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1.  Capgras syndrome in Dementia with Lewy Bodies 
Capgras syndrome is characterized by the recurrent, transient belief that a person has been replaced by an identical imposter. We reviewed clinical characteristics of Dementia with Lewy Bodies (DLB) patients with Capgras syndrome compared to those without Capgras.
We identified 55 consecutive DLB patients (11 cases with Capgras syndrome (DLB-C) and 44 cases without evidence of Capgras (DLB). Semi-structured interviews with the patient and an informant, neurological exams, and neuropsychological testing were performed. Caregivers were assessed for caregiver burden and depression. Primary comparisons were made between DLB-C and DLB. Exploratory analyses using stepwise logistic regression and bootstrap analyses were performed to determine clinical features associated with Capgras.
DLB-C patients experienced more visual hallucinations and self-reported anxiety, had higher scores on the Neuropsychiatric Inventory, and were less likely to be treated with cholinesterase inhibitors at time of initial evaluation. Extrapyramidal symptoms and depression were not associated with Capgras. Caregivers of DLB-C patients had higher caregiver burden. DLB-C was associated with self-reported anxiety (OR 10.9; 95% CI 2.6–47.6). In a bootstrap analysis, clinical findings that were predictors of Capgras included visual hallucinations (log(OR) 18.3; 95% CI 17.9–19.3) and anxiety (log(OR) 2.9; 95% CI (0.31–20.2).
Our study suggests that Capgras syndrome is common in DLB and usually occurs in the presence of anxiety and visual hallucinations, suggesting related etiopathogenesis. Early appreciation of Capgras syndrome may afford the opportunity to alleviate caregiver burden and improve patient and caregiver outcomes.
PMCID: PMC3713629  PMID: 12489921
Lewy body; dementia; Capgras syndrome; caregiver burden; hallucinations; delusions
2.  Missing Drivers with Dementia: Antecedents and Recovery 
Journal of the American Geriatrics Society  2012;60(11):10.1111/j.1532-5415.2012.04159.x.
To determine the circumstance in which persons with dementia become lost while driving, how missing drivers are found, and how Silver Alert notificationsare instrumental in those discoveries.
A retrospective, descriptive study.
Retrospective record review.
Conducted using 156 records from the Florida Silver Alert program for the time period October, 2008 through May 2010. These alerts were issued in Florida for a missing driver with dementia.
Information derived from the reports on characteristics of the missing driver, antecedents to missing event and discovery of a missing driver.
The majority of missing drivers were males, with ages ranging from 58’94, who were being cared for by a spouse. Most drivers became lost on routine, caregiver-sanctioned trips to usual locations. Only 15% were in the act of driving when found with most being found in or near a parked car and the large majority were found by law enforcement officers. Only 40% were found in the county they went missing and 10% were found in a different state. Silver Alert notifications were most effective for law enforcement; citizen alerts resulted in a few discoveries. There was a 5% mortality rate in the study population with those living alone more likely to be found dead than alive. An additional 15% were found in dangerous situations such as stopped on railroad tracks. Thirty-two percent had documented driving or dangerous errors such as, driving thewrong way or into secluded areas, or walking in or near roadways.
PMCID: PMC3827978  PMID: 23134069
dementia; driving; deaths
3.  Reply: The impact of dementia prevalence on the utility of the AD8 
Brain  2011;135(1):e204.
PMCID: PMC3267977
Primary care providers routinely evaluate older adults and are thus in a position to first detect symptoms and signs of Alzheimer’s disease. In urban areas, diagnostic or management difficulties may be referred to specialists; however, in rural areas, specialists may not be available. The Clinician Partners Program (CPP) was initiated to enhance rural health providers’ ability in dementia diagnosis and care, and to increase research recruitment into dementia research studies of participants from rural communities.
The CPP is a 3-day “mini-residency” of didactic, observational and skill-based teaching techniques. Participants completed pre- and post-tests evaluating dementia knowledge, confidence in providing care, and practice behaviors.
Between 2000–2009, 146 healthcare professionals with a mean age of 45.7±10.8y attended the CPP; 79.2% were Caucasian, 58.2% were female, and 58% of participants had been in practice for more than 10y. Post-tests showed improvements in knowledge and confidence to diagnose and treat and increased use of dementia screening tools. Rural research participation in an urban Alzheimer Disease Research Center increased 52% over the pre-CPP period.
