Neuropsychiatric symptoms in severe dementia: Associations with specific cognitive domains the Cache County Dementia Progression Study.

OBJECTIVES: To examine the prevalence of neuropsychiatric symptoms (NPS) and cognitive correlates in severe dementia. METHODS: A population-based sample of 56 individuals with severe dementia (85.7% Alzheimer's type; 67.9% female) were assessed with the Severe Cognitive Impairment Profile (SCIP) and the Neuropsychiatric Inventory (NPI). Descriptive statistics displayed the frequency of NPS and bivariate and multiple regression analyses examined the associations between cognitive domains on the SCIP and NPS total, domain, and cluster scores. RESULTS: NPS were common in severe dementia with 98% of the sample exhibiting at least one symptom. Most common were delusions, apathy, agitation/aggression, and aberrant motor behavior, affecting 50% or more of participants. SCIP comportment was significantly associated with NPI total score and apathy (r = -.350 and -.292, respectively). All SCIP domains except for arithmetic, visuospatial, comportment, and motor behavior were significantly associated with agitation/aggression (r = -.285 to -.350). These associations remained in individual multiple regression models. CONCLUSION: In severe dementia, impairment in specific cognitive domains was associated with more severe NPS. Environmental manipulations to reduce processing demands in persons with severe dementia may be a useful strategy to target agitation and aggressive behaviors.

Neuropsychiatric symptoms in patients with dementia and the longitudinal costs of informal care in the Cache County population.

INTRODUCTION: Severity of dementia and neuropsychiatric symptoms contribute to increasing informal care costs. We examined which neuropsychiatric symptoms subdomains (NPS-SD) were associated with informal costs in a population-based sample. METHODS: Dementia progression and informal costs (2015 dollars) were estimated from the Cache County Dementia Progression Study. Overall NPS and specific NPS-SD were assessed with the Neuropsychiatric Inventory. Generalized Estimating Equations (GEE with gamma-distribution/log-link) modeled the relationship between NPS-SDs and informal cost trajectories. RESULTS: Two hundred eighty participants (52.1% female; age M = 85.67, SD = 5.60) exhibited an adjusted cost increase of 5.6% (P = .005), 6.4% (P < .001), 7.6% (P = .030), and 13% (P = .024) for every increasing Neuropsychiatric Inventory unit in psychosis-SD, affective-SD, agitation/aggression-SD, and apathy-SD, respectively. An increase in each unit of apathy was associated with a 2% annual decrease in costs (P = .040). DISCUSSION: We extend our prior work on informal costs and dementia severity by identifying NPS-SD associated with informal costs. Interventions targeting NPS-SD may lower informal costs.

Caregiver-Care Recipient Relationship Closeness is Associated With Neuropsychiatric Symptoms in Dementia.

OBJECTIVE: Closer caregiver-care recipient (CG-CR) relationships are associated with better cognitive and functional abilities, activities of daily living (in persons with dementia), and lower informal care costs. METHODS: Due to the difficulty in treating neuropsychiatric symptoms (NPSs) and their detrimental effects on caregivers and care recipients, we examined whether closeness of CG-CR relationships was associated with overall NPS severity or with specific NPS symptom domains in care recipients. In a longitudinal population-based study in Cache County, Utah, the 12-item Neuropsychiatric Inventory (NPI-12) was assessed in 300 CG-CR dyads. Caregivers reported current relationship closeness using the Whitlatch Relationship Closeness Scale. Linear mixed models examined associations between CG-CR closeness and NPI-12 total score or selected symptom domains over time (observation period: 2002-2012). RESULTS: In unadjusted linear mixed models, higher closeness scores were associated with a five-point lower NPI-12 score and a one-point lesser increase in NPI-12 per year. NPI scores also showed lower affective cluster scores (two points) and lesser increase in psychosis cluster (approximately 0.5 points per year) and agitation/aggression (0.16 points per year) for each unit increase in closeness. When controlling for NPI caregiver distress, associations between closeness and NPSs diminished to a 0.5-point lesser increase in total NPI-12 score per year. Adjusted models for NPI domains/clusters showed -0.32 points per year for the psychosis cluster, -0.11 points per year for agitation/aggression, and -0.67 overall for the affective cluster. CONCLUSION: Higher CG-CR closeness, a potentially modifiable factor, is associated with lower NPS severity and may provide a target for intervention.

