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1.  Cultural Diversity and Views on Alzheimer’s Disease in Older African Americans 
Cultural constructs prevalent in older African Americans may influence their risk perceptions and knowledge of Alzheimer’s disease (AD). To examine this issue, we administered 3 sociocultural scales, the Alzheimer’s Disease Knowledge Scale, and a Risk Perception questionnaire to 271 older African Americans who were recruited from a large community senior center and local churches. Higher Present Time Orientation was significantly related to perceptions of having little control over risks to health (p = .004), God’s Will in determining AD (p = .001), and lower AD knowledge (p < .0001), and marginally related to having little control over developing AD (p = .052). Religiosity was marginally related to having little control over risks to health (p = .055) and getting AD″ (p =.057). Post hoc inter-group comparisons found significant differences in the highest vs. lowest scoring Religiosity groups. There were no significant differences by Future Time Orientation. Most subjects (57.6%) were unaware that African Americans were at higher risk for AD than whites. These data indicate that cultural diversity within older African Americans may shape health perceptions and knowledge of AD. This diversity may contribute to disparities in the detection and treatment of AD in this high risk population.
doi:10.1097/WAD.0b013e3182654794
PMCID: PMC3492535  PMID: 22828323
Cultural Diversity; Alzheimer’s Disease; African Americans
2.  Ventricular atrophy and its clinical correlates in the imaging cohort from the ADCS MCI Donepezil/Vitamin E study 
We analyzed the baseline and 3-year T1-weighted magnetic resonance imaging data of 110 amnestic mild cognitive impairment (MCI) participants with minimal hippocampal atrophy at baseline from the Alzheimer’s Disease Cooperative Study group (ADCS) MCI Donepezil/Vitamin E trial. 46 subjects converted to AD (MCIc) while 64 remained stable (MCInc). We used the radial distance technique to examine the differences in lateral ventricle shape and size between MCIc and MCInc and the associations between ventricular enlargement and cognitive decline.
MCIc group had significantly larger frontal and right body/occipital horns relative to MCInc at baseline and significantly larger bilateral frontal, body/occipital and left temporal horns at follow-up. Global cognitive decline measured with ADAScog and MMSE and decline in activities of daily living (ADL) were associated with posterior lateral ventricle enlargement. Decline in ADAScog and ADL were associated with left temporal and decline in MMSE with right temporal horn enlargement. After correction for baseline hippocampal volume decline in ADL showed a significant association with right frontal horn enlargement. Executive decline was associated with right frontal and left temporal horn enlargement.
doi:10.1097/WAD.0b013e3182677b3d
PMCID: PMC3662002  PMID: 23694947
Alzheimer’s disease; AD; mild cognitive impairment; MCI; imaging; MRI; brain atrophy; ventricular enlargement
3.  Caregiver burden, health utilities and institutional service costs among community-dwelling paients with Alzheimer's disease 
This study examined the moderating effect of caregiver burden on the relationship between patients’ health status and institutional costs in Alzheimer's disease (AD). Data were obtained on whether 421 community-dwelling patients with AD in the CATIE-AD trial received institutional services in the month preceding baseline and at 3-, 6-, and 9-months follow-up. All participants had a caregiver who lived with or visited them regularly. Outcome variables include hospital, nursing home, residential, and combined institutional costs. Mixed models were employed to estimate the interaction of Health Utility Index (HUI)-III scores (a health status measure) and five measures of caregiver burden. Wherever significant, results indicate that greater caregiver burden weakens the inverse relationship between health utilities and institutional costs, leading to greater costs than would be expected at a given level of health. Altogether 45.0% of the models (9/20) showed this effect (positive coefficient on the burden-HUI interaction term). Interventions should be based on caregiver burden, regardless of care recipient health status, for even seemingly manageable patients may be at heightened risk for institutionalization if caregivers experience sufficiently high levels of burden.
