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BackgroundMany older adults living with dementia have not been formally diagnosed. Even when clinicians document the diagnosis, patients and families may be unaware of the diagnosis. Knowledge of how individual characteristics affect detection and awareness of dementia is limited.ObjectiveTo identify characteristics associated with dementia diagnosis and awareness of diagnosis.DesignCross-sectional observational study.ParticipantsFive hundred eighty-five adults aged ≥ 65 in the National Health and Aging Trends Study who met assessment-based study criteria for probable dementia in 2011 and had 3 years of continuous, fee-for-service Medicare claims prior to 2011.Main MeasuresUsing multivariable logistic regression, we compared participants with undiagnosed versus diagnosed dementia (based on Medicare claims) on demographic, social/behavioral, functional, medical, and healthcare utilization characteristics. Among those diagnosed, we compared characteristics of participants unaware versus aware of the diagnosis (based on self or proxy report).Key ResultsAmong older adults with probable dementia, 58.7% were either undiagnosed (39.5%) or unaware of the diagnosis (19.2%). In adjusted analyses, individuals who were Hispanic (OR 2.48, 95% CI 1.19, 5.14), had less than high school education (OR 0.54 for at least high school education, 95% CI 0.32, 0.91), attended medical visits alone (OR 1.98, 95% CI 1.11, 3.51), or had fewer functional impairments (OR 0.79 for each impairment, 95% CI 0.69, 0.90) were more likely to be undiagnosed. Similarly, among those diagnosed, having less education (OR 0.42), attending medical visits alone (OR 1.97), and fewer functional impairments (OR 0.72) were associated with unawareness of diagnosis (all ps < 0.05).ConclusionsThe majority of older adults with dementia are either undiagnosed or unaware of the diagnosis, suggesting shortcomings in detection and communication of dementia. Individuals who may benefit from targeted screening include racial/ethnic minorities and persons who have lower educational attainment, any functional impairment, or attend medical visits alone.

Neuropsychiatric symptoms (NPSs) are nearly universal in cognitive disorders. The mild behavioral impairment construct postulates that NPS may be the first symptom of impending dementia. Participants were cognitively normal volunteers followed up approximately annually at Alzheimer's Disease Centers, who were assessed on the Neuropsychiatric Inventory and had at least one follow-up visit during which they were diagnosed with mild cognitive impairment (MCI) or dementia. Descriptive statistics were used to determine sequencing of NPS presence with cognitive diagnoses. Data were available for 1998 participants who progressed to MCI or dementia. Over 59% developed NPS before the diagnosis of any cognitive disorder. Depression and irritability were the most common NPSs to precede cognitive diagnoses (24 and 21%, respectively). NPSs precede a cognitive diagnosis in most people who develop cognitive decline, both MCI and dementia. These individuals are an important group to focus clinical and research efforts. •A majority developed neuropsychiatric symptoms before diagnosis of cognitive disorder.•Depression and irritability were most common NPSs before diagnosis.•Apathy, agitation, hallucinations, and delusions were rare before cognitive decline.

Individuals with mild cognitive impairment (MCI) are at high risk of developing dementia and/or Alzheimer disease (AD). Among persons with MCI, depression and anxiety have been associated with an increased risk of incident dementia. We examined whether neuropsychiatric symptoms in MCI increased the risk of incident dementia (all-cause) and incident AD. Longitudinal cohort study followed annually (median: 1.58 years). National Alzheimer's Coordinating Center database combining clinical data from 29 Alzheimer's Disease Centers. A total of 1,821 participants with MCI. 1) Progression to dementia (all-cause) or AD, 2) Neuropsychiatric Inventory Questionnaire (NPI-Q), 3) Geriatric Depression Scale (GDS), 4) Clinical Dementia Rating Global Score and Sum of Boxes, and 5) Mini-Mental State Examination (MMSE). The association of covariates with risk of incident dementia or AD was evaluated with hazard ratios (HR) determined by Cox proportional-hazards models adjusted for age, ethnicity, Clinical Dementia Rating Global Score and Sum of Boxes, and MMSE. A total of 527 participants (28.9%) progressed to dementia and 454 (24.9%) to AD. Baseline GDS > 0 was associated with an increased risk of incident dementia (HR: 1.47, 95% CI: 1.17–1.84) and AD (HR: 1.45, 95% CI: 1.14–1.83). Baseline NPI > 0 was associated with an increased risk of incident dementia (HR: 1.37, 95% CI: 1.12–1.66) and AD (HR: 1.35, 95% CI: 1.09–1.66). Neuropsychiatric symptoms in MCI are associated with significantly an increased risk of incident dementia and AD. Neuropsychiatric symptoms may be among the earliest symptoms of preclinical stages of AD and targeting them therapeutically might delay transition to dementia.

ABSTRACTBackgroundAgitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. There is no consensus definition of agitation and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Group (ADWG) to develop a provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definition will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs. MethodsThe ADWG developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process. ResultsAgitation was defined broadly as: (1) occurring in patients with a cognitive impairment or dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors that cause excess disability and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definition as “strongly agree” or “somewhat agree” (68–88% across elements). A majority of the respondents agreed that the definition is appropriate for clinical and research applications. ConclusionsA provisional consensus definition of agitation has been developed. This definition can be used to advance interventional and non-interventional research of agitation in patients with cognitive impairment.

A 2013 systematic review and Delphi consensus study identified 12 modifiable risk and protective factors for dementia, which were subsequently merged into the “LIfestyle for BRAin health” (LIBRA) score. We systematically evaluated whether LIBRA requires revision based on new evidence. To identify modifiable risk and protective factors suitable for dementia risk reduction, we combined an umbrella review of systematic reviews and meta‐analyses with a two‐round Delphi consensus study. The review of 608 unique primary studies and opinions of 18 experts prioritized six modifiable factors: hearing impairment, social contact, sleep, life course inequalities, atrial fibrillation, and psychological stress. Based on expert ranking, hearing impairment, social contact, and sleep were considered the most suitable candidates for inclusion in updated dementia risk scores. As such, the current study shows that dementia risk scores need systematic updates based on emerging evidence. Future studies will validate the updated LIBRA score in different cohorts. Highlights An umbrella review was combined with opinions of 18 dementia experts. Various candidate targets for dementia risk reduction were identified. Experts prioritized hearing impairment, social contact, and sleep. Re‐assessment of dementia risk scores is encouraged. Future work should evaluate the predictive validity of updated risk scores.

This study examines the relationship of unmet dementia-related care needs of community-dwelling persons, and their caregivers (CGs), to measures of caregiver burden. Cross-sectional baseline data were analyzed from participants in a dementia care coordination trial of community-residing persons with dementia (PWD) (n = 254) and their caregivers (n = 246). Participants were recruited from Northwest Baltimore, Maryland. The Zarit Burden Inventory (ZBI) was used to measure subjective caregiver burden. Objective burden was measured by estimating the total hours per week spent doing things for the PWD and/or how many hours CGs missed paid work in the prior month due to caregiving responsibilities. The Johns Hopkins Dementia Care Needs Assessment was used to identify unmet dementia-related care needs. Bivariate and multivariate linear regressions examined the relationship of unmet needs, demographic, clinical, or functional characteristics with caregiver burden measures. In adjusted multivariable models, patient neuropsychiatric symptoms and caregiver unmet emotional needs explained 22% of the variance in ZBI scores. In adjusted multivariable models, caregiver need for respite, patient functional dependency, and caregiver unmet specialty medical needs explained 26% of the variance in the hours per week spent caregiving. PWD's level of functional dependency was the sole correlate of missed time at work, explaining 11% of the variance. Addressing potentially modifiable unmet caregiver needs may reduce subjective and objective caregiver burden.