Primary goals were accomplished: increased knowledge and confidence, changed practice habits, and enhanced research recruitment. Educational programs such as the CPP may be beneficial for increasing access to accurate diagnoses and appropriate treatment of Alzheimer’s disease while also enhancing research participation.
PMCID: PMC3288449  PMID: 21399484
Alzheimer’s disease; physician education; research recruitment; dementia
Alzheimer’s disease (AD) is characterized by progressive declines in cognitive function and ability to carry out activities of daily living; and the emergence and worsening of behavioral/neuropsychiatric symptoms. While there is no cure for AD, non-pharmacologic interventions and medications that modulate neurotransmission can slow symptomatic progression. Medical foods may also be useful as adjuncts to pharmacologic agents in AD. Medium chain triglycerides aimed at improving cerebral metabolism significantly improve Alzheimer’s Disease Assessment Scale-Cognitive scores when added to ongoing pharmacotherapy in patients with mild-to-moderate AD. Combination of interventions, such as non-pharmacologic treatments, pharmacotherapy, and medical foods, with complementary mechanisms of action may provide a rational approach that may result in maximum preservation of cognitive function in patients with AD.
PMCID: PMC3437664  PMID: 22973426
biomarker; FDG-PET; ketone body; medical food
6.  Dementia screening, biomarkers and protein misfolding 
Prion  2011;5(1):16-21.
Misfolded proteins are at the core of many neurodegenerative diseases, nearly all of them associated with cognitive impairment. For example, Creutzfeldt-Jacob disease is associated with aggregation of prion protein,1,2 Lewy body dementia and Parkinson disease with α-synuclein3,4 and forms of frontotemporal dementia with tau, TDP43 and a host of other proteins.5,6 Alzheimer disease (AD), the most common cause of dementia,7 and its prodromal syndrome mild cognitive impairment (MCI)8 are an increasing public health problem and a diagnostic challenge to many clinicians. AD is characterized pathologically by the accumulation of amyloid β-protein (Aβ)9,10 as senile plaques and in the walls of blood vessels as amyloid angiopathy.11,12 Additionally, there are accumulations of tau-protein as neurofibrillary tangles and dystrophic neurites.11,12 Biological markers of AD and MCI can serve as in vivo diagnostic indicators of underlying pathology, particularly when clinical symptoms are mild13–15 and are likely present years before the onset of clinical symptoms.16–19 Research to discover and refine fluid and imaging biomarkers of protein aggregation has undergone a rapid evolution20–22 and combined analysis of different modalities may further increase diagnostic sensitivity and specificity.23–26 Multi-center trials are now investigating whether imaging and/or cerebrospinal fluid (CSF) biomarker candidates can be used as outcome measures for use in phase III clinical trials for AD.27–29
PMCID: PMC3038001  PMID: 21164279
dementia; screening; biomarkers; amyloid; tau; Alzheimer disease; preclinical; presymptomatic
7.  Use of medical foods and nutritional approaches in the treatment of Alzheimer’s disease 
Alzheimer’s disease, the most common cause of dementia, has a high global economic impact. To date, there is no curative treatment; therefore, many efforts are directed not only at novel potential disease-modifying treatments and interventions, but also to develop alternative symptomatic and supportive treatments. Examples of these efforts include the medical foods. There are three medical foods that claim to offer symptomatic benefits: Axona®, Souvenaid® and CerefolinNAC®. Axona supplies ketone bodies as alternative energy source to neurons. Souvenaid provides precursors thought to enhance synaptic function. CerefolinNAC addresses the role of oxidative stress related to memory loss. The current scientific evidence on these medical foods is reviewed in this article. Furthermore, we also review the concept and evidence supporting use of the Mediterranean diet, a possible alternative to medical foods that, if implemented correctly, may have lower costs, fewer side effects and stronger epidemiological health outcomes.
PMCID: PMC3556480  PMID: 23362453
Clinics in geriatric medicine  2010;26(1):125-147.