doi:10.1097/WAD.0b013e3181eb2f2e
PMCID: PMC3951163  PMID: 20625266
Alzheimer's disease; costs; caregiver burden; Health Utilities Index; correlates; institutions
4.  Novel TARDBP sequence variant and C9ORF72 repeat expansion in a family with frontotemporal dementia 
Alzheimer disease and associated disorders  2012;10.1097/WAD.0b013e318266fae5.
doi:10.1097/WAD.0b013e318266fae5
PMCID: PMC3511614  PMID: 22892647
frontotemporal lobar degeneration; frontotemporal dementia; mutation; TARDBP; TDP-43; C9ORF72
5.  Polyadenylated Messenger RNA in Paired Helical Filament-Immunoreactive Neurons in Alzheimer Disease 
Summary
An antibody raised against isolated paired helical filaments (PHF) was used to identify tangle-bearing (PHF+) neurons in autopsy brain tissue from six Alzheimer disease (AD) patients and six age-matched controls (AMC). A comparison of the levels of polyadenylated messenger RNA [poly(A)+ mRNA] in PHF+ and PHF− neurons of similar cross-sectional area in temporal and parietal lobe and cerebellum from four AD and four AMC brains was made by analysis of in situ hybridization of [3H] polyuridylate [poly(U)] to intracellular poly(A)+ mRNA. In PHF+ neurons, the level of poly(A)+. mRNA was approximately two-thirds that in similar-sized PHF− neurons in either AD or AMC. The level of poly(A)+ mRNA in PHF− neurons in regions of the brain that have more of the histopathologically defined effects in AD was similar to that in regions with less effects.
PMCID: PMC3886638  PMID: 1972628
Paired helical filament; Tangle-bearing neurons; Alzheimer disease; Polyadenylated messenger RNA
6.  Characterization of Apathy in Persons with Frontotemporal Dementia and The Impact on Family Caregivers 
This study characterized daytime activity and apathy in patients with behavioral variant frontotemporal dementia (bvFTD) and semantic dementia (SD) and their family caregivers. Twenty-two patient-caregiver dyads were enrolled,13 bvFTD and 9 SD.Data were collected on behaviors and movement. Patients and caregivers wore Actiwatches for 2 weeks to record activity. We predicted that bvFTD patients would show greater caregiver report of apathy and less daytime activity than patients diagnosed with SD. Findings: Patients with bvFTD spent 25% of their day immobile while patients with SD spent 16% of their day inactive. BvFTD caregivers spent 11% of their day immobile and SD caregivers 9%. Apathy was described as present in 100% of the patients with bvFTD and in all but one patient with SD, the severity of apathy was greater in bvFTD compared to SD. Apathy correlated with caregiver emotional distress in both groups. In conclusion, apathy has been defined as a condition of diminished motivation that is difficult to operationalize. Among patients with FTD, apathy was associated with lower levels of activity, greater number bouts of immobility and longer immobility bout duration. Apathy and diminished daytime activity appeared to have an impact on the caregiver. Objective measures of behavioral output may help in formulation of a more precise definition of apathy.
doi:10.1097/WAD.0b013e3182471c54
PMCID: PMC3383924  PMID: 22261729
frontotemporal dementia; semantic dementia; activity; caregiving; actigraphy; apathy
7.  Relating Memory To Functional Performance In Normal Aging to Dementia Using Hierarchical Bayesian Cognitive Processing Models 
Determining how cognition affects functional abilities is important in Alzheimer’s disease and related disorders (ADRD). 280 patients (normal or ADRD) received a total of 1,514 assessments using the Functional Assessment Staging Test (FAST) procedure and the MCI Screen (MCIS). A hierarchical Bayesian cognitive processing (HBCP) model was created by embedding a signal detection theory (SDT) model of the MCIS delayed recognition memory task into a hierarchical Bayesian framework. The SDT model used latent parameters of discriminability (memory process) and response bias (executive function) to predict, simultaneously, recognition memory performance for each patient and each FAST severity group.
The observed recognition memory data did not distinguish the six FAST severity stages, but the latent parameters completely separated them. The latent parameters were also used successfully to transform the ordinal FAST measure into a continuous measure reflecting the underlying continuum of functional severity.