Differences in Maternal Risk Factors Among Undocumented Latinas in Nebraska by Country of Origin.

OBJECTIVE: This study compared maternal risk factors by country of origin for 4,188 Mexican and Guatemalan unauthorized immigrants. METHOD: Data were drawn from 2007 to 2011 public birth certificate records of unauthorized immigrant mothers residing in Nebraska at the time of delivery. The study sample included 4,188 women ages 18 years or older and originating from either Mexico or Guatemala. Risk factors, including age risk, preexisting health risks, pregnancy health risks, and prior pregnancy risks, were examined by country of origin. Stata 11.0 was used to compute descriptive statistics and conduct χ2 test for binary variables and Student t test for continuous variables. RESULTS: Analyses found that Mexican and Guatemalan participants have distinct maternal risk factors. Mexican participants were older and at greater risk of obesity and excessive weight gain during pregnancy, while Guatemalan participants were more likely to receive inadequate prenatal care. CONCLUSION: Findings suggest that both Mexican and Guatemalan immigrants encounter maternal risk factors that could threaten not only their own health but that of their infants as well. Health and social service providers can tailor education and outreach efforts that are specific to Latina subgroups by origin. Furthermore, targeted strategies to delivering prenatal care to unauthorized immigrants are essential for the well-being of mothers and newborns.

Sex Differences in Risk for Alzheimer's Disease Related to Neurotrophin Gene Polymorphisms: The Cache County Memory Study.

Neurotrophins, including nerve-growth factor and brain-derived neurotrophic factor, have been implicated in Alzheimer's disease (AD). Associations between AD and neurotrophin signaling genes have been inconsistent, with few studies examining sex differences in risk. We examined four single-nucleotide polymorphisms (SNPs) involved in neurotrophin signaling (rs6265, rs56164415, rs2289656, rs2072446) and risk for AD by sex in a population-based sample of older adults. Three thousand four hundred and ninety-nine individuals without dementia at baseline [mean (standard deviation) age = 74.64 (6.84), 58% female] underwent dementia screening and assessment over four triennial waves. Cox regression was used to examine time to AD or right censoring for each SNP. Female carriers of the minor T allele for rs2072446 and rs56164415 had a 60% (hazard ratio [HR] = 1.60, 95% confidence interval [CI] = 1.02-2.51) and 93% (HR = 1.93, 95% CI = 1.30-2.84) higher hazard for AD, respectively, than male noncarriers of the T allele. Furthermore, male carriers of the T allele of rs2072446 had a 61% lower hazard (HR = 0.39, 95% CI = 0.14-1.06) than male noncarriers at trend-level significance (p = .07). The association between certain neurotrophin gene polymorphisms and AD differs by sex and may explain inconsistent findings in the literature.

Preclinical Alzheimer's disease and longitudinal driving decline.

INTRODUCTION: Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. METHODS: 104 OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries and self-reported their driving habits. RESULTS: Higher values of CSF tau/Aß42 and ptau181/Aß42 ratios, but not uptake on PIB amyloid imaging (p=.12), predicted time to a rating of Marginal or Fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70-19.53), p=.005 for CSF tau/Aß42; 6.19 (1.75-21.88) and p=.005 for CSF ptau181/Aß42. DISCUSSION: Preclinical AD predicted time to receiving a Marginal or Fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.

Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals.

Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF Aß42, tau, ptau181, tau/Aß42, ptau181/Aß42). Higher ratios of CSF tau/Aß42, ptau181/Aß42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving.

Development and interval testing of a naturalistic driving methodology to evaluate driving behavior in clinical research.

