Neurotrophic Factor Genetics of Cognitive Progression and Neuropsychiatric Symptom Presentation in Alzheimer\u27s Disease and Related Disorders

The Cache County Study on Memory in Aging (CCSMA) and subsequent Dementia Progression Study (DPS) were two research studies that took place in Cache County, Utah. These studies followed 5092 participants aged 65 or older for approximately 12 years and looked at risk and protective factors for dementia, including Alzheimer’s disease. One of the factors investigated was genes that are known to influence brain health, such as brain-derived neurotrophic factor (BDNF), a protein found in the brain that helps with the survival of brain cells. BDNF genes have been shown to be associated with Alzheimer’s disease and related dementia (ADRD) risk, but little is known about the influence these genes have after dementia is diagnosed. The current study looked at how BDNF related genes were associated with learning and memory abilities (i.e. cognitive ability) and problematic behaviors (e.g. delusions, agitation/aggression, anxiety) in individuals from the CCSMA and DPS who were diagnosed with ADRD. This research is important to help understand what may contribute to often-seen differences in dementia progression and help inform possible treatment decisions. The results of the current project showed that BDNF genes influenced both progression of cognitive difficulties and problematic behaviors in individuals with ADRD. Additionally, it was shown that many of these effects depended on the sex of the individual, such that men and women progressed at different rates and were influenced by different BDNF related genotypes. These results provide evidence of the influence of BDNF genes after dementia diagnosis and highlights the need to investigate contributing factors related to the sex of the individual. Targeted medication or behavioral treatment of dementia that both improves BDNF function in the brain, as well as mitigates any sex-related effects, may also be another avenue for future research

Specific Cognitive/Behavioral Domains Predict Neuropsychiatric Symptoms in Severe Dementia

Background: Neuropsychiatric symptoms (NPS) have high prevalence in Alzheimer’s disease and related disorders (ADRD), with nearly 100% of individuals experiencing some type of symptom over the course of dementia (Tschanz et al, 2011). The occurrence of NPS is highly variable and fluctuates in severity (Tschanz et al., 2016). Their occurrence differs by type of dementia and increases over time (Kazui et al., 2016). Although risk factors for NPS in ADRD have been studied (e.g., Steinberg et al., 2014; Treiber et al, 2008), greater understanding of the nature of NPS and their triggers is needed to inform care management strategies (Gauthier et al., 2010). While much research has examined NPS in mild-to-moderate dementia, fewer studies have examined NPS in severe dementia. We investigated the cognitive correlates of NPS in patients with severe dementia in a community-based sample, examining whether impairments in specific cognitive or behavioral domains were more predictive of specific NPS. We hypothesized that poorer cognitive abilities would be associated with more severe NPS (e.g., agitation) and higher cognitive scores with affective symptoms in severe dementia. Methods: Eighty-nine (27%) out of 328 total participants of a longitudinal study of dementia progression (the Cache County Dementia Progression Study) met criteria for severe dementia: Mini-Mental State Exam (MMSE) score of ≤10 or Clinical Dementia Rating of 3 (severe). Forty-eight (54%) of these individuals completed the Severe Cognitive Impairment Profile (SCIP), which assessed the following domains: Comportment, Attention, Language, Memory, Motor, Conceptualization, Arithmetic, and Visuospatial abilities. NPS were assessed by caregiver report using the Neuropsychiatric Inventory (NPI). The NPI assesses delusions, hallucinations, depression, anxiety, irritability, apathy, agitation/aggression, judgement, aberrant motor behaviors, euphoria, sleep and appetite. Demographic information, overall health, place of residence (private home, assisted living facility and nursing home), and dementia duration were also assessed. NPI severity scores (intensity x frequency) were summed across domains to yield a total NPI score (Total NPI-12) and domain clusters of psychotic symptoms (hallucinations and delusions), affective symptoms (depression, anxiety, and irritability), apathy, and agitation/aggression were examined. Bivariate correlations between SCIP domain scores and Total NPI-12 and the domain clusters were examined. SCIP domain scores that were significantly correlated with NPI scores in bivariate analyses were entered into multiple regression models. Covariates tested included the age at which severe dementia criteria was met, the duration of dementia from age of onset, gender, place of residence, overall health and years of education. Results: Mean (SD) age and education were 86.23 (6.12) and 13.13 (3.13), respectively. Total NPI-12 scores showed significant correlations with the SCIP sub scores of comportment ( r = -0.36, p = 0.017) and memory (r = - 0.31, p = 0.047). Apathy significantly correlated with comportment (r = -0.38, p = 0.010) while agitation/aggression correlated with conceptualization (r = -0.41, p = 0.007), language (r = -0.36, p = 0.017), memory (r = -0.48, p = 0.001), and visuospatial ability (r = -0.31, p = 0.045). In multiple regression models (with inclusion of significant covariates), total NPI-12 scores were significantly associated with comportment (β = -1.32, SE = 0.56, p = 0.02); apathy was significantly associated with comportment (β = -0.01, SE = 0.02, p = 0.003); and agitation/aggression was significantly associated with memory (β = -0.43, SE = 0.12, p = 0.001). NPI affective and psychotic scores were not associated with any SCIP domains. Conclusion: In this sample of individuals with severe dementia, we found several cognitive or behavioral domains were associated with NPS. Poorer abilities in Comportment, which consisted of responses to social questions (e.g., greetings) were associated with more severe apathy, and poorer abilities in conceptualization, language, memory and visuospatial skills were associated with more severe agitation/aggression. With the latter, multiple regression models found only memory scores to independently predict agitation/aggression, reflecting moderate correlation between cognitive domains. Our results suggest that poor cognitive abilities may increase vulnerability to NPS, possibly as a result of impaired comprehension of activities and events in the environment. Cognitive testing may be useful to identify those at greatest risk for NPS. Furthermore, environmental manipulations that aim to decrease the complexity and therefore degree of stimulation for persons with dementia to a level more appropriate to their level of cognitive function may help reduce the occurrence of NPS in severe dementia