HBCP models applied to recognition memory data from clinical practice settings accurately translated a latent measure of cognition to a continuous measure of functional severity for both individuals and FAST groups. Such a translation links two levels of brain information processing, and may enable more accurate correlations with other levels, such as those characterized by biomarkers.
doi:10.1097/WAD.0b013e31824d5668
PMCID: PMC3387504  PMID: 22407225
Neuropsychological Testing; Wordlist Memory; Recognition Memory; Functional Assessment Staging Test; Clinical Dementia Rating
8.  Patterns of striatal degeneration in frontotemporal dementia 
Behavioral variant frontotemporal dementia and semantic dementia have been associated with striatal degeneration, but few studies have delineated striatal subregion volumes in vivo or related them to clinical phenotype. We traced caudate, putamen, and nucleus accumbens on MR images to quantify volumes of these structures in behavioral variant frontotemporal dementia, semantic dementia, Alzheimer’s disease, and healthy controls (n = 12 per group). We further related these striatal volumes to clinical deficits and neuropathological findings in a subset of patients. Behavioral variant frontotemporal dementia and semantic dementia showed significant overall striatal atrophy compared with controls. Moreover, behavioral variant frontotemporal dementia showed panstriatal degeneration whereas semantic dementia featured a more focal pattern involving putamen and accumbens. Right-sided striatal atrophy, especially in the putamen, correlated with overall behavioral symptom severity and with specific behavioral domains. At autopsy, patients with behavioral variant frontotemporal dementia and semantic dementia showed striking and severe tau or TAR DNA-binding protein of 43 kDa pathology, especially in ventral parts of the striatum. These results demonstrate that ventral striatum degeneration is a prominent shared feature in behavioral variant frontotemporal dementia and semantic dementia and may contribute to social-emotional deficits common to both disorders.
doi:10.1097/WAD.0b013e31824a7df4
PMCID: PMC3389579  PMID: 22367382
9.  Impact of Subcortical Hyperintensities on Dual-tasking in Alzheimer’s Disease and Aging 
Alzheimer disease and associated disorders  2012;26(1):10.1097/WAD.0b013e3182172c58.
Subcortical hyperintensities (SH) on brain MRI are associated with cognitive and gait impairment in elderly but their impact on dual-tasking (performing cognitive tasks while walking) in patients with Alzheimer’s disease (AD) is unknown. This study explored the costs of dual-tasking in relation to SH severity in AD and normal controls (NC). Cadence while walking on a treadmill, and speed-accuracy-tradeoff (SAT), on three working memory tasks, were measured during single- and dual-task conditions. Dual-task costs (DTC) on SAT, cadence and overall DTC were measured for each of these tasks. On visual rating of SH severity, AD and NC groups were subdivided into high- and low-SH subgroups. Compared to the NC, the AD group performed poorly on all working memory tasks across both conditions, decreased cadence on dual-tasking and showed a decrement in overall DTC (all p< 0.01). When grouped according to SH severity, the low-SH-NC group performed superiorly on working-memory tasks (p<0.001) and the high-SH-AD group (p=0.001) showed a decrease in dual task costs of cadence. While the AD group showed a decrement in overall DTC (p<0.01) compared to NC, when assessed in terms of SH severity, the high-SH-AD group showed the largest decrement in DTC (p<0.01). Greater SH severity is associated with a decrement in overall dual-tasking ability in AD.
doi:10.1097/WAD.0b013e3182172c58
PMCID: PMC3874593  PMID: 21502852
Alzheimer’s Disease; subcortical; hyperintensities; gait; working memory; white matter disease; white matter hyperintensities; dual-tasking; cadence; cognition; walking; treadmill
10.  CSF Proteins Predict Longitudinal Hippocampal Degeneration in Early Stage Dementia of the Alzheimer Type 
Objective
Biomarkers are needed to improve the sensitivity and accuracy of diagnosis as well as prognosis in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type.
