The influence of cerebrospinal fluid (CSF) biomarkers on clinical dementia evaluations.

BACKGROUND: Cerebrospinal fluid (CSF) proteins have become accepted biomarkers of Alzheimer's disease (AD) in research settings. The extent of their use, perceived utility, and influence on decision making in clinical settings, however, are less well studied. METHODS: Clinicians who evaluate older adults (N = 193) were randomized to view normal, borderline, AD-consistent, or no CSF information in two vignettes portraying patients with borderline and mild AD symptoms. Clinicians also reported on the use and perceived utility of CSF biomarkers. RESULTS: Although clinicians reported infrequent use and low perceived utility of CSF biomarkers, viewing AD-consistent CSF values made clinicians more likely to make an AD-related diagnosis, increased diagnostic confidence, and led clinicians to initiate treatment more often than clinicians who had no CSF information. CONCLUSIONS: CSF biomarkers influence decision making depending on the extent to which biomarkers reflect AD pathology, consistency between clinical-pathologic information, and the ambiguity of protein values.

Pathological correlates of white matter hyperintensities on magnetic resonance imaging.

BACKGROUND/AIMS: We investigated the histopathological correlates of white matter hyperintensities (WMHs) in participants with Alzheimer's disease (AD) or cerebrovascular disease, and in aged controls. METHODS: We reviewed 57 participants who had neuropathology and in whom neuroimaging was done. In addition to AD pathology, cortical microinfarcts, lacunes, and cerebral hemorrhages were assessed. Small-vessel disease included arteriolosclerosis and cerebral amyloid angiopathy. Postmortem brain tissue corresponding to regions of WMHs was investigated in 14 participants. The variables included: demyelination of the deep and periventricular white matter (WM), atrophy of the ventricular ependyma, and thickness of blood vessels. Partial Spearman's rank test and linear regression analysis, adjusted for age at the clinical evaluation and the duration to death, were performed. RESULTS: The severity of arteriosclerosis was correlated with the volume of periventricular hyperintensity (PVH) estimated by magnetic resonance imaging. Deep white matter hyperintensity (DWMH) volume was correlated with the presence of cortical microinfarcts and cerebral hemorrhages. The severity of the breakdown of the ventricular lining was correlated with PVHs, and DWMHs correlated with the severity of deep WM demyelination. The diameter of small blood vessels was not associated with WMHs. CONCLUSION: WMHs are consistent with small-vessel disease and increase the tissue water content. We found no association between WMHs and the thickness of small blood vessels.

Unified Parkinson's Disease Rating Scale-Motor Exam: inter-rater reliability of advanced practice nurse and neurologist assessments.

AIM: This paper is a report of a study to establish the inter-rater reliability of advanced practice nurse and neurologist neurological assessments which included ratings with the Unified Parkinson's Disease Rating Scale-Motor Exam. BACKGROUND: Around the world, advanced practice nurses are performing tasks once completed only by physicians. To promote consumer and provider confidence, it is important to establish that nurse and physician ratings using assessment tools are similar. In addition in research settings, when different raters are used, establishment of inter-rater reliability for study assessments is needed. METHOD: Advanced practice nurses and neurologists independently recorded findings on neurological examinations of 46 participants in a study conducted between August 2007 and January 2008. An intraclass correlation coefficient was calculated to estimate overall agreement between the nurse and neurologist ratings. Agreement for individual items measured on a dichotomous scale was assessed by calculating Cohen's kappa. RESULTS: There was substantial agreement between advanced practice nurses and neurologists on the mean Unified Parkinson's Disease Rating Scale-Motor Exam ratings (intraclass correlation coefficient = 0.65) and the U.S. National Alzheimer's Coordinating Center Uniform Data Set neurological examination ratings of unremarkable findings (kappa = 0.74) and of gait disorder (kappa = 0.73). Moderate agreement (kappa = 0.53) was reached for the rating of whether all Unified Parkinson's Disease Rating Scale-Motor Exam items were normal. CONCLUSION: These findings are consistent with studies of the inter-rater agreement of the Unified Parkinson's Disease Rating Scale-Motor Exam and support the conduct of neurological assessments by advanced practice nurses.

Informant-based dementia screening in a population-based sample of African Americans.

BACKGROUND: An informant-based screening tool for dementia may be useful in population-based studies of minority populations. OBJECTIVE: Investigate the feasibility of screening for very mild dementia in a community sample of African Americans using an informant-based screening tool (AD8). DESIGN: Cohort study. PARTICIPANTS: One hundred forty-seven persons from the African American Health (AAH) project were screened for dementia; 61 of 93 who were invited had follow-up clinical assessments for dementia diagnosis. MEASUREMENTS: The AD8, Mini-Mental State Examination, Short Blessed Test, Brief Instrument for Dementia Detection, and a neuropsychologic battery were administered at visit 1. The Clinical Dementia Rating (CDR) was administered at visit 2 by clinicians blinded to visit 1 results; the presence of dementia was determined by a CDR greater than 0. RESULTS: Four hundred sixty-five individuals from the AAH cohort were sent a letter describing the study and, among this group, 252 individuals were contacted by phone to request participation in this study. Six percent (14/252) of the participants contacted by phone were unable to identify an informant (required for the AD8). One hundred fifty individuals agreed by phone to participate of which 2% (n=3) did not have an informant available at the time of participation. The AD8 alone was effective at discriminating between CDR 0 and CDR 0.5 (area under the curve=0.847; P<0.001; 95% confidence interval, 0.73-0.96). CONCLUSIONS: A brief informant-based instrument, the AD8, has high sensitivity and specificity for distinguishing CDR 0 from CDR 0.5 in the community. Informant availability may not be a barrier for using the AD8 in an African American community sample; however, further study in larger samples with a higher response rate, different community settings (eg, community clinics), and among older age groups (eg, age 75+) is warranted to confirm this.