Intelligence and neural activation : a test of the relationship between the neural efficiency hypothesis and repetition suppression

honors thesisCollege of Social & Behavioral SciencePsychologyMatthew J. EulerThe Neural Efficiency Hypothesis (NEH) states that individuals with higher measured intelligence exhibit less neural activation on relatively simple tasks compared to those with lower intelligence (Haier et al., 1988). Furthermore, this phenomenon may interact with repetition suppression, or the reduction of neural activity following repeat stimulus exposure (Grill-Spector et al., 2006). The current study examined the relationship between intelligence and event-related EEG amplitudes and latencies during the third of three task conditions, a visual repetition paradigm. Full Scale IQ (FSIQ) scores from the Wechsler Adult Intelligence Scale III (WAIS-III; Wechsler, 1997) were collected on 30 participants, 18 of whom had sufficient numbers of EEG trials for further analysis (FSIQ: M = 111.56, SD = 13.28, range = 91 to 131). During EEG recording, participants were asked to respond to randomized line drawings representing one of three stimulus conditions from the previous two tasks: Repeated stimuli, Once-viewed, and Novel stimuli. Time-frequency analyses were conducted to identify peak phase-locked activity in the theta (4-7 Hz) and alpha (8-12 Hz) bands between 0 and 500 milliseconds poststimulus. Results demonstrated no significant effects of IQ or stimulus condition on peak theta and alpha amplitudes. However, difference scores between Novel and Once-viewed conditions in peak theta latency showed a strong positive correlation with IQ (r[16] = .712, p < .01). These findings appear consistent with the NEH in suggesting that higher IQ individuals may process previously-seen stimuli more efficiently than lower IQ individuals, as evidenced by shorter peak latencies relative to stimulus onset

Lifetime Estrogen Exposure and Brain-Derived Neurotrophic Factor: Implications for Cognitive Decline in Late Life

The Cache County Study on Memory in Aging (CCSMA) is a longitudinal population-based study which took place in Cache County, Utah. The study followed 5092 older-adult residents (aged 65+) for approximately 12 years to examine risk and protective factors for dementia. Participants completed dementia screening and follow-up assessments across four triennial visits. Additionally, researchers gathered information regarding demographics, reproductive history (e.g. age of menopause; hormone replacement therapy [HRT]) and other health-related factors, such as physical activity. Genotyping of DNA was completed for a genetic variation of genes for brain-derived neurotrophic factor (BDNF), a protein found in the brain associated with neuronal health and survival. Estrogen has been associated with cognitive health and has been shown to interact with BDNF in the brain to promote neuronal survival. The current research investigated the associations between estrogen, BDNF, and cognitive decline in older adult women from the CCSMA. An examination of how reproductive history, including the reproductive window (age of menarche to menopause) and use of HRT, affects the cognitive health of women in older adulthood can provide a clearer understanding of how estrogen exposure across the lifespan contributes to cognition in late life. This research can be helpful in determining the implications of events such as pregnancy, breastfeeding, surgical menopause and use of HRT on cognitive decline. Additionally, an investigation of how these reproductive factors interact with BDNF genetics is important to understand gene-by-environment interactions. The results of the current project demonstrated that increased lifelong estrogen exposure, both in the form of the reproductive window and HRT use, had small cognitive benefits for women in late life. Additionally, it was shown that women who initiated HRT use closer to menopause had increased cognitive status compared to those who initiated later. The specific BDNF gene under investigation was not associated with cognitive status in late life, neither was the interaction between BDNF and lifetime estrogen exposure. This research contributes to the discussion of sex-dependent factors of cognitive health and can help provide a better understanding late life cognitive decline

Neuropsychiatric Symptoms as Risk Factors for Cognitive Decline in Clinically Normal Older Adults: The Cache County Study.

INTRODUCTION: There has been considerable progress in identifying early cognitive and biomarker predictors of Alzheimer\u27s disease (AD). Neuropsychiatric symptoms (NPS) are common in AD and appear to predict progression after the onset of mild cognitive impairment or dementia. OBJECTIVES: The objective of the study is to examine the relationship between NPS in clinically normal older adults and subsequent cognitive decline in a population-based sample. METHODS: The Cache County Study on Memory in Aging consists of a population-based sample of 5,092 older adults. We identified 470 clinically normal adults who were followed for an average period of 5.73 years. NPS were evaluated at the baseline clinical assessment using the Neuropsychiatric Inventory (NPI). NPI domain scores were quantified as the product of frequency X severity in individual NPI domains, and then summed for the NPI-Total. Neuropsychological measures were collected at baseline and at each subsequent follow-up wave. Linear mixed-effects models assessed the association of NPI-Total, NPI-Depression, and NPI-Anxiety scores (obtained at baseline) on longitudinal change in neuropsychological performance, controlling for age, sex, and education. RESULTS: Baseline NPI-Total score was associated with a more rapid rate of decline in word list memory, praxis recall, and animal fluency. Baseline NPI-Depression was not associated with later decline on any of the cognitive tests, while baseline NPI-Anxiety was associated with decline in Symbol Digit Modality. CONCLUSION: In conclusion, among clinically normal older adults derived from this population-based study, total burden of NPS was associated with longitudinal cognitive decline. These results add to the evidence that NPS are risk factors for or clinical indicators of preclinical dementia syndrome. Our study was an exploratory study and we did not control for multiple comparisons