Design
A single CSF sample and longitudinal MR scans were collected. The CSF samples were assayed for tau, p-tau181, Aβ1–42 and Aβ1–40 by ELISA. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference.
Setting:
Patients or Other Participants
13 participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0).
Intervention
None.
Main Outcome Measures
Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum and CA2-4+DG cellular subfields. Their correlations with initial CSF measures.
Results
Lower CSF Aβ1–42 levels and higher tau/Aβ1–42 and p-tau181/Aβ1–42 ratios were strongly correlated with decreases in hippocampal volume and measure of progressive inward deformations of the CA1 subfield in participants with early AD, but not cognitively normal participants.
Conclusions
Despite small sample size, we found that Aβ1–42 and tau-related CSF measures were related to hippocampal degeneration in individuals with clinically diagnosed early AD, and may reflect an association with a common underlying disease mechanism.
doi:10.1097/WAD.0b013e31823c0cf4
PMCID: PMC3309103  PMID: 22156755
Magnetic Resonance Imaging (MRI); Hippocampal subfields; β-Amyloid; Tau; P-Tau; biomarkers
11.  Smoking, death, and Alzheimer’s disease: A case of competing risks 
If smoking is a risk factor for Alzheimer’s disease (AD) but a smoker dies of another cause before developing or manifesting AD, smoking-related mortality may mask the relationship between smoking and AD. This phenomenon, referred to as competing risk, complicates efforts to model the effect of smoking on AD. Typical survival regression models assume that censorship from analysis is unrelated to an individual’s probability of developing AD (i.e., that censoring is noninformative). However, if individuals who die before developing AD are younger than those who survive long enough to develop AD, and if they include a higher percentage of smokers than nonsmokers, the incidence of AD will appear to be higher in older individuals and in nonsmokers. Further, age-specific mortality rates are higher in smokers because they die earlier than nonsmokers. Therefore, if we fail to take into account the competing risk of death when we estimate the effect of smoking on AD, we bias the results and are really only comparing the incidence of AD in nonsmokers with that in the healthiest smokers. In this study, we demonstrate that the effect of smoking on AD differs in models that are and are not adjusted for competing risks.
doi:10.1097/WAD.0b013e3182420b6e
PMCID: PMC3321062  PMID: 22185783
Alzheimer disease; competing risks; elderly; mortality; smoking
13.  Subjective cognitive complaints of older adults at the population level: An item response theory analysis 
Subjective cognitive complaints (SCCs) are increasingly a focus in studies of prodromal Alzheimer disease (AD) and risk for dementia. Little is known about the optimal approach to measure SCCs. We used item response theory (IRT) to examine characteristics of 24 SCC items in a sample of 3,495 older adults pooled from four community-based studies. We investigated the potential advantages of IRT scoring over conventional scoring, based on participants' item response patterns. Items most likely endorsed by individuals low in SCC severity relate to word retrieval and general subjective memory decline. Items likely endorsed only by individuals high in SCC severity relate to non-episodic memory changes, such as decline in comprehension, judgment and executive functions, praxis and procedural memory, and social behavior changes. IRT scoring of SCCs was associated with performance on objective cognitive test performance above and beyond total SCC scores, and was associated with objective cognitive test performance among participants endorsing only one SCC item. Thus, IRT scoring captures additional information beyond a simple sum of SCC symptoms. Modern psychometric approaches including IRT may be useful in developing 1) brief community screening questionnaires, and 2) more sensitive measures of very subtle subjective decline for use in prodromal AD research.