The cellular mechanisms underlying neuronal loss and neurodegeneration have been an area of interest in the last decade. Although neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) each have distinct clinical symptoms and pathologies, they all share common mechanisms such as protein aggregation, oxidative injury, inflammation, apoptosis and mitochondrial injury that contribute to neuronal loss. Although cerebrovascular disease is due to etiologies quite different from the neurodegenerative disorders, many of the same common disease mechanisms come into play following a stroke. Novel therapies that target each of these mechanisms may be effective in decreasing the risk of disease, abating symptoms or slowing down their progression. While most of these therapies are experimental, and require further investigation, a few seem to offer promise in the near future.
PMCID: PMC2828394  PMID: 20176298
Parkinson’s disease; Alzheimer’s disease; ischemic stroke; amyotrophic lateral sclerosis; Huntington’s disease
9.  Longitudinal Study of the Transition From Healthy Aging to Alzheimer Disease 
Archives of neurology  2009;66(10):1254-1259.
Detection of the earliest cognitive changes signifying Alzheimer disease is difficult.
To model the cognitive decline in preclinical Alzheimer disease.
Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory.
Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri.
One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented.
Main Outcome Measures
Inflection point in longitudinal cognitive performance.
The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n=44) with autopsy-confirmed Alzheimer disease.
There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease.
PMCID: PMC2795328  PMID: 19822781
10.  Distinguishing Alzheimer's disease from other major forms of dementia 
Expert review of neurotherapeutics  2011;11(11):1579-1591.
Alzheimer's disease (AD) is the most common and most studied cause of dementia. Significant advances have been made since the first set of clinical criteria for AD were put forth in 1984 that are now captured in the new criteria for AD published in 2011. Key features include recognition of a broad AD spectrum (from preclinical to mild cognitive impairment to AD dementia) and requirement of AD biomarkers for diagnosis. Correctly diagnosing dementia type is increasingly important in an era when potential disease-modifying agents are soon to be marketed. The typical AD dementia syndrome has at its core, an amnestic syndrome of the hippocampal type, followed by associated deficits in word-finding, spatial cognition, executive functions and neuropsychiatric changes. Atypical presentations of AD have also been identified that are presumed to have a different disease course. It can be difficult to distinguish between the various dementia syndromes given the overlap in many common clinical features across the dementias. The clinical difficulty in diagnosis may reflect the underlying pathology, as AD often co-occurs with other pathologies at autopsy, such as cerebrovascular disease or Lewy bodies. Neuropsychological evaluation has provided clinicians and researchers with profiles of cognitive strengths and weaknesses that help to define the dementias. There is yet no single behavioral marker that can reliably discriminate AD from the other dementias. The combined investigation of cognitive and neurobehavioral symptoms coupled with imaging markers could provide a more accurate approach for differentiating between AD and other major dementia syndromes in the future.
PMCID: PMC3225285  PMID: 22014137
Alzheimer's disease; cognition; dementia; depression; differential diagnosis; frontotemporal dementia; Lewy body; vascular
11.  Internet-Based Dementia Resources: Physician Attitudes and Practices 
Despite the potential of the internet for informing clinical practice, little is know about physicians’ use of and attitudes about internet use for dementia care. We surveyed 373 physicians to inform development of on-line dementia education resources. Two thirds reported using internet-based resources in their clinical practices at least three times per week; 61% participated in on-line continuing medical education. Three fourths agreed that internet-based resources are helpful in clinical care but most expressed mixed views about quality of available information. Respondents reported limited awareness and use of dementia-specific internet resources, but expressed an interest in such information regarding screening, treatment, community resources, and patient education. National Institute on Aging-funded Alzheimer’s Disease Centers are in a unique position to disseminate on-line resources for physicians on dementia diagnosis, treatment, and care. Our study suggests that such a resource would be well received and utilized by physicians.
PMCID: PMC3137376  PMID: 21769164
Alzheimer’s disease; Internet; Medical Education
12.  Practical clinical tool to monitor dementia symptoms: the HABC-Monitor 
Dementia care providers need a clinical assessment tool similar to the blood pressure cuff (sphygmomanometer) used by clinicians and patients for managing hypertension. A “blood pressure cuff ” for dementia would be an inexpensive, simple, user-friendly, easily standardized, sensitive to change, and widely available multidomain instrument for providers and informal caregivers to measure severity of dementia symptoms. The purpose of this study was to assess the reliability and validity of the Healthy Aging Brain Care Monitor (HABC-Monitor) for measuring and monitoring the severity of dementia symptoms through caregiver reports.
