Oscillating Square Wave Transcranial Direct Current Stimulation (tDCS) Delivered During Slow Wave Sleep Does Not Improve Declarative Memory More Than Sham: A Randomized Sham Controlled Crossover Study.

BACKGROUND: A 2006 trial in healthy medical students found that anodal slow oscillating tDCS delivered bi-frontally during slow wave sleep had an enhancing effect in declarative, but not procedural memory. Although there have been supporting animal studies, and similar findings in pathological groups, this study has not been replicated, or refuted, in the intervening years. We therefore tested these earlier results for replication using similar methods with the exception of current waveform (square in our study, nearly sinusoidal in the original). OBJECTIVE/HYPOTHESIS: Our objective was to test the findings of a 2006 trial suggesting bi-frontal anodal tDCS during slow wave sleep enhances declarative memory. METHODS: Twelve students (mean age 25, 9 women) free of medical problems underwent two testing conditions (active, sham) in a randomized counterbalanced fashion. Active stimulation consisted of oscillating square wave tDCS delivered during early Non-Rapid Eye Movement (NREM) sleep. The sham condition consisted of setting-up the tDCS device and electrodes, but not turning it on during sleep. tDCS was delivered bi-frontally with anodes placed at F3/F4, and cathodes placed at mastoids. Current density was 0.517 mA/cm(2), and oscillated between zero and maximal current at a frequency of 0.75 Hz. Stimulation occurred during five-five minute blocks with 1-min inter-block intervals (25 min total stimulation). The primary outcomes were both declarative memory consolidation measured by a paired word association test (PWA), and non-declarative memory, measured by a non-dominant finger-tapping test (FTT). We also recorded and analyzed sleep EEG. RESULTS: There was no difference in the number of paired word associations remembered before compared to after sleep [(active = 3.1 ± 3.0 SD more associations) (sham = 3.8 ± 3.1 SD more associations)]. Finger tapping improved, (non-significantly) following active stimulation [(3.6 ± 2.7 SD correctly typed sequences) compared to sham stimulation (2.3 ± 2.2 SD correctly typed sequences)]. CONCLUSION: In this study, we failed to find improvements in declarative or performance memory and could not replicate an earlier study using nearly identical settings. Specifically we failed to find a beneficial effect on either overnight declarative or non-declarative memory consolidation via square-wave oscillating tDCS intervention applied bi-frontally during early NREM sleep. It is unclear if the morphology of the tDCS pulse is critical in any memory related improvements.

Antihypertensive medication persistence 1-year post-stroke hospitalization.

To optimize the translation of clinical trial evidence that antihypertensive treatment reduces recurrent stroke risk into clinical practice, it is important to assess the frequency of long-term antihypertensive drug persistence after stroke and identify the factors associated with low persistence. Structured telephone interviews to determine antihypertensive regimen persistence 1-year post-stroke hospitalization were conducted in 270 stroke survivors, of which 212 (78.5%) were discharged on antihypertensive therapy (two thirds on >1 drug class). Continued use of any antihypertensive agent at 1 year of follow-up was relatively high (87.3%); however, persistence on all or two or more drug classes prescribed at discharge was relatively low (38.7%). Continued use varied by drug class, with the highest rates among angiotensin-converting enzyme inhibitor (69.1%) and the lowest rates among diuretic (24.4%) users. Black patients (adjusted odds ratio, 0.35; 95% confidence interval, 0.16-0.78) and those with a high comorbidity burden (adjusted odds ratio , 0.39; 95% confidence interval, 0.18-0.86) were less likely to exhibit persistence on prescribed treatments 1-year post-stroke hospitalization. These results indicate the need for further study to identify appropriate persistence of antihypertensive therapies for secondary stroke prevention and to investigate reasons for racial disparities in persistence on prescribed treatments in a real-world clinical setting.

The impact of ICD-9 revascularization procedure codes on estimates of racial disparities in ischemic stroke.