doi:10.1097/WAD.0b013e3182420bdf
PMCID: PMC3337955  PMID: 22193355
Subjective memory; item response theory; dementia; neuropsychological tests; subjective cognitive impairment
14.  Maternal Transmission of Alzheimer Disease 
Some propose maternal Alzheimer disease (1) inheritance. We compared dementia family histories in AD cases and cognitively normal controls. We expected more mothers to have AD in both groups. If maternal risk was not only due to female longevity more AD cases’ than controls’ mothers should be demented. We matched 196 AD cases to 200 controls by gender and age. We obtained parent dementia status and age of death for 348 AD and 319 control parents. 24 (12%) controls’ fathers, 26 (13%) AD patient fathers, 58 (29%) controls’ mothers and 55 (28%) AD mothers had memory difficulty. More mothers than fathers had memory problems in both groups and the statistical significance persisted after adjusting for parent age at death and APOE for controls (OR=2.40, p=0.004) but not cases (OR=1.63, p=0.14), although results are qualitatively similar. There was no evidence of a real difference between the two groups in interaction analysis (p=0.41). Mothers of both cases and controls were more often affected than fathers, even after adjusting for age. Cases’ mothers were no more often demented than controls’ mothers, which does not support the maternal AD transmission. Rather, the increased number of affected mothers relates, at least in part, to female longevity.
doi:10.1097/WAD.0b013e318247d203
PMCID: PMC3371291  PMID: 22273801
Alzheimer disease; Inheritance; Genetics; Maternal
15.  Scales for the Evaluation of End-of-Life Care in Advanced Dementia: Sensitivity to Change 
The paucity of valid and reliable instruments designed to measure end-of-life experiences limits advanced dementia and palliative care research. Two end-of-life in dementia (EOLD) scales that evaluate the experiences of severely cognitively impaired persons and their health care proxies (HCP) have been developed: 1) symptom management (SM) and 2) satisfaction with care (SWC). The study objective was to examine the sensitivity of the EOLD scales to detect significant differences in clinically relevant outcomes in nursing home residents with advanced dementia. The SM-EOLD scale was sensitive to detecting changes in comfort among residents with pneumonia, pain, dyspnea, and receiving burdensome interventions. The SWC-EOLD scale was sensitive to detecting changes in HCP satisfaction with the care of residents when addressing whether the health care provider spent > 15 minutes discussing the resident’s advanced care planning, whether the physician counseled about the resident’s live expectancy, whether resident resided in a special care unit and whether the physician counseled possible resident health problems. This study extends the psychometric properties of the EOLD scales by showing the sensitivity to clinically meaningful change in these scales to specific outcomes related to end-of-life care and quality of life among residents with end-stage advanced dementia and their HCPs.
doi:10.1097/WAD.0b013e318247c41b
PMCID: PMC3424399  PMID: 22273800
Dementia; Nursing homes; End-of-life; Health care proxy; Sensitivity to change; Responsiveness
16.  A Single Ascending Dose Study of Bapineuzumab in Patients With Alzheimer Disease 
The safety, tolerability, and pharmacokinetics (PKs) of bapineuzumab (AAB–001), a humanized monoclonal antibody to amyloid β, were evaluated in patients with mild-to-moderate Alzheimer disease in a phase 1, randomized, third-party unblinded, placebo-controlled, single ascending dose trial. Thirty patients received bapineuzumab infusion of 0.5, 1.5, or 5mg/kg or placebo (6 active, 2 placebo for 0.5 and 1.5-mg/kg cohorts; 10 active, 4 placebo for 5.0-mg/kg cohort). Three patients in the highest dose cohort (5.0mg/kg) developed magnetic resonance imaging abnormalities consistent with vasogenic edema, predominantly high signal abnormalities on fluid-attenuated inversion recovery sequences, all of which resolved over time. Plasma amyloid β was elevated from baseline, peaking approximately 24 hours after infusion. PK analysis demonstrated a half-life of 21 to 26 days, supporting a 13-week dosing interval for bapineuzumab. This small, single-dose study demonstrated the safety profile and PK characteristics of bapineuzumab and was used to design later safety and efficacy trials.
