Meaningful benefit of disease-modifying treatment: Evaluating changes in health-related resource use.

INTRODUCTION: Are reductions in the rate of decline from the new disease-modifying treatments (DMTs) in early Alzheimer's disease (AD) meaningful? We examined whether such reductions may be reflected in changes in health-related resource use. METHODS: Patients with Clinical Dementia Rating (CDR) = 0.5 or 1 with a clinical diagnosis of mild cognitive impairment or AD, reflecting clinical trial populations. Health-related resource use was reported using the Resource Use Inventory (RUI) including direct medical care, non-medical care, unpaid informal care, and time use. RESULTS: Faster decline in CDR-Sum of Boxes (CDR-SB) from baseline was independently associated with higher likelihood and hours of informal care received, and lower likelihood of employment/volunteer work, but not with direct medical care. DISCUSSION: Reductions in the rate of decline in CDR-SB seen from DMTs significantly affect patients' work capacity and need for informal care, indicators of economic impact meaningful to patients, families, and health systems. These measures are not readily captured in administrative data sets. Highlights: Following a cohort of participants with MCI or mild dementia due to AD that mimics participants targeted for AD trials, this study showed slower decline in CDR-SB have significant effects on patients' work capacity and need for informal care, but not on their direct medical care utilization such as hospitalizations, ED use, and doctors' visits.Capturing potential benefits in health-related resource use may require direct measures of informal care and work/volunteer effort which are meaningful outcomes to patients, families and health systems.Caution is needed in our effort to assess benefits of recently developed disease modifying treatment in AD using electronic health records and administrative data from which utilization of direct medical care are routinely collected as these data sources may not capture the most apparent changes in resource utilization during early disease stages.

Racial and ethnic disparities in potentially inappropriate medication use in patients with dementia.

INTRODUCTION: Racial and ethnic disparities in potentially inappropriate medication (PIM) use among older adults with dementia are unclear. METHODS: Data were drawn from the baseline visits of participants who were ≥60 years old and diagnosed with dementia in the National Alzheimer's Coordinating Center Uniform Data Set (NACCUDS) recruited from National Institute on Aging (NIA)-funded Alzheimer's Disease Research Centers (ADCs) throughout the United States. PIM utilization was evaluated using the 2019 American Geriatrics Society Beers Criteria for PIM Use in Older Adults. We estimated the association between race and ethnicity and the following outcomes and estimation models: (1) any PIM use, any PIM in each drug class, and any PIM best avoided in dementia patients using logistic regression models, (2) total number of medications, total number of PIMs, and anticholinergic burden scale (ACBS) using Poisson or negative binomial regression models, and (3) proportion of total medications that were PIMs using generalized linear models (GLM). RESULTS: Compared to White participants, Black, Hispanic, and Asian participants reported taking fewer total medications (incidence rate ratio [IRR] ± standard error[SE] = 0.903 ± 0.017, 0.875 ± 0.021, and 0.912 ± 0.041, respectively, all p < 0.01). Asian participants were less likely to be exposed to any PIM (odds ratio [OR] ± SE = 0.619 ± 0.118, p < 0.05). Compared to White participants, Black participants were less likely to be exposed to benzodiazepine (OR ± SE = 0.609 ± 0.094, p < 0.01) and antidepressant (OR ± SE = 0.416 ± 0.103, p < 0.001) PIMs, but greater antipsychotic (OR ± SE = 1.496 ± 0.204, p < 0.01), cardiovascular (OR ± SE = 2.193 ± 0.255, p < 0.001), and skeletal muscle relaxant (OR ± SE = 2.977 ± 0.860, p < 0.001) PIMs. Hispanic participants were exposed to greater skeletal muscle relaxant PIMs and had lower anticholinergic burden. Asian participants were exposed to fewer benzodiazepine PIMs. DISCUSSION: Significant racial and ethnic disparities in exposure to PIMs and PIMs by medication category in dementia research participants who have access to dementia experts found in the study suggest that disparities may be wider in the larger community.

Neuropsychiatric Symptom Profile in Alzheimer's Disease and Their Relationship With Functional Decline.