The first prototype of the HABC-Monitor was developed in collaboration with the Indianapolis Discovery Network for Dementia, which includes 200 members representing 20 disciplines from 20 local organizations, and an expert panel of 22 experts in dementia care and research. The HABC-Monitor has three patient symptom domains (cognitive, functional, behavioral/psychological) and a caregiver quality of life domain. Patients (n = 171) and their informal caregivers (n = 171) were consecutively approached and consented during, or by phone shortly following, a patient’s routine visit to their memory care provider.
The HABC-Monitor demonstrated good internal consistency (0.73–0.92); construct validity indicated by correlations with the caregiver-reported Neuropsychiatric Inventory (NPI) total score and NPI caregiver distress score; sensitivity to three-month change compared with NPI “reliable change” groups; and known-groups validity, indicated by significant separation of Mini-Mental Status Examination severity groups and clinical diagnostic groups. Although not designed as a screening study, there was evidence for good operating characteristics, according to area under the receiver-operator curve with respect to gold standard clinical diagnoses, relative to Mini-Mental Status Examination or NPI.
The HABC-Monitor demonstrates good reliability and validity as a clinically practical multidimensional tool for monitoring symptoms of dementia through the informal caregiver.
PMCID: PMC3393358  PMID: 22791987
dementia; symptoms; monitor; validation; cognitive impairment; memory care
13.  Four Sensitive Screening Tools to Detect Cognitive Dysfunction in Geriatric Emergency Department Patients: Brief Alzheimer’s Screen, Short Blessed Test, Ottawa 3DY, and the Caregiver-completed AD8 
Cognitive dysfunction, including dementia and delirium, is prevalent in geriatric emergency department (ED) patients, but often remains undetected. One barrier to reliable identification of acutely or chronically impaired cognitive function is the lack of an acceptable screening tool. While multiple brief screening instruments have been derived, ED validation trials have not previously demonstrated tools that are appropriately sensitive for clinical use.
The primary objective was to evaluate and compare the Ottawa 3DY (O3DY), Brief Alzheimer’s Screen (BAS), Short Blessed Test (SBT), and caregiver-completed AD8 (cAD8) diagnostic test performance for cognitive dysfunction in geriatric ED patients using the Mini Mental Status Exam (MMSE) as the criterion standard. A secondary objective was to assess the diagnostic accuracy for the cAD8 (which is an informant-based instrument) when used in combination with the other performance-based screening tools.
In an observational cross-sectional cohort study at one urban academic university-affiliated medical center, trained research assistants collected patients’ responses on the Confusion Assessment Method for the Intensive Care Unit, BAS, and SBT. When available, reliable caregivers completed the cAD8. The MMSE was then obtained. The O3DY was reconstructed from elements of the MMSE and the BAS. Consenting subjects were non-critically ill, English-speaking adults over age 65 years, who had not received potentially sedating medications prior to or during cognitive testing. Using an MMSE score ≤ 23 as the criterion standard for cognitive dysfunction, the sensitivity, specificity, likelihood ratios, and receiver operating characteristic area under the curve were computed. Venn diagrams were constructed to quantitatively compare the degree of overlap among positive test results between the performance-based instruments.
The prevalence of cognitive dysfunction for the 163 patients enrolled with complete data collection was 37%, including 5.5% with delirium. Dementia was self-reported in 3%. Caregivers were available to complete the cAD8 for 56% of patients. The SBT, BAS, and O3DY each demonstrated 95% sensitivity, compared with 83% sensitivity for the cAD8. The SBT had a superior specificity of 65%. No combination of instruments with the cAD8 significantly improved diagnostic accuracy. The SBT provided the optimal overlap with the MMSE.
The SBT, BAS, and O3DY are three brief performance-based screening instruments to identify geriatric patients with cognitive dysfunction more rapidly than the MMSE. Among these three instruments, the SBT provides the best diagnostic test characteristics and overlap with MMSE results. The addition of the cAD8 to the other instruments does not enhance diagnostic accuracy.