doi:10.1097/WAD.0b013e3181c53b00
PMCID: PMC3715117  PMID: 20505438
bapineuzumab; Alzheimer disease; humans; pharmacokinetics; monoclonal antibody
17.  Novel Progranulin Mutation Detected in 2 Patients With FTLD 
Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions, and linkage to chromosome 17 was recently found to be caused by mutations in the progranulin (PGRN) gene. In this study, we screened a group of 51 FTLD patients for PGRN mutations and identified a novel exon 6 splice donor site deletion (IVS6+5_8delGTGA) in 2 unrelated patients. This mutation displayed an altered splicing pattern generating 2 aberrant transcripts and causing frameshifts of the coding sequence, premature termination codons, and a near absence of PGRN mRNA from the mutated alleles most likely through nonsense-mediated decay. The subsequent PGRN haploinsufficiency is consistent with previously described PGRN mutations. We present a molecular characterization of the IVS6+5_8delGTGA mutation and also describe clinical and neuropathologic features from the 2 patients carrying this PGRN mutation. From the screening of these 51 FTLD patients, we could also identify the earlier reported mutation Gln130fs, and several coding sequence variants that are most likely nonpathogenic.
doi:10.1097/WAD.0b013e3181fbc22c
PMCID: PMC3710288  PMID: 20975516
frontotemporal lobar degeneration; frontotemporal dementia; progranulin; ubiquitin; TDP-43
18.  Total Daily Activity Measured With Actigraphy and Motor Function in Community-Dwelling Older Persons With and Without Dementia 
Actigraphic measures of physical activity do not rely on participant self-report and may be of particular importance for efforts to examine the health benefits of physical activity across the full spectrum of older individuals especially those with dementia, a group in which loss of motor function is particularly salient. We tested whether actigraphy could be employed to examine the relationship between total daily physical activity and motor function in community-dwelling older persons both with (n=70) and without clinical dementia (n=624). Total daily activity was measured with actigraphy for a median of 9 (range 2–16) days. All participants also underwent a structured examination including 9 muscle strength and 9 motor performance measures summarized as a composite measure. In linear regression models controlling for age, sex, and education, total daily activity was associated with global motor scores (β=0.13, SD=0.01, p<0.001). This association remained significant after adjusting for body composition, cognition, depressive symptoms, disability, vascular risk factors and diseases (β=0.07, SD=0.01, p < 0.001). The association did not vary by dementia status (interaction p=0.53). In persons without dementia, the association was independent of self-reported physical activity. Total daily activity was associated with both muscle strength (β=0.10, SD=0.02, p<0.001) and motor performance (β=0.16, SD=0.02, p<0.001). Actigraphy can be employed in the community-setting to provide objective measures of total daily activity that are associated with a broad range of motor performances and these associations did not vary by dementia status. Actigraphy may provide a means to more fully explicate the nature and course of motor impairment in old age.
doi:10.1097/WAD.0b013e31822fc3cb
PMCID: PMC3251727  PMID: 21946015
actigraphy; physical activity; motor function
19.  The SIST-M: Predictive validity of a brief structured Clinical Dementia Rating interview 
Background
We previously established reliability and cross-sectional validity of the SIST-M (Structured Interview and Scoring Tool–Massachusetts Alzheimer's Disease Research Center), a shortened version of an instrument shown to predict progression to Alzheimer disease (AD), even among persons with very mild cognitive impairment (vMCI).
Objective
To test predictive validity of the SIST-M.
Methods
Participants were 342 community-dwelling, non-demented older adults in a longitudinal study. Baseline Clinical Dementia Rating (CDR) ratings were determined by either: 1) clinician interviews or 2) a previously developed computer algorithm based on 60 questions (of a possible 131) extracted from clinician interviews. We developed age+gender+education-adjusted Cox proportional hazards models using CDR-sum-of-boxes (CDR-SB) as the predictor, where CDR-SB was determined by either clinician interview or algorithm; models were run for the full sample (n=342) and among those jointly classified as vMCI using clinician- and algorithm-based CDR ratings (n=156). We directly compared predictive accuracy using time-dependent Receiver Operating Characteristic (ROC) curves.