Background: The number of older adults in the United States will double by 2056. Additionally, the number of licensed drivers will increase along with extended driving-life expectancy. Motor vehicle crashes are a leading cause of injury and death in older adults. Alzheimer's disease (AD) also negatively impacts driving ability and increases crash risk. Conventional methods to evaluate driving ability are limited in predicting decline among older adults. Innovations in GPS hardware and software can monitor driving behavior in the actual environments people drive in. Commercial off-the-shelf (COTS) devices are affordable, easy to install and capture large volumes of data in real-time. However, adapting these methodologies for research can be challenging. This study sought to adapt a COTS device and determine an interval that produced accurate data on the actual route driven for use in future studies involving older adults with and without AD.  Methods: Three subjects drove a single course in different vehicles at different intervals (30, 60 and 120 seconds), at different times of day, morning (9:00-11:59AM), afternoon (2:00-5:00PM) and night (7:00-10pm). The nine datasets were examined to determine the optimal collection interval. Results: Compared to the 120-second and 60-second intervals, the 30-second interval was optimal in capturing the actual route driven along with the lowest number of incorrect paths and affordability weighing considerations for data storage and curation. Discussion: Use of COTS devices offers minimal installation efforts, unobtrusive monitoring and discreet data extraction.  However, these devices require strict protocols and controlled testing for adoption into research paradigms.  After reliability and validity testing, these devices may provide valuable insight into daily driving behaviors and intraindividual change over time for populations of older adults with and without AD.  Data can be aggregated over time to look at changes or adverse events and ascertain if decline in performance is occurring.

Mood Changes in Cognitively Normal Older Adults are Linked to Alzheimer Disease Biomarker Levels.

OBJECTIVES: To evaluate whether cerebrospinal fluid (CSF) and PET Pittsburgh Compound B (PiB) biomarkers of underlying Alzheimer disease (AD) pathology (ß-amyloid42 [Aß42], tau, phosphorylated tau181 [ptau181], tau/Aß42, ptau181/Aß42 and mean cortical binding potential [MCBP] for PET-PiB) predict changes in mood in cognitively normal older adults. SETTING: Knight Alzheimer's Disease Research Center (ADRC) at Washington University (WU). PARTICIPANTS: Participants, 65 years of age or older, were enrolled from longitudinal studies at the WU Knight ADRC. MEASUREMENTS: CSF, PET-PiB biomarkers, Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), Profile of Mood States-Short Form (POMS-SF), the Geriatric Depression Scale (GDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Data from 118 participants at baseline and 66 participants at one-year follow-up were analyzed. CSF and PET biomarkers were not associated cross-sectionally with any mood disturbances at baseline (p > 0.05). Changes in mood as indicated by the total mood disturbance score on the POMS-SF, selected POMS-SF subscales, GDS, and NPI-Q scores from baseline to one-year follow-up were associated with (p < 0.05) CSF and PET-PiB biomarkers. There was no statistically significant decline in cognitive functioning. CONCLUSIONS: Generally, higher values of CSF and PET-PiB biomarkers are associated with more changes in mood in cognitively normal older adults. Further work is needed to understand the temporal development of mood changes over several years during the phase of preclinical AD. Evaluating mood as a noncognitive outcome may provide further insight into the development of preclinical AD in cognitively normal older adults.

Distinct muscle targets do not vary in the developmental regulation of brain-derived neurotrophic factor. J Comp Neurol 470:317-329,2004.

Developing neurons depend on many target-derived signals. One of these signals is the neurotrophin brain-derived neurotrophic factor (BDNF). Exogenous application of BDNF in vitro and in vivo rescues a population of lumbar motoneurons from programmed cell death. Given that BDNF does not rescue all motoneurons and that motoneurons differ in trophic factor receptor expression, subpopulations of motoneurons may have different sensitivities to the factor. These differences may be reflected in distinct target muscles specialized to produce different protein concentrations, or muscles may contain equal amounts of the factor and receptor expression determines motoneuron responsiveness. By using a sensitive electrochemiluminescent immunoassay (ECLIA), we measured normal developmental changes in BDNF protein concentration in anatomically and functionally distinct chick embryonic thigh muscles from E6 to E18. We found that there were no significant differences in BDNF protein concentration between muscles classified according to function (fast vs. slow) or anatomical position (flexor vs. extensor) and that the quantity of BDNF in the target did not appear to be activity dependent. These results suggest that, during development, the differences in the response of motoneurons to BDNF are not due to the anatomical or functional diversity of muscle targets. J. Comp. Neurol. 470:330-337, 2004.