PMCID: PMC3080244  PMID: 21496140
14.  Longitudinal Changes in Cognition in Parkinson's Disease with and without Dementia 
The longitudinal cognitive course in Parkinson's disease (PD) with and without dementia remains undefined. We compared cross-sectional models of cognition in PD (both with and without dementia), Alzheimer's disease (AD), and nondemented aging and followed the participants over time.
Previously validated models of cognitive performance in AD and nondemented aging were extended to individuals with PD (with dementia, n = 71; without dementia, n = 47). Confirmatory factor analysis and piecewise regression were used to compare the longitudinal course of participants with PD with 191 cognitively healthy subjects and 115 individuals with autopsy-confirmed AD.
A factor analytic model with one general factor and three specific factors (verbal memory, visuospatial memory, working memory) fit demented and nondemented PD. Longitudinal change indicated that individuals with PD with dementia declined significantly more rapidly on visuospatial and verbal memory tasks than AD alone. Cognitive declines across all factors in AD and PD dementia accelerated several years prior to clinical dementia diagnosis.
Both specific and global cognitive changes are witnessed in PD and AD. Longitudinal profiles of cognitive decline in PD and AD differed. PD with or without dementia has a core feature of longitudinal decline in visuospatial abilities.
PMCID: PMC3047760  PMID: 21242691
Alzheimer's disease; Parkinson's disease with dementia; Parkinson's disease/parkinsonism; Longitudinal cognitive course; Confirmatory factor analysis
15.  Using biomarkers to improve detection of Alzheimer’s disease 
Disease-modifying approaches for Alzheimer’s disease (AD) might be most effective when initiated very early in the course, before the pathologic burden and neuronal and synaptic degeneration make it unlikely that halting disease progression would have a significant impact on patient outcomes. Biomarkers of disease may provide important avenues of research to enhance the diagnosis of individuals with early AD and could assist in the identification of those individuals at risk for developing AD. However, for such biomarkers to become clinically useful, long-term follow-up studies are necessary to evaluate the relevance of cross-sectional biomarker changes to the longitudinal course of the disease. The objective of this article is to review recent progress in AD biomarkers for the early diagnosis, classification, progression and prediction of AD and their usefulness in new treatment trials.
PMCID: PMC3209959  PMID: 22076127
16.  Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease 
Jama  2010;304(17):1903-1911.
Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology.
To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease.
Design, Setting, and Patients
A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14–26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer’s Disease Cooperative Study.
Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months.
Main Outcome Measures
Change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102).
A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51–9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72–9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44–3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44–3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm3 (95% CI, 21.4–28.0 cm3) during 18 months and a 1.32% (95% CI, 1.14%–1.50%) volume decline per year compared with 24.0 cm3 (95% CI, 20–28 cm3) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%–1.51%) volume decline per year (P = .79).
Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease.
PMCID: PMC3259852  PMID: 21045096
Approximately 3.2 million hospital stays annually involve a person with dementia, leading to higher costs, longer lengths of stay and poorer outcomes. Older adults with dementia are vulnerable when hospitals are unable to meet their special needs.
We developed, implemented and evaluated a training program for 540 individuals at 4 community hospitals. Pre-test, post-test and a 120-day delayed post-test were collected to assess knowledge, confidence and practice parameters.
The mean age of the sample was 46y; 83% were Caucasian, 90% were female and 60% were nurses. Upon completion, there were significant gains (p’s <.001) in knowledge and confidence in recognizing, assessing and managing dementia. Attendees reported gains in communication skills and strategies to improve the hospital environment, patient safety and behavioral management. At 120 days, 3 of 4 hospitals demonstrated maintenance of confidence. In the hospital that demonstrated lower knowledge and confidence scores, the sample was older and had more nurses and more years in practice.
We demonstrate the feasibility of training hospital staff about dementia and its impact on patient outcomes. At baseline, there was low knowledge and confidence in the ability to care for dementia patients. Training had an immediate impact on knowledge, confidence and attitudes with lasting impact in 3 of 4 hospitals. We identified targets for intervention and the need for ongoing training and administrative reinforcement in order to sustain behavioral change. Community resources, such as local chapters of the Alzheimer’s Association, may be key community partners in improving care outcomes for hospitalized persons with dementia.