BACKGROUND: The use of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) diagnostic codes can identify racial disparities in ischemic stroke hospitalizations; however, inclusion of revascularization procedure codes as acute stroke events may affect the magnitude of the risk difference. This study assesses the impact of excluding revascularization procedure codes in the ICD-9 definition of ischemic stroke, compared with the traditional inclusive definition, on racial disparity estimates for stroke incidence and recurrence. METHODS: Patients discharged with a diagnosis of ischemic stroke (ICD-9 codes 433.00-434.91 and 436) were identified from a statewide inpatient discharge database from 2010 to 2012. Race-age specific disparity estimates of stroke incidence and recurrence and 1-year cumulative recurrent stroke rates were compared between the routinely used traditional classification and a modified classification of stroke that excluded primary ICD-9 cerebral revascularization procedures codes (38.12, 00.61, and 00.63). RESULTS: The traditional classification identified 7878 stroke hospitalizations, whereas the modified classification resulted in 18% fewer hospitalizations (n = 6444). The age-specific black to white rate ratios were significantly higher in the modified than in the traditional classification for stroke incidence (rate ratio, 1.50; 95% confidence interval [CI], 1.43-1.58 vs. rate ratio, 1.24; 95% CI, 1.18-1.30, respectively). In whites, the 1-year cumulative recurrence rate was significantly reduced by 46% (45-64 years) and 49% (≥ 65 years) in the modified classification, largely explained by a higher rate of cerebral revascularization procedures among whites. There were nonsignificant reductions of 14% (45-64 years) and 19% (≥ 65 years) among blacks. CONCLUSIONS: Including cerebral revascularization procedure codes overestimates hospitalization rates for ischemic stroke and significantly underestimates the racial disparity estimates in stroke incidence and recurrence.

Persistent racial disparity in stroke hospitalization and economic impact in young adults in the buckle of stroke belt.

BACKGROUND AND PURPOSE: Mounting evidence points to a decline in stroke incidence. However, little is known about recent patterns of stroke hospitalization within the buckle of the stroke belt. This study aims to investigate the age- and race-specific secular trends in stroke hospitalization rates, inpatient stroke mortality rates, and related hospitalization charges during the past decade in South Carolina. METHODS: Patients from 2001 to 2010 were identified from the State Inpatient Hospital Discharge Database with a primary discharge diagnosis of stroke (International Classification of Diseases, Ninth Revision codes: 430-434, 436, 437.1). Age- and race-stroke-specific hospitalization rates, hospital charges, charges associated with racial disparity, and 30-day stroke mortality rates were compared between blacks and whites. RESULTS: Of the 84,179 stroke hospitalizations, 31,137 (37.0%) were from patients aged<65 years and 29,846 (35.5%) were blacks. Stroke hospitalization rates decreased in the older population (aged≥65 years) for both blacks and whites (P<0.001) but increased among the younger group (aged<65 years; P=0.004); however, this increase was mainly driven by a 17.3% rise among blacks (P=0.001), with no difference seen among whites (P=0.84). Of hospital charges totaling $2.77 billion, $453.2 million (16.4%) are associated with racial disparity (79.6% from patients aged<65 years). Thirty-day stroke mortality rates decreased in all age-race-stroke-specific groups (P<0.001). CONCLUSIONS: The stroke hospitalization rate increased in the young blacks only, which results in a severe and persistent racial disparity. It highlights the urgent need for a racial disparity reduction in the younger population to alleviate the healthcare burden.

Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial.