OBJECTIVE: Understanding the course of individual neuropsychiatric symptoms (NPS) and their relationship with function is important for planning targeted interventions for preventing and delaying functional decline. This study aims to disentangle relative contributions of individual NPS on functional decline. METHODS: Longitudinal study of 9,358 well-characterized participants with baseline diagnoses of Mild Cognitive Impairment or AD in the National Alzheimer's Coordinating Center Uniform Data Set. Function was measured using the Functional Assessment Questionnaire (FAQ). Clinician judgment of seven common behavioral symptoms were examined simultaneously: apathy-withdrawal, depressed mood, visual or auditory hallucinations, delusions, disinhibition, irritability, and agitation. RESULTS: Apathy was the most common NPS at baseline (33.7%) and throughout follow-up, endorsed by clinicians in 63.7% of visits. Apathy was the most persistent with 36.7% of participants having clinician-endorsed apathy in ≥50% of their visits. Apathy strongly correlated with faster rate of functional decline. Compared to those who never had apathy, baseline FAQ was worse in those with intermittent or persistent/always apathy (intermittent: estimated coefficient ±SE=1.228±0.210, 95% CI=[0.817, 1.639]; persistent/always: 2.354±0.244 (95% CI=[1.876, 2.832], both p <0.001). Over time, rate of functional decline was faster in those with intermittent and persistent/always apathy (intermittent: 0.454±0.091, 95% CI=[0.276, 0.632]; persistent/always: 0.635±0.102, 95% CI=[0.436, 0.835], both p <0.001). Worse agitation, delusions, and hallucinations also correlated with functional decline, but magnitudes of the estimates were smaller. CONCLUSION: Individual NPS may be sensitive targets for tracking longitudinal change in function. The study raises awareness of the need for more comprehensive assessment of functional decline in AD patients with noncognitive symptoms.

Abdominal fat depots are related to lower cognitive functioning and brain volumes in middle-aged males at high Alzheimer's risk.

OBJECTIVE: High BMI, which poorly represents specific fat depots, is linked to poorer cognition and higher dementia risk, with different associations between sexes. This study examined associations of abdominal fat depots with cognition and brain volumes and whether sex modifies this association. METHODS: A total of 204 healthy middle-aged offspring of Alzheimer's dementia patients (mean age = 59.44, 60% females) underwent abdominal magnetic resonance imaging to quantify hepatic, pancreatic, visceral, and subcutaneous adipose tissue and to assess cognition and brain volumes. RESULTS: In the whole sample, higher hepatic fat percentage was associated with lower total gray matter volume (ß = -0.17, p < 0.01). Primarily in males, higher pancreatic fat percentage was associated with lower global cognition (males: ß = -0.27, p = 0.03; females: ß = 0.01, p = 0.93) executive function (males: ß = -0.27, p = 0.03; females: ß = 0.02, p = 0.87), episodic memory (males: ß = -0.28, p = 0.03; females: ß = 0.07, p = 0.48), and inferior frontal gyrus volume (males: ß = -0.28, p = 0.02; females: ß = 0.10, p = 0.33). Visceral and subcutaneous adipose tissue was inversely associated with middle frontal and superior frontal gyrus volumes in males and females. CONCLUSIONS: In middle-aged males at high Alzheimer's dementia risk, but not in females, higher pancreatic fat was associated with lower cognition and brain volumes. These findings suggest a potential sex-specific link between distinct abdominal fat with brain health.

Lessons From the Coronavirus Disease Experience: Research Participant and Staff Satisfaction With Remote Cognitive Evaluations.

OBJECTIVE: In New York City in 2020 the pandemic shut down in-person research. Icahn School of Medicine's Alzheimer's Disease Research Center transitioned longitudinal evaluations from in-person to telephone to enhance equity of access. We assessed diverse research participants' and clinical research coordinators' (CRC) satisfaction with remote evaluation and examined sociodemographic, cognitive, and behavioral factors that might impact satisfaction. METHODS: Data collected: 241 participants with Clinical Dementia Rating (CDR) = 0/0.5 (3/2020 to 6/2021). A Telehealth Satisfaction Questionnaire for CRCs and participants was administered at the end of remote evaluations. We compared Telehealth Satisfaction Questionnaire items by CDR and Geriatric Depression Scale. RESULTS: Participants' mean age was 78.4, 61.4% were females, 16.2% were Hispanic, 17.1% Asian, 15.8% were non-Hispanic black, and 72.6% CDR = 0. Participant satisfaction was high [14.1 ± 1.4 (out of 15)] but was lower among those with depression. CRC satisfaction was high [16.9 ± 1.8 (out of 18)] but was lower concerning the ability to explain the test battery and interact with participants with CDR = 0.5. CONCLUSION: Telephone research assessments provide flexibility in a hybrid model. They offer equitable access to research participation for those who do not use computer technology and may promote the retention of diverse elderly research participants.