PMCID: PMC2955811  PMID: 20625267
Dementia; Hospital Care; Education
18.  Negotiating the Joint Career: Couples Adapting to Alzheimer's and Aging in Place 
Journal of Aging Research  2011;2012:797023.
To understand the impact of memory loss on aging in place, this paper investigated dyads where one spouse had been diagnosed with memory loss. In-depth qualitative interviews were conducted with ten couples (N = 20). Grounded theory methods were used to collect, code, and analyze data into themes. Data revealed consensus among and between dyads that it was best to focus on living, rather than what had been or might someday be lost. Nonetheless, differences according to gender and cognitive status (e.g., diagnosed or spouse) were reported. Given population aging, identifying the impact of gender roles and social norms on the potential for aging in place with memory loss is critical. Community services and care practices must be sensitive to the ways that couples prioritized and organized their relationship prior to diagnosis in order to encourage positive patterns of care between couples, foster successful adaptation to changing needs, and support in-home arrangements as long as possible.
PMCID: PMC3246797  PMID: 22220277
19.  Relationship of dementia screening tests with biomarkers of Alzheimer’s disease 
Brain  2010;133(11):3290-3300.
Screening tests for Alzheimer’s disease lack sensitivity and specificity. We developed the AD8, a brief dementia screening interview validated against clinical and cognitive evaluations, as an improvement over current screening methods. Because insufficient follow-up has occurred to validate the AD8 against the neuropathologic findings of Alzheimer’s disease, we investigated whether AD8 scores correspond to impairment in episodic memory testing and changes in biomarkers of Alzheimer’s disease (cerebrospinal fluid and amyloid imaging with Pittsburgh compound B) characteristic of symptomatic Alzheimer’s disease. We also compared informant-based assessments with brief performance-based dementia screening measurements such as the Mini Mental State Exam. The sample (n = 257) had a mean age of 75.4 years with 15.1 years of education; 88.7% were Caucasian and 45.5% were male. The sample was divided into two groups based on their AD8 scores: those with a negative dementia screening test (AD8 score 0 or 1, n = 137) and those with a positive dementia screening test (AD8 score ≥2, n = 120). Individuals with positive AD8 scores had abnormal Pittsburgh compound B binding (P < 0.001) and cerebrospinal fluid biomarkers (P < 0.001) compared with individuals with negative AD8 scores. Individuals with positive AD8 tests and positive biomarkers scored in the impaired range on the Wechsler Logical Memory Story A (mean score 7.0 ± 4.5 for Pittsburgh compound B; mean score 7.6 ± 5.3 for cerebrospinal fluid amyloid beta protein 1–42). The AD8 area under the curve for Pittsburgh compound B was 0.737 (95% confidence interval: 0.64–0.83) and for cerebrospinal fluid amyloid beta protein 1–42 was 0.685 (95% confidence interval: 0.60–0.77) suggesting good discrimination. The AD8 had superior sensitivity in detecting early stages of dementia compared with the Mini Mental State Examination. The AD8 had a likelihood ratio of a positive test of 5.8 (95% confidence interval: 5.4–6.3) and likelihood ratio of a negative test of 0.04 (95% confidence interval: 0.03–0.06), increasing the pre-test probability of an individual having symptomatic Alzheimer’s disease. Individuals with AD8 scores of ≥2 had a biomarker phenotype consistent with Alzheimer’s disease and lower performance on episodic memory tests, supporting a diagnosis of Alzheimer’s disease. Informant-based assessments may be superior to performance-based screening measures such as the Mini Mental State Examination in corresponding to underlying Alzheimer’s disease pathology, particularly at the earliest stages of decline. The use of a brief test such as the AD8 may improve strategies for detecting dementia in community settings where biomarkers may not be readily available, and may enrich clinical trial recruitment by increasing the likelihood that participants have underlying biomarker abnormalities.