BACKGROUND: Little is known about the effect of methylphenidate (MPH) on attention in Alzheimer's disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses. METHODS: MPH (10 mg PO twice daily) or placebo was administered for six weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory (NPI) Apathy ≥ 4). Attention was measured with the Wechsler Adult Intelligence Scale--Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as δ (MPH (DS week 6-DS baseline)) - (placebo (DS week 6-DS baseline)). RESULTS: In 60 patients (37 females, age = 76 ± 8, Mini-Mental State Examination (MMSE) = 20 ± 5, NPI Apathy = 7 ± 2), the change in DS forward (δ = 0.87 (95% CI: 0.06-1.68), p = 0.03) and DS total (δ = 1.01 (95% CI: 0.09-1.93), p = 0.03) favored MPH over placebo. Of 57 completers, 17 patients had improved apathy (≥3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder, or non-responder groups. DS scores did not predict apathy response to MPH treatment. CONCLUSION: These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population.

Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial.

OBJECTIVE: In a recent crossover trial, methylphenidate treatment decreased apathy in Alzheimer's disease. We further assessed this finding in the Apathy in Dementia Methylphenidate Trial (ADMET). METHOD: Six-week, randomized, double-blind, placebo-controlled multicenter trial enrolling Alzheimer's disease participants (NINCDS-ADRDA criteria) with apathy assigned to methylphenidate 20 mg daily or placebo, conducted from June 2010 to December 2011. Primary outcomes were change in Apathy Evaluation Scale (AES) score and modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGI-C). Secondary outcomes included change in Neuropsychiatric Inventory (NPI) apathy score, Mini-Mental State Examination (MMSE) score, and safety. RESULTS: 60 participants were randomly assigned (29 methylphenidate, 31 placebo). At baseline, mean (SD) age = 76 (8) years, MMSE score = 20 (5), AES score = 51 (12), NPI total score = 16 (8), and 62% of the participants (n = 37) were female. After 6 weeks' treatment, mean (SD) change in AES score was -1.9 (1.5) for methylphenidate and 0.6 (1.4) for placebo (P = .23). Odds ratio for improvement in ADCS-CGI-C was 3.7 (95% CI, 1.3 to 10.8) (P = .02), with 21% of methylphenidate versus 3% of placebo rated as moderately or markedly improved. NPI apathy score improvement was 1.8 points (95% CI, 0.3 to 3.4) greater on methylphenidate than on placebo (P = .02). MMSE trended toward improvement on methylphenidate (P = .06). There were trends toward greater anxiety and weight loss > 2% in the methylphenidate-treated group. CONCLUSIONS: Methylphenidate treatment of apathy in Alzheimer's disease was associated with significant improvement in 2 of 3 efficacy outcomes and a trend toward improved global cognition with minimal adverse events, supporting the safety and efficacy of methylphenidate treatment for apathy in Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01117181.

Performance on Standard Indexes of Effort Among Patients with Dementia.

Assessment of response validity is an integral part of neuropsychological practice. Although many studies have demonstrated the efficacy of stand alone and embedded effort measures in a variety of medical and compensation-seeking contexts, much less is known about the robustness of these measures in elderly populations, particularly in patients with dementia. Although older adults may be viewed as less likely to intentionally feign symptoms for an external gain, there are a variety of other factors that could result in suboptimal effort, including fatigue, lack of interest or cooperation in the testing process, or failure to fully appreciate the implications of the assessment on treatment care and outcome. The current study examined the clinical utility of several stand alone and embedded effort measures including the Repeatable Battery for the Assessment of Neuropsychological Status Effort Index, Trail-Making Test Ratio, Rey 15-Item Test, and the Test of Memory Malingering in a sample of patients with dementia. Results found that the majority of effort indexes demonstrated unacceptably high false-positive error rates with specificity levels as high as 83%. These findings demonstrate the need for caution in interpreting effort measure performance in dementia samples due to the fact that despite their best effort, many patients with dementia fail effort measures and are at risk for being misclassified.

Embedded indices of effort in the repeatable battery for the assessment of neuropsychological status (RBANS) in a geriatric sample.