Apathy in Lewy body disease and its effects on functional impairment over time.

Background and objectives: Apathy strongly affects function in Alzheimer's disease and frontotemporal dementia, however its effect on function in Lewy Body Disease (LBD) has not been well-described. This study aims to (1) examine the prevalence and persistence of apathy in a large, national cohort of well-characterized patients with LBD, and (2) estimate the effect of apathy on function over time. Methods: Study included 676 participants with mild cognitive impairment (MCI) or dementia in the National Alzheimer's Coordinating Center Uniform Data Set. Participants were followed for an average of 3.4 ± 1.7 years and consistently had a primary diagnosis of LBD. Apathy was defined by clinician judgment, categorized into four mutually exclusive profiles: (1) never apathetic across all visits, (2) at least one but <50% of visits with apathy (intermittent apathy), (3) ≥50% but not all visits with apathy (persistent apathy), and (4) always apathy across all visits. Dementia severity was measured by baseline Clinical Dementia Rating score. Parkinsonism was defined by the presence of bradykinesia, resting tremor, rigidity, gait, and postural instability. Functional impairment was assessed using the Functional Assessment Questionnaire (FAQ). Results: Baseline characteristics of the sample were: average age = 72.9 ± 6.9, years of education = 15.6 ± 3.4, Mini Mental State Exam (MMSE) = 24.4 ± 5.4, Geriatric Depression Scale (GDS) = 3.8 ± 3.2, FAQ = 12.0 ± 9.1. 78.8% were male and 89% were non-Hispanic white. Prevalence of apathy increased from 54.4% at baseline to 65.5% in year 4. 77% of participants had apathy at some point during follow-up. Independent of cognitive status and parkinsonian features, FAQ was significantly higher in participants with intermittent/persistent and always apathetic than never apathetic. Annual rate of decline in FAQ was faster in participants who were always apathetic than never apathy. Discussion: In this large national longitudinal cohort of LBD patients with cognitive impairment, apathy was strongly associated with greater functional impairment at baseline and faster rate of decline over time. The magnitude of these effects were clinically important and were observed beyond the effects on function from participants' cognitive status and parkinsonism, highlighting the importance of specifically assessing for apathy in LBD.

Poor self-rated health is associated with faster cognitive decline and greater small vessel disease in older adults with type 2 diabetes.

OBJECTIVE: Self-rated health (SRH) is a predictor for poor health outcomes and cognition. Older adults with type 2 diabetes mellitus (T2D) have multi-morbidity and greater cognitive impairment. In the present study we investigated the association of SRH with cognitive decline and brain pathology in older adults with T2D. METHODS: Participants (n = 1122) were from the Israel Diabetes and Cognitive Decline study, and SRH was categorised as low (n = 202), moderate (n = 400) or high (n = 520). Cognition was measured by four cognitive domains: episodic memory, executive functions, language, and attention/working memory. Global cognition was the average of the cognitive domains. Statistical models adjusted for sociodemographic, cardiovascular, and clinical variables. In a randomly selected subsample (n = 230) that had magnetic resonance imaging, we examined relationships between baseline SRH and brain characteristics (white matter hyperintensities [WMHs], hippocampal, and total grey matter [GM] volumes). RESULTS: Low SRH was associated with a decline in executive functions, which accelerated over time when compared to high SRH (est = -0.0036; p = <0.001). Compared to high SRH, low SRH was associated with a faster decline in global cognition (est = -0.0024; p = 0.009). Low SRH at baseline was associated with higher volumes of WMHs (est = 9.8420; p < 0.0008). SRH was not associated with other cognitive domains, or with hippocampal and total GM. CONCLUSIONS: Low SRH is associated with cognitive decline in T2D older adults and may serve as a risk assessment. WMHs may represent an underlying mechanism.