AbstractObjectivesAmong people with dementia, poor nutritional status has been associated with worse cognitive and functional decline, but few studies have examined its association with neuropsychiatric symptoms (NPS). We examined this topic in a population-based sample of persons with dementia. DesignLongitudinal, observational cohort study. SettingCommunity. ParticipantsTwo hundred ninety-two persons with dementia (71.9% Alzheimer’s disease, 56.2% women) were followed up to 6 years. MeasurementsWe used a modified Mini-Nutritional Assessment (mMNA) and the Neuropsychiatric Inventory (NPI) to evaluate nutritional status and NPS, respectively. Individual linear mixed effects models examined the associations between time-varying mMNA total score or clinical categories (malnourishment, risk for malnourishment, or well-nourished) and NPI total score (excluding appetite domain) or NPI individual domain or cluster (e.g. psychosis) scores. Covariates tested were dementia onset age, type, and duration, medical comorbidities, sex, apolipoprotein E (APOE) genotype, and education. ResultsCompared to the well-nourished, those at risk for malnourishment and those malnourished had higher total NPI scores [ b (95% CI) = 1.76 (0.04, 3.48) or 3.20 (0.62, 5.78), respectively], controlling for significant covariates. Higher mMNA total score (better nutritional status) was associated with lower total NPI [ b (95% CI) = −0.58 (−0.86, −0.29)] and lower domain scores for psychosis [ b (95% CI) = −0.08 (−0.16,.004)], depression [ b (95% CI = −0.11 (−0.16, −0.05], and apathy [ b (95% CI = −0.19 (−0.28, −0.11)]. ConclusionsWorse nutritional status is associated with more severe NPS. Dietary or behavioral interventions to prevent malnutrition may be beneficial for persons with dementia.

The hallmarks of Alzheimer’s disease (AD) pathology are senile plaques containing amyloid-beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. Additional pathologies often co-exist, whereas multiple pathogenic mechanisms are involved in AD, especially synaptic degeneration, which necessitate the need for synaptic integrity-related biomarkers alongside Aβ- and tau-related biomarkers. Plasma neuron-derived Extracellular Vesicles EVs (NDEVs) provide biomarkers related to Aβ and tau and synaptic degeneration. Here, to further establish the latter as a “liquid biopsy” for AD, we examined their relationship with ante-mortem cognition in pathologically-confirmed AD cases. We immunoprecipitated NDEVs by targeting neuronal marker L1CAM from ante-mortem plasma samples from 61 autopsy-confirmed cases of pure AD or AD with additional pathologies and measured Aβ42, p181-Tau, total Tau, synaptophysin, synaptopodin and three canonical EV markers, CD63, CD81 and CD9. Higher NDEV Aβ42 levels were consistently associated with better cognitive status, memory, fluency, working memory and executive function. Higher levels of NDEV synaptic integrity-related biomarkers were associated with better performance on executive function tasks. Our findings motivate the hypothesis that releasing Aβ42-laden NDEVs may be an adaptive mechanism in AD.

The purpose of this paper is to establish single-participant white matter atlases based on diffusion tensor imaging. As one of the applications of the atlas, automated brain segmentation was performed and the accuracy was measured using Large Deformation Diffeomorphic Metric Mapping (LDDMM). High-quality diffusion tensor imaging (DTI) data from a single-participant were B0-distortion-corrected and transformed to the ICBM-152 atlas or to Talairach coordinates. The deep white matter structures, which have been previously well documented and clearly identified by DTI, were manually segmented. The superficial white matter areas beneath the cortex were defined, based on a population-averaged white matter probability map. The white matter was parcellated into 176 regions based on the anatomical labeling in the ICBM-DTI-81 atlas. The automated parcellation was achieved by warping this parcellation map to normal controls and to Alzheimer's disease patients with severe anatomical atrophy. The parcellation accuracy was measured by a kappa analysis between the automated and manual parcellation at 11 anatomical regions. The kappa values were 0.70 for both normal controls and patients while the inter-rater reproducibility was 0.81 (controls) and 0.82 (patients), suggesting “almost perfect” agreement. A power analysis suggested that the proposed method is suitable for detecting FA and size abnormalities of the white matter in clinical studies.

There is strong association of Alzheimer's disease (AD) pathology with gait disorder and falls in older adults without dementia. The goal of the study was to examine the prevalence and severity of AD pathology in older adults without dementia who fall and sustain hip fracture. Cerebrospinal fluid (CSF) was obtained from 168 hip fracture patients. CSF Aβ42/40 ratio, p-tau, and t-tau measures were dichotomized into normal vs. abnormal, and categorized according to the A/T/N classification. Among the hip fracture patients, 88.6% of the cognitively normal (Clinical Dementia Rating-CDR 0; n = 70) and 98.8% with mild cognitive impairment (CDR 0.5; n = 81) fell in the abnormal biomarker categories by the A/T/N classification. A large proportion of older hip fracture patients have CSF evidence of AD pathology. Preoperative determination of AD biomarkers may play a crucial role in identifying persons without dementia who have underlying AD pathology in perioperative settings.