The "portable" CDR: translating the clinical dementia rating interview into a PDA format.

The Clinical Dementia Rating (CDR) is a common rating system used in clinical trials and longitudinal research projects to rate the presence and severity of cognitive problems in Alzheimer disease and related disorders. The interview process requires training and can be time-consuming. Here, we describe the validity, reliability, and discriminative ability of a computer-generated CDR using a personal digital assistant format. This project used clinical data from 138 archival and live evaluations (patient and informant interviews) collected for research purposes at Washington University to develop and test a software-based system for the administration and automatic scoring of the CDR. The system was programmed for use on a hand-held computer via the Palm Operating System. We developed domain-specific algorithms to quantify and translate clinical scoring decisions for the 3 cognitive (Memory, Orientation, Judgment and Problem Solving) and the 3 functional (Community Affairs, Home and Hobbies, Personal Care) domains of the CDR. An acceptable set of algorithms were developed using data from 104 research cases, reflecting a range of impairment levels (CDR 0 to 3) and expert scoring decisions. These algorithms were then tested for accuracy in a validation sample of 34 cases. The computer-generated CDR has excellent internal consistency (Cronbach's alpha ranging from 0.94 to 0.98) and interrater reliability (intraclass correlation coefficient ranging from 0.88 to 0.96). The computer-generated CDR showed excellent discrimination between demented and nondemented cases (Area under the curve=0.95; 95% confidence interval, 0.84-1.1). The computer-generated CDR using a Palm Operating System is easy to use, valid, and reliable. The level of agreement compares favorably to published interrater reliability data for the CDR. Software-based administration and automatic scoring of the CDR is a viable alternative to paper-based methods and may be useful in research and clinical settings, especially where electronic data management and reliability in scoring are critical.

Patient's rating of cognitive ability: using the AD8, a brief informant interview, as a self-rating tool to detect dementia.

OBJECTIVE: To test the ability of patients to rate their own cognitive ability using the AD8 compared with informant and clinician ratings of cognitive status. DESIGN, SETTING, AND PATIENTS: The AD8 was administered to 325 consecutive participant-informant dyads enrolled in a longitudinal study at Washington University School of Medicine between April 4, 2005, and December 15, 2005. The number of AD8 items endorsed by the participant was compared with informant answers and an independently derived Clinical Dementia Rating. MAIN OUTCOME MEASURE: Strength of association was measured with Spearman (rho) and intraclass correlation coefficients. Receiver operator characteristic curves assessed the discriminative properties of the AD8. RESULTS: The mean age of participants and informants was 72.8 years (range, 43-104 years) and 66.4 years (range, 24-101 years), respectively. The Clinical Dementia Rating was correlated with both informant (rho = 0.75, P<.001) and participant (rho = 0.34, P<.001) AD8 scores. Participants' AD8 scores had adequate agreement with informants' AD8 scores (intraclass correlation coefficient, 0.53; 95% confidence interval, 0.41-0.62) and correlated with subjective complaints of memory problems (rho = 0.47, P<.001) but not with estimates of symptom duration. The area under the receiver operator characteristic curve for the informant AD8 was 0.89 (95% confidence interval, 0.86-0.93); for the participant AD8, it was 0.78 (95% confidence interval, 0.68-0.78). CONCLUSIONS: The AD8 is a brief measure that, when completed by an informant, differentiates nondemented from demented individuals. We now demonstrate that a self-completed AD8 also differentiates nondemented from demented individuals, although the utility was better in mildly impaired individuals compared with more demented individuals. In the absence of a reliable informant, the AD8 may be asked of the participant to gain an understanding of their perception of cognitive status.

Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life.

BACKGROUND: Cases of early-onset Alzheimer disease (AD) with an autosomal dominant inheritance pattern (familial AD [FAD]) are rare but have greatly advanced our understanding of the molecular pathogenesis of AD. We describe herein a kindred with very early-onset FAD (age, <40 years) with unusual pathological features and a novel mutation in the presenilin 1 (PSEN1) gene (S170F) and review the existing literature on very early-onset FAD. OBJECTIVE: To analyze the neuropathological and genetic features of a family with onset of AD in the third decade of life. DESIGN, SETTING, AND PARTICIPANTS: The proband underwent full clinical assessment and postmortem examination at the Washington University Alzheimer's Disease Research Center, St Louis, Mo. Limited pathological samples and autopsy records of 2 affected family members were available. The proband underwent screening for mutations in genes linked with FAD. RESULTS: Dementia developed in 3 family members in this kindred at a mean age of 27 years; the proband had myoclonus, seizures, and rigidity, similar to findings in previously described kindreds with PSEN1 mutations. All 3 family members were confirmed to have AD by neuropathological examination. The proband also had widespread Lewy body pathology in the brainstem, limbic areas, and neocortex; specific staining for Lewy bodies was not performed in the other 2 family members. The proband had a single mutation (S170F) in exon 6 of the PSEN1 gene, which segregates with disease. CONCLUSIONS: A novel PSEN1 mutation causes very-early-onset FAD with associated Lewy bodies. To our knowledge, this kindred has the earliest reported onset of pathologically confirmed FAD and dementia with Lewy bodies.