PMCID: PMC2965421  PMID: 20823087
AD8; Alzheimer’s disease; screening; biomarkers; preclinical; cognition
Lewy body dementia (LBD) is a common cause of dementia but to date, little is known about caregiver burden. The Lewy Body Dementia Association ( conducted a web-based survey of 962 caregivers (mean age 56y; 88% women). The most common initial symptoms were cognitive (48%), motor (39%), or both (13%). Caregivers expressed concerns about fear of future (77%), feeling stressed (54%), loss of social life (52%) and uncertainty about what to do next (50%). Caregivers reported moderate to severe burden; 80% felt the people around them did not understand their burden and 54% reported feelings of isolation with spousal caregivers reporting more burden than non-spousal caregivers. Only 29% hired in-home assistance while less than 40% used respite or adult day care, geriatric case managers or attended a support group meeting. Lack of service utilization occurred despite two-thirds of caregivers reporting medical crises requiring emergency services, psychiatric care or law enforcement. Caregivers reported preferences for web-based information, directories of LBD expert providers, information on LBD research and location of local support groups. These findings highlight significant unmet needs for LBD caregivers and provide targets for intervention to reduce caregiver burden. Community resources such as the Lewy Body Dementia Association may serve this end, while also providing practical information and support for caregivers.
PMCID: PMC2879080  PMID: 20505434
Lewy body dementia; caregiver burden; stress
21.  Correction: The Neurotoxicity of DOPAL: Behavioral and Stereological Evidence for Its Role in Parkinson Disease Pathogenesis 
PLoS ONE  2011;6(2):10.1371/annotation/819cbf4a-7e3e-4e4e-a449-b667bc6e8957.
PMCID: PMC3047588
22.  Effect of cognitive fluctuation on neuropsychological performance in aging and dementia 
Neurology  2010;74(3):210-217.
Cognitive fluctuations are spontaneous alterations in cognition, attention, and arousal. Fluctuations are a core feature of dementia with Lewy bodies, but the impact of fluctuations in healthy brain aging and Alzheimer disease (AD) are unknown.
Research participants (n = 511, age 78.1 ± 8 years, education 14.9 ± 3 years) enrolled in a longitudinal study of memory and aging at the Washington University Alzheimer Disease Research Center were assessed for the presence and severity of dementia with the Clinical Dementia Rating (CDR) and a neuropsychological test battery. Informant assessments of fluctuations with the Mayo Fluctuations Questionnaire and daytime level of alertness with the Mayo Sleep Questionnaire were completed.
After controlling for age and alertness level, participants with cognitive fluctuations (3 or 4 individual symptoms) were 4.6 times more likely to have dementia (95% confidence interval: 2.05, 10.40). Participants who presented with disorganized, illogical thinking were 7.8 times more likely to be rated CDR >0. The risk of being rated CDR 0.5 among those with fluctuations was 13.4 times higher than among those without fluctuations. The risk of being rated CDR 1 increased 34-fold among participants with fluctuations. Compared with participants without fluctuations, the presence of cognitive fluctuations corresponds to a decrease in performance across individual neuropsychological tests as well as composite scores.
Cognitive fluctuations occur in Alzheimer disease and, when present, significantly affect both clinical rating of dementia severity and neuropsychological performance. Assessment of fluctuations should be considered in the evaluation of patients for cognitive disorders.
= Alzheimer disease;
= Clinical Dementia Rating;
= confidence interval;
= dementia with Lewy bodies;
= mild cognitive impairment;
= odds ratio;
= Selective Reminding Test;
= Wechsler Adult Intelligence Scale;
= Wechsler Memory Scale.
PMCID: PMC2809035  PMID: 20083796
Archives of neurology  2010;67(1):99-106.
We compared longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil, untreated very mild DAT subjects and nondemented controls.
MPRAGE sequences were collected approximately two years apart on two 1.5T Siemens Vision systems, yielding two cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields.
Subjects came from two sources: 18 untreated DAT subjects and 26 controls were drawn from a previous longitudinal study; 18 treated DAT subjects were studied prospectively, and 44 controls were drawn from a longitudinal study from the same time period.
Patients attending a dementia clinic at Washington University School of Medicine were prescribed Donepezil by their physician.
There was no significant cohort effect at baseline; therefore the two groups of control subjects were combined. The potential confounding effect of cohort/scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate-of-change of hippocampal volume or subfields deformation. Further exploration showed that compared with the untreated DAT subjects, the treated DAT subjects did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated DAT subjects differed from the controls in the rates-of-change of hippocampal volume, CA1 and subiculum subfield deformations.