Results
AD hazard ratios (HRs) were similar for clinician-based and algorithm-based CDR-SB: for a 1-point increment in CDR-SB, respective HRs (95% CI)=3.1 (2.5,3.9) and 2.8 (2.2,3.5); among those with vMCI, respective HRs (95% CI) were 2.2 (1.6,3.2) and 2.1 (1.5,3.0). Similarly high predictive accuracy was achieved: the concordance probability (weighted average of the area-under-the-ROC curves) over follow-up was 0.78 vs. 0.76 using clinician-based vs. algorithm-based CDR-SB.
Conclusion
CDR scores based on items from this shortened interview had high predictive ability for AD – comparable to that using a lengthy clinical interview.
doi:10.1097/WAD.0b013e318231cd30
PMCID: PMC3257375  PMID: 21986342
Alzheimer disease; mild cognitive impairment; dementia; CDR; instrument; questionnaire; validity; prediction; psychometric
20.  Agreement about diagnosis among patients, companions, and professionals following a dementia evaluation 
A dementia diagnosis is challenging to deliver and to hear, yet agreement about a diagnosis is essential for effective dementia care. We examined consensus about the results of a dementia evaluation in 90 patients assessed at an Alzheimer’s Disease Research Center. Diagnostic impressions were obtained from five sources: 1) the physician’s chart diagnosis, 2) the patient who was evaluated, 3) a companion present at the evaluation, 4) a diagnostic summary written by a nurse present during the evaluation, and 5) raters who watched a video of the diagnostic disclosure conversation. Overall, diagnostic consensus was only moderate. Patients and companions exhibited just fair agreement with one another. Agreement was better between physicians and companions compared to physicians and patients, though imperfect between the physician and video raters and the written summary. Agreement among sources varied by dementia severity, with lowest agreement occurring in instances of very mild dementia. This study documents discrepancies that can arise in diagnostic communication, which could influence adjustment to a dementia diagnosis and decisions regarding future planning and care.
doi:10.1097/WAD.0b013e3182351c04
PMCID: PMC3277665  PMID: 22037598
Alzheimer’s disease; dementia; diagnostic disclosure; doctor-patient communication; patient education
21.  Sources of Stress for Family Members of Nursing Home Residents with Advanced Dementia 
The sources of stress for families of nursing home (NH) residents with advanced dementia have not been well described. Semi--structured interviews were conducted with 16 family members previously enrolled in the Choices, Attitudes and Strategies for Care of Advanced Dementia at the End-of-Life (CASCADE) study, a prospective cohort of 323 NH residents with advanced dementia and their family members. Questions inquired about the experience of having a family member in the NH, communication with health care professionals, surrogate decision-making, emotional distress and recommendations for improvement in care. Transcripts were analyzed using the constant comparative method. The majority of participants were female (63%), children of the resident (94%) and white (94%). The average age was 62 years. Four themes emerged: 1) inadequate resident personal care, resulting in family member vigilance and participation in care; 2) stress at the time of NH admission; 3) lack of communication with NH physicians; and 4) challenges of surrogate decision making, including the need for education to support advance care planning and end-of-life decisions. Our results support the provision of emotional support to families upon resident admission, education regarding prognosis to guide decision making, improved resident care and greater communication with health care professionals.
doi:10.1097/WAD.0b013e31823899e4
PMCID: PMC3288670  PMID: 22037596
caregivers; long-term care; Alzheimer’s disease
22.  The Influence of Chronic Stress on Dementia-Related Diagnostic Change in Older Adults 
Increased susceptibility of the aging brain to both chronic stress and incipient dementia-related neuropathology may accelerate cognitive decline. We investigated associations between chronic stress and diagnostic change in 62 individuals (mean age=78.7) participating in an Alzheimer’s disease research center longitudinal study. Subjects, diagnosed at baseline as cognitively normal (CN) or Mild Cognitive Impairment (MCI) were followed an average of 2.5 years. Senior neurologists, blind to detailed measures of stress and cognition, assigned diagnoses annually. Logistic regression analyses assessed accuracy with which measures of stress (event-based ratings, cortisol levels) predicted conversion to MCI and dementia. Eleven individuals with MCI at baseline received a dementia diagnosis during follow-up. Sixteen converted from CN to MCI. Prolonged, highly stressful experiences were associated with conversion from MCI to dementia. The cortisol awakening response, with age and education, was associated with diagnostic change to MCI. Cortisol measures were not associated with progression from MCI to dementia, and there was no association between stressful experiences and change to MCI. Mechanisms associated with the transition from normal cognition to MCI may differ from those associated with diagnostic change to dementia. These findings could facilitate identification of interventional strategies to reduce risk of decline at different stages of susceptibility.
