple objective assessments over an extended follow-up duration identified groups that more accurately reflect differences in PD course, prognosis, and outcomes than assessing single parameters over shorter intervals.

Socio-Clinical factors associated with Parkinson's disease-related specific self-management behaviours.

To test associations between socio-clinical factors, self-management and patient activation among patients with Parkinson's disease (PD), and to explore the use of regression tree to find the cut-off levels of socio-clinical factors which associate with lower or higher self-management behaviours and patient's activation. A cross-sectional study of patients with PD (n = 62) who underwent assessment of their socio-clinical factors including age, gender, cognitive status, comorbidities, disease severity (motor and non-motor symptoms) and social support. The associations of these factors to specific aspects of self-management behaviours including utilization of rehabilitative treatments, physical activity and patient activation were tested. Most patients did not utilize rehabilitative treatments. Non-motor symptoms and cognitive status were significantly associated with physical activity (R2 = 0.35, F(3, 58) = 10.50, p < 0.001). Non-motor symptoms were significantly associated with patient activation (R2 = 0.30, F(1, 30) = 25.88, p < 0.001). Patients with Mini-Mental State Exam score ≤24 performed less physical activity, relative to those with a higher score. Patients with ≤5 non-motor symptoms showed higher activation relative to those with >5. In PD, disease-specific clinical characteristics overshadow other personal factors as determinants of self-management behaviours. The role of non-motor symptoms in reduced self-management behaviours and activation is highlighted.

Using artificial intelligence to learn optimal regimen plan for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological disorder with no specific curative medications. Sophisticated clinical skills are crucial to optimize treatment regimens given the multiple coexisting comorbidities in the patient population. Here, we propose a study to leverage reinforcement learning (RL) to learn the clinicians' decisions for AD patients based on the longitude data from electronic health records. In this study, we selected 1736 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We focused on the two most frequent concomitant diseases-depression, and hypertension, thus creating 5 data cohorts (ie, Whole Data, AD, AD-Hypertension, AD-Depression, and AD-Depression-Hypertension). We modeled the treatment learning into an RL problem by defining states, actions, and rewards. We built a regression model and decision tree to generate multiple states, used six combinations of medications (ie, cholinesterase inhibitors, memantine, memantine-cholinesterase inhibitors, hypertension drugs, supplements, or no drugs) as actions, and Mini-Mental State Exam (MMSE) scores as rewards. Given the proper dataset, the RL model can generate an optimal policy (regimen plan) that outperforms the clinician's treatment regimen. Optimal policies (ie, policy iteration and Q-learning) had lower rewards than the clinician's policy (mean -3.03 and -2.93 vs. -2.93, respectively) for smaller datasets but had higher rewards for larger datasets (mean -4.68 and -2.82 vs. -4.57, respectively). Our results highlight the potential of using RL to generate the optimal treatment based on the patients' longitude records. Our work can lead the path towards developing RL-based decision support systems that could help manage AD with comorbidities.

"Mmm, Smells like Coffee!": How a Brief Odor Identification Test Could Help to Identify People with Mild Cognitive Impairment and Dementia.

(1) Background: Dementia and mild cognitive impairment (MCI) are still underdiagnosed in the general population. Impaired odor identification has been identified as an early marker of MCI and dementia. We aimed to compare the additional diagnostic value of two odor identification tests to a cognitive screening test in detecting MCI or dementia. (2) Methods: The Sniffin' Sticks odor identification test (SS-OIT), a brief odor identification test (B-OIT) requiring the identification of coffee scent, and the Mini-Mental State Exam (MMSE) were administered to a consecutive series of 174 patients (93 with dementia, 42 with mild cognitive impairment, and 39 without cognitive impairment) referred for neuropsychological testing. (3) Results: Both participants with dementia and with MCI exhibited impairments in odor identification. The SS-OIT and the B-OIT were substantially correlated. Complementing MMSE scores with the SS-OIT or the B-OIT similarly improved the diagnostic accuracy of individuals with dementia and MCI. (4) Conclusions: People with suspected dementia or MCI may already benefit from brief odor identification tests. Although these tests require little additional time, they can notably increase sensitivity for dementia or MCI.

