Faculty Bibliography

Background: Subjective Cognitive Impairment (SCI), Global Deterioration Scale stage 2, is common in older persons. A study of otherwise healthy persons found that 54% of SCI subjects followed over 7 years progressed toMild Cognitive Impairment (MCI) or dementia (Reisberg, et al., Alzheimer's & Dementia, 2010).1 Medications may contribute to SCI occurrence, however, their influence on SCI outcome is largely unknown. Therefore, we investigated the impact of medications subsequently associated with dementia risk in our previously characterized cohort.1 Methods: Subjects with SCI at baseline from our 2010 publication1 were studied. These subjects had baseline evaluations between 1/1/1984 and 12/31/1997 and were followed until 12/31/2001. Medication data was available on 143 of 166 subjects. Subjects receiving topical estrogen at the baseline evaluationwere excluded fromthese analyses. At baseline, evaluable subjects (N = 140; 91 women, 49 men) had a mean age of 66.5 +/- 8.4 years; 15.6 +/- 2.7 years of education; and MMSE scores of 29.0 +/- 1.2. Twenty-two women (24.2%) were receiving HRT, comprising estrogen (n = 10) or estrogen-progesterone combination (n = 12). Results: Subjects were followed over 7.0 +/- 3.4 years. Increased age and education were associated with clinical progression in this cohort (OR = 1.06 and 0.78 respectively; p-values < 0.05). Three of ten estrogenonly (30%) subjects progressed (2 to MCI, 1 to dementia); seven of twelve estrogen-progesterone (58.3%) subjects progressed (6 toMCI, 1 to dementia). In the total HRT group, 45.5% progressed, whereas in the control group (no-HRT), 62 of 118 progressed (52.5%), (49 to MCI, 13 to dementia). Age, education and gender did not differ significantly between subjects in the study groups (t-test and chi-square p-values, NS). Multivariate logistic regression for each condition was performed investigating differences in therapy, age, gender and education. Therapy was not associated with progression status. Conclusions: HRT did not influence 7-year outcome in SCI subjects. Therefore, SCI subjects were not particularly sensitive to reported deleterious effects of HRT on progression of cognitive decline. Systematic longitudinal investigation of possible effects of other medications/conditions on progression of SCI to MCI/dementia is required to identify substances that may regulate/prevent this process

Background: Impairment in functional capacities is an integral domain in AD presentation, diagnosis and progression. Among many functional scales for AD assessment, the Functional Assessment Staging scale (FAST) (Table 1) uniquely: (1) charts the entire course of AD, from normal aging to most severe AD; (2) has relevance for AD diagnosis and differential diagnosis; and (3) is brief and easy to utilize. Methods: Reliability, validity, and utility of the FAST have been documented in worldwide studies and clinical settings. Results: The FAST has excellent reliability (e.g., Foster et al., Int J Geriatr. Psychiatry,1988; Sclan and Reisberg, Int. Psychogeriatr., 1992). Concurrent validity has been demonstrated with: cognitive assessments across the severity spectrum (e.g., Reisberg, et al., Int. Psychogeriatr., 1992; Shimada, et al., Psychogeriatrics, 2003; Auer et al., JAGS, 1994); other dementia scales (Na et al., JAD, 2010); and neurologic assessments (Franssen and Reisberg, Int. Psychogeriatr., 1997). Criterion validity investigations have indicated superiority of the FAST in comparison with the MMSE, in tracking the course of AD. E.g., in a 5 year prospective longitudinal study of AD course, the FAST accounted for w 2x the temporal variance of the MMSE (Reisberg, et al., Int. Psychogeriatr., 1996). Also, in a range where the MMSE is zero, the FAST demonstrated very robust relationships to AD neuropathology (e.g., r = 0.9 [p 0.01], with hippocampal cornu ammonis neuronal loss), (Bobinski, et al., J. Neuropathol. Exp. Neurol., 1997). Additionally, in a pivotal trial, associated with worldwide approvals of memantine for AD treatment, FAST scores were sensitive to the intervention, MMSE change was not (Reisberg, et al., N Engl J Med., 2003). The FAST has shown widespread utility (e.g., usage mandated by U.S.A. Medicare since 1998, and the U.S.A. Veterans Administration System, since 2008). Conclusions: As noted in a Korean publication, the FAST is a rapid and easy to use staging tool with excellent validity. it. successfully measure[ s] detailed function throughout the entire course of AD. the FAST is composed of simple . and easy to understand sentences

OBJECTIVES: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. DESIGN: Association study of AD and CLU, PICALM, CR1, and APOE genotypes. SETTING: Academic research institutions in the United States, Canada, and Israel. PARTICIPANTS: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. RESULTS: Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE epsilon4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE epsilon4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE epsilon4, and an interaction term showed significant interaction between presence or absence of APOE epsilon4 and PICALM. CONCLUSIONS: We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE epsilon4-positive subjects. Thus, APOE and PICALM synergistically interact.