doi:10.1097/WAD.0b013e3182389a9c
PMCID: PMC3290680  PMID: 22037597
chronic stress; aging; Alzheimer’s disease; mild cognitive impairment; dementia; diurnal rhythm; cortisol awakening response
23.  Effects of Simvastatin on Cholesterol Metabolism and Alzheimer Disease Biomarkers 
Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-β (Aβ) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 40 mg/d and then 80 mg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of Aβ and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment.
doi:10.1097/WAD.0b013e3181d61fea
PMCID: PMC3694274  PMID: 20473136
Alzheimer disease; simvastatin; cholesterol; biomarker
24.  Cardiovascular risk factors and incident Alzheimer disease: A systematic review of the literature 
Objective
The purpose of this study was to conduct a systematic review of the literature of cardiovascular factors pertaining to incident Alzheimer disease (AD).
Methods
A systematic literature review was conducted of all studies of cardiovascular risk factors for incident AD listed in PUBMED in English from 2000–2007. Risk factors included hypertension, diabetes, exercise, alcohol intake, smoking, B complex vitamins, homocysteine, stroke, atrial fibrillation, APOE, lipids, and diet. Inclusion criteria consisted of diagnoses of incident AD and longitudinal studies with cohorts of 500 or more.
Results
Individual clinically defined risk factors such as hypertension and diabetes were not significantly associated with increased risk for AD. The strength of the association for hypertension could be considerably strengthened by changing criteria such as midlife measurements or using higher cutoffs for systolic blood pressure. APOE ε4 was the most consistent risk factor. Interactions between risk factors modify risk particularly for hypertension and diabetes. Interactions modifying risk were also found for exercise and physical function, APOE ε4, diabetes and cholesterol.
Conclusions
In this review the evidence that single clinically defined cardiovascular risk factors are significantly associated with incident Alzheimer disease is inconsistent at best. The strength of the association of cardiovascular risk factors and AD can be influenced greatly by changing the parameters of measurement of risk factors and by identifying interactions between the factors.
doi:10.1097/WAD.0b013e318187541c
PMCID: PMC3689425  PMID: 18703981
incident Alzheimer disease; cardiovascular risk factors; interactions
25.  Trajectories of Caregiving Time Provided by Wives to Their Husbands With Dementia 
Spouses are often the first providers of informal care when their partners develop dementia. We used The National Longitudinal Caregiver Study (NLCS, 4 annual surveys, 1999 to 2002) and identified 3 distinct longitudinal patterns (trajectory classes) of total daily caregiving time provided by the wife to her husband using Generalized growth mixture models (GGMM). About 56.4% of the sample (N=828) was found to have an increase in the trajectory of total daily caregiving time (mean 252 min/d at baseline, rising to 471 min/d at time 4). Four hundred forty-four (30.3%) caregivers had a trajectory described by a moderate increase in caregiving time (an increase from a mean of 464 min/d at baseline to 533 at wave 4), whereas 195 (13.3%) had a sharply declining trajectory (a decline from a mean of 719 min/d at baseline to 421 at wave 4). There was no significant difference in the duration (time since onset) of caregiving at baseline for these 3 trajectories. GGMM are well suited for the identification of distinct trajectory classes. Here they show that there are large differences in caregiving time provided to persons with dementia, who seem to be quite similar.
doi:10.1097/WAD.0b013e31815bebba
PMCID: PMC3679901  PMID: 18525284
informal caregiving; longitudinal methods; burden of Alzheimer disease/dementia

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