Fall-Risk-Increasing Drugs and Gait Performance in Community-Dwelling Older Adults: Exploratory Results from the Gait and Brain Study.

While several psychotropic and cardiovascular drugs have been identified as fall-risk-increasing drugs (FRIDs) in older adults, the intervening mechanisms linking FRIDs and falls are unclear. It is plausible that gait performance is an intermediate variable on the causal pathway between FRIDs and falls. The current evidence on the relationship between medication use and gait performance in older adults is scarce. We aimed to assess the association between FRIDs and gait performance in community-dwelling older adults. This was a cross-sectional analysis using data from the Gait and Brain Study, a study of community-dwelling older adults aged 65years old and over (N=345). The following drug classes were assessed: antidepressants, benzodiazepines, alpha-blockers, beta-blockers, vasodilators, diuretics, statins and aspirin. Medication use was ascertained through validated questionnaires and electronic medical records. Multiple linear regression models were used to assess the association between each of the drug classes and gait speed and gait variability. Gait variability was expressed as the coefficient of variation (CV=mean/standard deviation) of stride time. Models were adjusted for age, sex, education, body mass index (BMI), mini-mental status exam (MMSE) score, Geriatric Depression Scale (GDS) score, general activity level, use of other FRIDs and comorbidity propensity score. Diuretic use was associated with significantly reduced gait speed (B=-7.97cm/s, 95% CI: -13.94, -2.00, P=0.009). Statin use was associated with significantly increased stride time CV (B=0.13, 95% CI: 0.02, 0.24, P=0.026). Other drugs did not have a statistically significant relationship with gait speed or variability. The association between diuretic use and reduced gait speed is consistent with existing evidence on diuretic use and increased fall risk. The association between statins and increased stride time variability is notable given inconclusive evidence in previous studies. Our results provide initial estimates of the association between FRIDs and gait performance in older adults for future longitudinal studies.

1520-P: Metabolic Dysregulation in Probable Alzheimer’s Disease

Insulin resistance, T2D, and chronic inflammation increase risk of developing mild cognitive impairment and Alzheimer’s disease (AD). We report here baseline data from a multicenter, randomized, placebo-controlled Phase 3 study (NCT04669028) in patients with mild to moderate AD evaluating the effects of NE3107, an oral small molecule, blood-brain permeable anti-inflammatory insulin sensitizer that binds extracellular signal-regulated kinase. Inclusion criteria are diagnosis and progression of AD, supportive brain scan and Hachinski scale to exclude vascular dementia, Clinical Dementia Rating (CDR) score of 1-2, and Mini Mental State Exam (MMSE) score of 14-24. Primary outcomes are changes in cognition and function from baseline to 30 wks. Secondary outcomes include changes in neuropsychological deficits, functional performance, and regulation of glycemia. Aβ+ subjects were older and had worse MMSE, ADAS-Cog12 and AD Composite Scores than Aβ-patients, but had less evidence of inflammation (lower CRP) and less insulin resistance (lower fasting glucose, less IFG and T2D, lower fasting insulin and HOMA2-IR, and less hypertension) (Table). Metabolic dysregulation (elevated C1q, increased CGM mean and MAGE, increased cholesterol, triglycerides, and waist-hip ratio) was also observed independent of Aβ and APOEε4 status. Inflammation and insulin resistance may contribute to AD even in the absence of classical risk markers for AD. Disclosure C.L.Reading: Employee; BioVie, Inc. C.Ahlem: Employee; Biovie, Inc. J.M.Palumbo: Employee; BioVie, Zynerba, Other Relationship; Merck Sharp &amp; Dohme Corp. M.A.Testa: Stock/Shareholder; Phase V Technologies, Inc. D.C.Simonson: Stock/Shareholder; Phase V Technologies, Inc., GI Windows.