The clinical utility of embedded indices of effort in the RBANS was examined in a geriatric sample. Patients were classified as providing suspect effort (n = 45) or probable good effort (n = 258) using the TOMM and clinical consensus. Following the methodology of Silverberg and colleagues (2007), selected individual subtests and a summary Effort Index were evaluated. Setting specificity at approximately 85% yielded cut-offs of <15 on List Recognition, <8 on Digit Span, and >3 on the Effort Index. The modest sensitivity (51.1-64.4%) suggests that the indices should be used in conjunction with additional effort measures. In addition, the RBANS Picture Naming subtest was examined and showed modest sensitivity to detect suboptimal effort, but did not show notable incremental validity for detecting suboptimal effort beyond the Effort Index.

Establishment of a predominantly African-American cohort for the study of Alzheimer's disease: the South Carolina Alzheimer's disease clinical core.

BACKGROUND/AIMS: The recruitment of culturally diverse subject populations into research studies, particularly African-Americans (AA), has been the focus of intense interest by many groups. METHODS: In this paper, we present the methodology utilized to create a predominantly AA cohort for the longitudinal study of risk factors in Alzheimer's disease (AD). The underlying strategy was that of identifying geographically diverse clinical venues within South Carolina (SC) where large numbers of AA patients already come to seek medical care. RESULTS: This strategy was successful, although recruitment rates for AA subjects (43.4%) still fell below those for white subjects (70.3%; p = 0.0025). Subject characteristics of AA subjects that chose to enroll were not substantially different from those that declined to participate. The demographic characteristics of this cohort were largely similar to those of the SC Alzheimer Disease Registry, a population-based database. The problems of standardization of subject recruitment and assessment across diverse clinical venues are also addressed. CONCLUSION: The utilization of geographically diverse sites for research recruitment where minorities already receive medical care is one practical solution to the problem of minority participation in research. Multi-site recruitment to improve minority recruitment can be accomplished with acceptable standardization and inter-rater reliability.

Does it stick? Effects of an integrated vertical undergraduate aging curriculum on medical and surgical residents.

Experts acknowledge the unmet need for all physicians to have basic knowledge of aging and competency in geriatric care given the context of population aging. The University of South Carolina (USC) School of Medicine implemented a highly successful program of aging-oriented undergraduate medical training, including a geriatrics vertical curriculum and its senior mentor program-a required, 4-year experience matching students with older community volunteers, referred to herein as the integrated vertical curriculum in geriatrics (IVC). In earlier work, it was established that IVC graduating classes were significantly more likely to report exposure to and coverage of various geriatrics topics than prior USC classes or other U.S. medical graduates. Here the results of a follow-up survey of USC graduating classes before and after exposure to the IVC and contemporaneous Medical University of South Carolina (MUSC) graduates after two to three years of residency (before the initiation of a senior mentor program at MUSC) is reported. Of 403 graduates, 227 returned questionnaires (response rate 56%). Significantly more IVC (2004) than pre-IVC (2003) and 2003 and 2004 MUSC graduates rated themselves fairly or very well prepared by their undergraduate education to treat older adults seen in residency (95% vs 77% and 52%; P<.001). Implications of this and other findings are discussed.

Demographic and biologic influences on survival in whites and blacks: 40 years of follow-up in the Charleston Heart Study.

BACKGROUND: In the United States, life expectancy is significantly lower among blacks than whites. We examined whether socioeconomic status (SES) and cardiovascular disease (CVD) risk factors may help explain this disparity. METHODS: Forty years (1961 through 2000) of all-cause mortality data were obtained on a population-based cohort of 2,283 subjects in the Charleston Heart Study (CHS). We examined the influence of SES and CVD risk factors on all-cause mortality. RESULTS: Complete data were available on 98% of the original sample (647 white men, 728 white women, 423 black men, and 443 black women). After adjusting for SES and CVD risk factors, the hazard ratios (HRs) for white ethnicity were 1.14 (0.98 to 1.32) among men and 0.90 (0.75 to 1.08) among women, indicating that the mortality risk was 14% greater for white men and 10% lower for white women compared to their black counterparts. However the differences were not statistically significant. CONCLUSION: While there are marked contrasts in mortality among blacks and whites in the CHS, the differences can be largely explained by SES and CVD risk factors. Continued focus on improving and controlling cardiovascular disease risk factors may reduce ethnic disparities in survival.