Reduction and prevention of agitation in persons with neurocognitive disorders: an international psychogeriatric association consensus algorithm.

OBJECTIVES: To develop an agitation reduction and prevention algorithm is intended to guide implementation of the definition of agitation developed by the International Psychogeriatric Association (IPA). DESIGN: Review of literature on treatment guidelines and recommended algorithms; algorithm development through reiterative integration of research information and expert opinion. SETTING: IPA Agitation Workgroup. PARTICIPANTS: IPA panel of international experts on agitation. INTERVENTION: Integration of available information into a comprehensive algorithm. MEASUREMENTS: None. RESULTS: The IPA Agitation Work Group recommends the Investigate, Plan, and Act (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and acting with an emphasis on shared decision-making; the success of the plan is evaluated and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Psychosocial interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal/circadian agitation; mild-moderate agitation or agitation with prominent mood features; moderate-severe agitation; and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a variety of venues-home, nursing home, emergency department, hospice-and adjustments to the therapeutic approach are presented. CONCLUSIONS: The IPA definition of agitation is operationalized into an agitation management algorithm that emphasizes the integration of psychosocial and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision-making.

Agitation in cognitive disorders: Progress in the International Psychogeriatric Association consensus clinical and research definition.

BACKGROUND: The International Psychogeriatric Association (IPA) published a provisional consensus definition of agitation in cognitive disorders in 2015. As proposed by the original work group, we summarize the use and validation of criteria in order to remove "provisional" from the definition. METHODS: This report summarizes information from the academic literature, research resources, clinical guidelines, expert surveys, and patient and family advocates on the experience of use of the IPA definition. The information was reviewed by a working group of topic experts to create a finalized definition. RESULTS: We present a final definition which closely resembles the provisional definition with modifications to address special circumstances. We also summarize the development of tools for diagnosis and assessment of agitation and propose strategies for dissemination and integration into precision diagnosis and agitation interventions. CONCLUSION: The IPA definition of agitation captures a common and important entity that is recognized by many stakeholders. Dissemination of the definition will permit broader detection and can advance research and best practices for care of patients with agitation.

A feasibility study of the combination of intranasal insulin with oral semaglutide for cognition in older adults with metabolic syndrome at high dementia risk- Study rationale and design.

INTRODUCTION: We present the rationale and design of a double-blind placebo-controlled feasibility trial combining intranasal insulin (INI) with semaglutide, a GLP-1 receptor agonist, to improve cognition in older adults with metabolic syndrome (MetS) and mild cognitive impairment (MCI). Since both INI and dulaglutide have beneficial effects on the cerebrovascular disease (CVD), we anticipate that improved CVD will underlie the hypothesized cognitive benefits. METHODS: This 12-months trial will include 80 older adults aged > 60 with MetS and MCI, randomized to 4 groups: INI/oral semaglutide, intranasal placebo/oral semaglutide, INI/oral placebo, and intranasal placebo/oral placebo. Feasibility of combining INI with semaglutide will be tested by examining the ease of use of INI (20IU, twice/day) with semaglutide (14 once daily), adherence, and safety profile are the efficacy of combination therapy on global cognition and neurobiological markers: cerebral blood flow, cerebral glucose utilization, white matter hyperintensities, Alzheimer's related blood biomarkers and expression of insulin signaling proteins measured in brain-derived exosomes. Efficacy will be assessed for the intent-to-treat sample. DISCUSSION: This feasibility study is anticipated to provide the basis for a multi-center large-scale randomized clinical trial (RCT) of the cognitive benefits of the combination of INI with semaglutide in individuals enriched for CVD and at high dementia risk.

Neuroticism is associated with increase in depression symptoms over time in older adults with type 2 diabetes.