Treatment with donepezil did not alter the progression of hippocampal deformation in DAT subjects in this study. Small sample size may have contributed to this outcome.
PMCID: PMC2855123  PMID: 20065136
donepezil; Alzheimer’s disease; hippocampus; magnetic resonance imaging
24.  The Neurotoxicity of DOPAL: Behavioral and Stereological Evidence for Its Role in Parkinson Disease Pathogenesis 
PLoS ONE  2010;5(12):e15251.
The etiology of Parkinson disease (PD) has yet to be fully elucidated. We examined the consequences of injections of 3,4-dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite of dopamine, into the substantia nigra of rats on motor behavior and neuronal survival.
Methods/Principal Findings
A total of 800 nl/rat of DOPAL (1 µg/200 nl) was injected stereotaxically into the substantia nigra over three sites while control animals received similar injections of phosphate buffered saline. Rotational behavior of these rats was analyzed, optical density of striatal tyrosine hydroxylase was calculated, and unbiased stereological counts of the substantia nigra were made. The rats showed significant rotational asymmetry ipsilateral to the lesion, supporting disruption of dopaminergic nigrostriatal projections. Such disruption was verified since the density of striatal tyrosine hydroxylase decreased significantly (p<0.001) on the side ipsilateral to the DOPAL injections when compared to the non-injected side. Stereological counts of neurons stained for Nissl in pars compacta of the substantia nigra significantly decreased (p<0.001) from control values, while counts of those in pars reticulata were unchanged after DOPAL injections. Counts of neurons immunostained for tyrosine hydroxylase also showed a significant (p = 0.032) loss of dopaminergic neurons. In spite of significant loss of dopaminergic neurons, DOPAL injections did not induce significant glial reaction in the substantia nigra.
The present study provides the first in vivo quantification of substantia nigra pars compacta neuronal loss after injection of the endogenous toxin DOPAL. The results demonstrate that injections of DOPAL selectively kills SN DA neurons, suggests loss of striatal DA terminals, spares non-dopaminergic neurons of the pars reticulata, and triggers a behavioral phenotype (rotational asymmetry) consistent with other PD animal models. This study supports the “catecholaldehyde hypothesis” as an important link for the etiology of sporadic PD.
PMCID: PMC3001493  PMID: 21179455
Inadequate recruitment into Alzheimer disease (AD) clinical trials is an important threat to the validity and generalizability of the studies. The majority of dementia patients are first evaluated by community-based physicians; however, physician perceptions of clinical research are largely unknown.
A survey was distributed to 3,123 physicians in three states; 370 were returned. Survey items assessed attitudes, perceived benefits of and barriers to referral to clinical research and physicians use of the internet for medical information.
The mean age of the respondents was 50.6 ± 10.8y; 70% were male, 78% Caucasian, 61% were primary care providers; 63% used the internet ≥3 times/week. No demographic or medical specialty differences existed between those who were likely (n=193) and unlikely (n=162) to refer patients to clinical trials. Differences were discovered in perceived benefits reported by physicians who were more likely to refer, while differences in perceived barriers existed in primary care compared with specialists. Referral to clinical trials is predicted by close proximity to a research center (OR:4.0,95%CI:1.1–15.6) and availability of internet information regarding diagnostic evaluation (OR:2.3,95%CI:1.1–4.7). Primary barriers included concerns about exposure of patients to uncomfortable procedures (OR:4.7,95%CI:1.2–18.7) and lack of time to discuss research participation (OR:6.8,95%CI:1.4–32.3).
Proximity to a research center and availability of diagnostic clinical tools are strong predictors of clinical trial referral. Concern over risks to patients and lack of time are strong barriers. These results suggest that dementia outreach education targeted to physicians should emphasize the importance of clinical trials with a focus on discussing research participation in a time-efficient manner and increasing awareness of risk reduction and the safety of research protocols. Providing easy access to up-to-date, user-friendly educational materials on dementia diagnosis and research via the internet are likely to improve referrals of patients to AD clinical trials from community physicians.
PMCID: PMC2787738  PMID: 19561438
Alzheimer’s disease; Clinical Trials; Recruitment; Referral; Dementia; Physician

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