A synopsis of the practice parameters on dementia from the american academy of neurology on the diagnosis of dementia.

OBJECTIVE: The objective of this paper is to review the current practice guidelines as developed by the American Academy of Neurology (AAN) for the diagnosis of dementia. DATA SOURCES: The data sources were the Report of the Quality Standards Subcommittee of the American Academy of Neurology paper, which was published in the May 2001 issue of the journal Neurology. STUDY SELECTION: The studies used in this paper are those reviewed by the AAN Practice Parameter Committee, which reviewed the literature for evidence-based human studies pertaining to the diagnosis of dementia. Studies on Alzheimer's disease (AD) included had to have more than 25 subjects. Each article was classified based on the quality of evidence. After review of the evidence, the committee drafted recommendations and placed the evidence into Practice Standards, Guidelines, or Options. DATA SYNTHESIS: The main results of this review were the guidelines for diagnosing dementia of various forms. To diagnose dementia, the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-IIIR) should be used. For AD, the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer s Disease and Related Disorders Association) criteria should be used. The Modified Hachinski Ischemic Score criteria can be used in the diagnosis of vascular dementia. The Consortium for DLB (Dementia with Lewy Bodies) criteria may be of use in clinical practice. Neuroimaging with a noncontrast CT or MRI scan in the routine initial evaluation of persons with dementia is appropriate; other methods of neuroimaging are not recommended at this time. Genetic testing and use of apolipoprotein E (ApoE) genotyping is not recommended at this time. Depression, B12 deficiency, and hypothyroidism should be screened for and treated in patients with dementia. Unless the patient lives in an area in the United States with a high rate of syphilis, screening for tertiary syphilis is not warranted. CONCLUSION: The guidelines and their clinical applications are pertinent and important knowledge for consultant pharmacists. This practice parameter will need to be updated every few years to include new studies and information that becomes available.

Diagnostic challenges of using CSF assay of tau and beta-amyloid(42) in atypical degenerative dementias of the Alzheimer type.

This report presents three cases of atypical degenerative dementias in order to illustrate challenges associated with the use of biologic markers of Alzheimer's disease (AD) for diagnosis and management. Clinical diagnostic methods followed the NINCDS-ADRDA criteria for AD. Additional diagnostic studies included serial neurocognitive testing, MRI, neuroSPECT, ApoE genotyping, and a CSF assay of tau and beta-amyloid(42). For patient 1, both the clinical and biologic markers were consistent with AD. The patient was diagnosed with AD with a high degree of confidence, even though the base rate of nonfamilial AD at this age group (<55 years) is exceedingly rare. This case argues favorably for the use of biologic markers to aid in confirming a diagnosis in an atypical dementia. Patient 2 met the NINCDS-ADRDA criteria for AD, although with less confidence. Neurocognitive data indicated a progressive right hemispheric syndrome, insight was preserved, and ApoE was 3/3, but tau concentrations and beta-amyloid(42) were highly consistent with cut-offs for AD; the differential fell on the Pick's disease/frontotemporal degeneration spectrum. Patient 3 had no clinical evidence of the disease, even when evaluated via extensive neurocognitive testing over a 2-year interval. However, ApoE was 4/4, and CSF assay of tau and beta-amyloid(42) were within the AD range. Therefore, while the CSF assay of tau and beta-amyloid(42) markers was confirmatory of AD, each case was highly atypical. Results illustrate the lack of normative data available when using biologic markers for highly atypical cases, calling into question their usefulness for such patients. These cases illustrate the interplay between neuropsychological and biological markers in establishing neurodegenerative diagnoses.