OBJECTIVES: The likelihood of depression symptoms in those with type 2 diabetes (T2D) is high. Psychological risk factors enhancing comorbidity of depression symptoms in T2D are yet to be determined. The present study examines the cross-sectional and longitudinal relationship between personality traits and distinct depression dimensions in older adults with T2D. METHODS: Participants were older adults (age ≥65yeas) with T2D from the Israel Diabetes and Cognitive Decline (IDCD) study (N = 356), with complete data on depression [Geriatric Depression Scale (GDS) - 15 item version] and its dimensions- namely, dysphoric mood, apathy, hopelessness, memory complains and anxiety, and on personality [Big Five Inventory (BFI)]. Logistic and mixed linear regression models examined cross-sectional and longitudinal associations while adjusting for socio-demographics, cognition, cardiovascular and diabetes-related factors. RESULTS: Cross-sectionally, high neuroticism was associated with high scores in total GDS and in all depression-dimensions, except memory complaints. Higher extroversion was associated with lower total GDS and with lower scores on all depression dimensions, except anxiety. High levels of neuroticism were associated with increase in total number of depression symptoms over time. CONCLUSIONS: In older adults with T2D, neuroticism and extroversion are associated with most depression dimensions suggesting that these traits relate to a global depression symptomatology rather than to any specific dimension or phenomenology. High neuroticism was associated with increase in depression symptoms over time, highlighting its role in the development of depression symptoms in older adults with T2D.

Centrally acting ACE inhibitor (cACEi) and angiotensin receptor blocker (cARB) use and cognitive dysfunction in patients with SLE.

OBJECTIVE: Cognitive dysfunction (CD) is detectable in approximately 40% of patients with SLE. Despite this high prevalence, there are no approved pharmacological treatment options for this detrimental condition. Preliminary murine studies show potential for targeting microglial activation as a treatment of SLE-CD, which may be ameliorated with centrally acting ACE inhibitor (cACEi) and angiotensin receptor blocker (cARB) use. The aim of this study is to determine if there is an association of cACEi/cARB use with cognitive function in a human SLE cohort. METHODS: The American College of Rheumatology neuropsychological battery was administered to patients with consecutive SLE at a single academic health centre at baseline, 6 and 12 months. Scores were compared with sex-matched and age-matched control subjects. Clinical and demographic data were gathered at each visit. The primary outcome was CD defined as dysfunction in two or more cognitive domains. The primary predictor was a total cumulative dose of cACEi/cARB in milligrams per kilogram, recorded as an equivalent ramipril dose. Odds of CD with respect to cACEi/cARB use were determined through generalised linear mixed modelling. RESULTS: A total of 300 patients, representing 676 visits, completed this study. One hundred sixteen (39%) met the criteria for CD. Fifty-three participants (18%) were treated with a cACEi or cARB. Mean cumulative dose was 236 mg/kg (calculated as equivalent ramipril dose). Cumulative cACEi/cARB dose was not protective against SLE-CD. Caucasian ethnicity, current employment status and azathioprine cumulative dose were each associated with reduced odds of SLE-CD. Increasing Fatigue Severity Scale score was associated with increased odds of CD. CONCLUSIONS: In a single-centre SLE cohort, cACEi/cARB use was not associated with absence of CD. Many important confounders may have influenced the results of this retrospective study. A randomised trial is required to accurately determine if cACEi/cARB is a potential treatment for SLE-CD.

A feasibility study of the combination of intranasal insulin with dulaglutide for cognition in older adults with metabolic syndrome at high dementia risk - Study rationale and design.

INTRODUCTION: We present the rationale and design of a double-blind placebo-controlled feasibility trial combining intranasal insulin (INI) with dulaglutide, a GLP-1 receptor agonist, to improve cognition in older adults with metabolic syndrome (MetS) and mild cognitive impairment (MCI). Since both INI and dulaglutide have beneficial effects on the cerebrovascular disease (CVD), we anticipate that improved CVD will underlie the hypothesized cognitive benefits. METHODS: This 12-months trial will include 80 older adults aged > 60 with MetS and MCI, randomized to 4 groups: INI/dulaglutide injection, intranasal placebo/dulaglutide injection, INI/placebo injection, and intranasal placebo/placebo injection. Feasibility of combining INI with dulaglutide will be tested by examining the ease of use of INI (20IU, twice/day) with dulaglutide (1.5 mg/week), adherence, and safety profile are the efficacy of combination therapy on global cognition and neurobiological markers: cerebral blood flow, cerebral glucose utilization, white matter hyperintensities, Alzheimer's related blood biomarkers and expression of insulin signaling proteins measured in brain-derived exosomes. Efficacy will be assessed for the intent-to-treat sample. DISCUSSION: This feasibility study is anticipated to provide the basis for a multi-center large-scale randomized clinical trial of the cognitive benefits of the combination of INI with dulaglutide in individuals enriched for CVD and at high dementia risk.