Comparing Mini‐Mental Status Exam baseline data of cognitively normal individuals who declined to Alzheimer’s disease versus cognitively normal non‐decliners in the SIU Longitudinal cognitive aging study

AbstractBackgroundThe Mini‐Mental Status Exam (MMSE) is one of the most commonly used cognitive screening measures for diagnosing cognitive impairment in older adults. In the present study, we examined whether or not there were baseline differences in MMSE scores between cognitively normal individuals who developed Alzheimer’s disease over time (decliners) versus individuals who did not decline over time (non‐decliners).MethodWe included 67 participants who were administered the MMSE during a baseline assessment. All participants were enrolled in the SIU Longitudinal Cognitive Aging Study (SIU LCAS) as controls who were free of cognitive impairment at their baseline visits. Participants were divided into two groups (decliners versus non‐decliners). There were 25 participants in the decliner group and 39 participants in the non‐decliner group. Average age of decliners was 70.84, while average age of non‐decliners was 71.67. Average education of decliners was 15.76 years, while average education of non‐decliners was 16.49 years. The ratio of females to males was 4:1 among decliners and 1.6:1 among non‐decliners. A two‐sample t‐test was used to examine differences between the two groups with respect to their baseline MMSE scores.ResultThe decliner group (mean age = 70.8) was significantly younger than the non‐decliner group (mean age = 71.7). There were no significant differences between the two groups for education or gender distribution. 11 decliners had autopsy confirmed AD, while 14 decliners had AD diagnosis without autopsy. There were 5 individuals in the non‐decliner group with no evidence of AD pathology on autopsy. The decliner group had significantly lower baseline MMSE scores compared to the non‐decliner group (p &lt; 0.05). MMSE scores for decliners compared to non‐decliners using WORLD backwards was 28.96 versus 29.44, respectively, and was 28.32 versus 28.85, respectively, when using serial 7’s.ConclusionThe results of the present study indicate that there are subtle differences in baseline MMSE scores (approximately 0.5 points) in older adults who decline to AD compared to older adults who remained cognitively normal. More studies with larger sample sizes, including more participants with brain autopsy, are needed to confirm these findings.

Alzheimer’s Disease (AD): High cholesterol is associated with lower Mini‐Mental State Exam (MMSE) scores

AbstractBackgroundAlzheimer’s Disease (AD) is the leading cause of dementia in the elderly. The epsilon 4 allele of the apolipoprotein E gene that encodes the major brain lipid carrier and metabolic disorders, such as obesity and type 2 diabetes, were identified as AD risk factors, suggesting that abnormal lipid metabolism could influence the progression of the disease. Additionally, lowering cholesterol is associated with reduced central nervous system (CNS) amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies.Method154 outpatients with the diagnosis of AD conforming to criteria proposed by NINCDS‐ADRDA (2011), followed‐up at a public university hospital, had their cholesterol levels assessed and MMSE scores evaluated.Results90 patients (58,44%) presented high cholesterol (total cholesterol level ≥ 190 mg/dL and/or LDL level ≥ 130 mg/dL) and 64 patients (41,56%) presented cholesterol normal range (total cholesterol level &lt; 190 mg/d L and/or LDL level &lt; 130 mg/dL). From the high cholesterol group, 10 patients (11,11%) presented severe cognitive impairment (MMSE &lt; 10), 50 patients (55,55%) presented moderate cognitive impairment (MMSE = 10 – 20) and 30 patients (33,34%) presented mild cognitive impairment (MMSE &gt; 20). From the cholesterol normal range group, 5 patients (7,81%) presented severe cognitive impairment, 19 patients (29,69%) presented moderate cognitive impairment and 40 patients (62,5%) presented mild cognitive impairment. Both groups, high cholesterol and cholesterol normal range, had on average the same educational level: 2,91 and 3,42 years, respectively.ConclusionIn this sample of patients with AD, high cholesterol is associated with lower MMSE scores when compared to cholesterol normal range.