BACKGROUND:Cognitive, global and functional instruments have been extensively investigated for correlations with neuropathological changes such as neurofibrillary tangles (NFTs), plaques, and synapse loss in the brain. OBJECTIVE:Our objective is to correlate the functional, global and cognitive decline assessed clinically with the neuropathological changes observed in a large prospectively characterized cohort of mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS:We examined 150 subjects (16 MCI and 134 AD) that were prospectively assessed and longitudinally followed to autopsy. MCI subjects clinically met Petersen criteria for single or multi-domain amnestic MCI. AD subjects clinically met NINCDS-ADRDA criteria for probable or possible AD. All subjects received the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and the Mini Mental State Examination (MMSE) ante-mortem. Plaque and tangle counts were gathered for hippocampus, entorhinal cortex, frontal, temporal and parietal cortices. Braak staging was performed as well. RESULTS:The GDS, FAST and MMSE correlated with plaque counts in all regions. The GDS, FAST and MMSE correlated with tangle counts in in all regions. The three instruments also correlated with the Braak score. The MMSE and GDS correlate better than the FAST in most regions. CONCLUSIONS:Accumulation of neuropathology appears to correlate with functional, global, and cognitive decline as people progress from MCI through AD.

BACKGROUND: Subjective cognitive impairment (SCI) in older persons without manifest symptomatology is a common condition with a largely unclear prognosis. We hypothesized that (1) examining outcome for a sufficient period by using conversion to mild cognitive impairment (MCI) or dementia would clarify SCI prognosis, and (2) with the aforementioned procedures, the prognosis of SCI subjects would differ significantly from that of demographically matched healthy subjects, free of SCI, termed no cognitive impairment (NCI) subjects. METHODS: A consecutive series of healthy subjects, aged > or =40 years, presenting with NCI or SCI to a brain aging and dementia research center during a 14-year interval, were studied and followed up during an 18-year observation window. The study population (60 NCI, 200 SCI, 60% female) had a mean age of 67.2 +/- 9.1 years, was well-educated (mean, 15.5 +/- 2.7 years), and cognitively normal (Mini-Mental State Examination, 29.1 +/- 1.2). RESULTS: A total of 213 subjects (81.9% of the study population) were followed up. Follow-up occurred during a mean period of 6.8 +/- 3.4 years, and subjects had a mean of 2.9 +/- 1.6 follow-up visits. Seven NCI (14.9%) and 90 SCI (54.2%) subjects declined (P < .0001). Of NCI decliners, five declined to MCI and two to probable Alzheimer's disease. Of SCI decliners, 71 declined to MCI and 19 to dementia diagnoses. Controlling for baseline demographic variables and follow-up time, Weibull proportional hazards model revealed increased decline in SCI subjects (hazard ratio, 4.5; 95% confidence interval, 1.9-10.3), whereas the accelerated failure time model analysis with an underlying Weibull survival function showed that SCI subjects declined more rapidly, at 60% of the rate of NCI subjects (95% confidence interval, 0.45-0.80). Furthermore, mean time to decline was 3.5 years longer for NCI than for SCI subjects (P = .0003). CONCLUSIONS: These results indicate that SCI in subjects with normal cognition is a harbinger of further decline in most subjects during a 7-year mean follow-up interval. Relevance for community populations should be investigated, and prevention studies in this at-risk population should be explored

INTRODUCTION: Nonpharmacological therapies (NPTs) can improve the quality of life (QoL) of people with Alzheimer's disease (AD) and their carers. The objective of this study was to evaluate the best evidence on the effects of NPTs in AD and related disorders (ADRD) by performing a systematic review and meta-analysis of the entire field. METHODS: Existing reviews and major electronic databases were searched for randomized controlled trials (RCTs). The deadline for study inclusion was September 15, 2008. Intervention categories and outcome domains were predefined by consensus. Two researchers working together detected 1,313 candidate studies of which 179 RCTs belonging to 26 intervention categories were selected. Cognitive deterioration had to be documented in all participants, and degenerative etiology (indicating dementia) had to be present or presumed in at least 80% of the subjects. Evidence tables, meta-analysis and summaries of results were elaborated by the first author and reviewed by author subgroups. Methods for rating level of evidence and grading practice recommendations were adapted from the Oxford Center for Evidence-Based Medicine. RESULTS: Grade A treatment recommendation was achieved for institutionalization delay (multicomponent interventions for the caregiver, CG). Grade B recommendation was reached for the person with dementia (PWD) for: improvement in cognition (cognitive training, cognitive stimulation, multicomponent interventions for the PWD); activities of daily living (ADL) (ADL training, multicomponent interventions for the PWD); behavior (cognitive stimulation, multicomponent interventions for the PWD, behavioral interventions, professional CG training); mood (multicomponent interventions for the PWD); QoL (multicomponent interventions for PWD and CG) and restraint prevention (professional CG training); for the CG, grade B was also reached for: CG mood (CG education, CG support, multicomponent interventions for the CG); CG psychological well-being (cognitive stimulation, multicomponent interventions for the CG); CG QoL (multicomponent interventions for PWD and CG). CONCLUSION: NPTs emerge as a useful, versatile and potentially cost-effective approach to improve outcomes and QoL in ADRD for both the PWD and CG