The utility of word list and story recall for identifying older U.S. Chinese immigrants with cognitive impairment.

OBJECTIVE: This study examined the utility of the Chinese-language translations of the word list memory test (Philadelphia Verbal Learning Test) and story memory test (Logical Memory subtest of the Wechsler Memory Scale) for differentiating cognitive diagnosis in older U.S. Chinese immigrants. METHOD: Participants were ≥ 60 years old, with Chinese language proficiency to complete a diagnostic workup at the Mount Sinai's Alzheimer's Disease Research Center. The workup included an evaluation by a geriatric psychiatrist and cognitive testing with a psychometrician. Diagnosis of normal, mild cognitive impairment (MCI), and dementia was made independent of the cognitive tests at consensus led by a dementia expert physician. Multivariable logistic regression models were used to assess the sensitivity of story and word list memory tests for distinguishing between groups. Receiver operating characteristic (ROC area/area under the curve [AUC]) was used to compare the predictive accuracy of the two tests. RESULTS: The sample included 71 participants with normal cognition, 42 with MCI, and 24 with dementia. The MCI group was older and less educated than normal controls but younger and more educated than the dementia group. Delayed recall of both memory tests, but not immediate recall of either test, predicted diagnosis. While composite memory score of word list (AUC = 0.90) predicted diagnosis slightly better than that of stories (AUC = 0.85), the difference was not significant in this small sample (p = .14). CONCLUSIONS: Chinese-language translations of verbal memory tests, in particular delayed recall scores, were equally sensitive for classifying cognitive diagnosis in older U.S. Chinese immigrants. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Behavioral and Brain Correlates of Emotional Distress in Older Adults During COVID-19 Quarantine.

COVID-19 led to unprecedented lockdowns and changes in older adults' lives, especially those with type 2 diabetes who have high risk of complications and mortality. We investigated the associations of cognitive and motor function and gray matter volumes (GMVs) with COVID-19 lockdown-related emotional distress of type 2 diabetes older adults, participating in the Israel Diabetes and Cognitive Decline Study. We administered a questionnaire to obtain information about anxiety, depression, general well-being, and optimism during a mandated lockdown. Lower grip strength before lockdown was associated with increased sadness, anxiety, and less optimism. Slower gait speed was associated with greater sadness. Lower GMV was related to greater anxiety during the lockdown when compared with anxiety levels before the COVID-19 outbreak. Yet, global cognition was not associated with any emotional distress measure. These results support the role of good motor function on emotional well-being during acute stress and GMV as a potential underlying mechanism.

Evaluating memory testing to distinguish dementia severity among White, Black, and Spanish-speaking individuals in the Uniform Data Set (UDS).

INTRODUCTION: Little work has compared the effectiveness of using multiple types of memory tests alone or in combination to distinguish dementia severity in diverse research cohorts including Black individuals and Spanish speakers. Here we evaluate word list and paragraph recall tests to distinguish cognitively normal, mild cognitively impaired, and those with Alzheimer's disease in diverse cohorts. METHODS: Using Uniform Data Set (UDS) and site-specific supplemental data, logistic regression models and receiver operating characteristic-area under the curve were used to compare paragraph recall versus word list in differentiating among Clinical Dementia Rating (CDR) scale level. RESULTS: Results reveal high discriminability for all groups and no difference between either test in distinguishing between CDR levels. Combining tests improved discriminability for the whole group but did not for Black individuals or Spanish speakers. DISCUSSION: Our findings indicate that using multiple memory tests may not improve differentiation between cognitive impairment levels for diverse cohorts. The burden of added testing may be a barrier for maximizing inclusion of under-represented groups in research.

BCI-838, an orally active mGluR2/3 receptor antagonist pro-drug, rescues learning behavior deficits in the PS19 MAPTP301S mouse model of tauopathy.

Tauopathies are a heterogeneous group of neurodegenerative disorders that are clinically and pathologically distinct from Alzheimer's disease (AD) having tau inclusions in neurons and/or glia as their most prominent neuropathological feature. BCI-838 (MGS00210) is a group II metabotropic glutamate receptor (mGluR2/3) antagonist pro-drug. Previously, we reported that orally administered BCI-838 improved learning behavior and reduced anxiety in Dutch (APPE693Q) transgenic mice, a model of the pathological accumulation of Aß oligomers found in AD. Herein, we investigated effects of BCI-838 on PS19 male mice that express the tauopathy mutation MAPTP301S associated with human frontotemporal lobar degeneration (FTLD). These mice develop an aging-related tauopathy without amyloid accumulation. Mice were divided into three experimental groups: (1) non-transgenic wild type mice treated with vehicle, (2) PS19 mice treated with vehicle and (3) PS19 mice treated with 5 mg/kg BCI-838. Groups of 10-13 mice were utilized. Vehicle or BCI-838 was administered by oral gavage for 4 weeks. Behavioral testing consisting of a novel object recognition task was conducted after drug administration. Two studies were performed beginning treatment of mice at 3 or 7 months of age. One month of BCI-838 treatment rescued deficits in recognition memory in PS19 mice whether treatment was begun at 3 or 7 months of age. These studies extend the potential utility of BCI-838 to neurodegenerative conditions that have tauopathy as their underlying basis. They also suggest an mGluR2/3 dependent mechanism as a basis for the behavioral deficits in PS19 mice.

World Trade Center Site Exposure Duration Is Associated with Hippocampal and Cerebral White Matter Neuroinflammation.

Responders to the World Trade Center (WTC) attacks on 9/11/2001 inhaled toxic dust and experienced severe trauma for a prolonged period. Studies report that WTC site exposure duration is associated with peripheral inflammation and risk for developing early-onset dementia (EOD). Free Water Fraction (FWF) can serve as a biomarker for neuroinflammation by measuring in vivo movement of free water across neurons. The present case-controlled study aimed to examine associations between WTC site exposure duration as well as EOD status with increased hippocampal and cerebral neuroinflammation. Ninety-nine WTC responders (mean age of 56) were recruited between 2017 and 2019 (N = 48 with EOD and 51 cognitively unimpaired). Participants were matched on age, sex, occupation, race, education, and post-traumatic stress disorder (PTSD) status. Participants underwent neuroimaging using diffusion tensor imaging protocols for FWF extraction. Region of interest (ROI) analysis and correlational tractography explored topographical distributions of FWF associations. Apolipoprotein-e4 allele (APOEε4) status was available for most responders (N = 91). Hippocampal FWF was significantly associated with WTC site exposure duration (r = 0.30, p = 0.003), as was cerebral white matter FWF (r = 0.20, p = 0.044). ROI analysis and correlational tractography identified regions within the limbic, frontal, and temporal lobes. Hippocampal FWF and its association with WTC exposure duration were highest when the APOEε4 allele was present (r = 0.48, p = 0.039). Our findings demonstrate that prolonged WTC site exposure is associated with increased hippocampal and cerebral white matter neuroinflammation in WTC responders, possibly exacerbated by possession of the APOEε4 allele.

Does computerized cognitive training improve diabetes self-management and cognition? A randomized control trial of middle-aged and older veterans with type 2 diabetes.

AIMS: This randomized control trial compared an adaptive computerized cognitive training intervention with a non-adaptive version. The primary hypothesis predicted better diabetes self-management in type 2 diabetes patients at 6 months post-intervention than baseline in the adaptive arm, with seven secondary outcomes. METHODS: Intent-to-treat analysis of veterans without dementia aged 55+ from the Bronx, NY and Ann Arbor, MI (N = 90/per arm) used linear mixed model analyses. RESULTS: Contrary to the hypothesis, only memory showed more improvement in the adaptive arm (p < 0.01). Post-hoc analyses combined the two arms; self-management improved at six-months post-intervention (p < 0.001). Memory, executive functions/attention, prospective memory, diastolic blood pressure, and systolic blood pressure improved (p < 0.05); hemoglobin A1c and medication adherence did not improve significantly. CONCLUSIONS: The adaptive computerized cognitive training was not substantially better than non-adaptive, but may improve memory. Post-hoc results for the combined arms suggest computer-related activities may improve diabetes self-management and other outcomes for middle-aged and older patients with type 2 diabetes. Practice effects or awareness of being studied cannot be ruled out.