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Objective: To improve the timely recognition of patients with treatment-responsive causes of rapidly progressive dementia (RPD)., Methods: A total of 226 adult patients with suspected RPD were enrolled in a prospective observational study and followed for up to 2 years. Diseases associated with RPD were characterized as potentially treatment-responsive or non-responsive, referencing clinical literature. Disease progression was measured using Clinical Dementia Rating® Sum-of-Box scores. Clinical and paraclinical features associated with treatment responsiveness were assessed using multivariable logistic regression. Findings informed the development of a clinical criterion optimized to recognize patients with potentially treatment-responsive causes of RPD early in the diagnostic evaluation., Results: A total of 155 patients met defined RPD criteria, of whom 86 patients (55.5%) had potentially treatment-responsive causes. The median (range) age-at-symptom onset in patients with RPD was 68.9 years (range 22.0-90.7 years), with a similar number of men and women. Seizures, tumor (disease-associated), magnetic resonance imaging suggestive of autoimmune encephalitis, mania, movement abnormalities, and pleocytosis (≥10 cells/mm 3 ) in cerebrospinal fluid at presentation were independently associated with treatment-responsive causes of RPD after controlling for age and sex. Those features at presentation, as well as age-at-symptom onset <50 years (ie, STAM 3 P), captured 82 of 86 (95.3%) cases of treatment-responsive RPD. The presence of ≥3 STAM 3 P features had a positive predictive value of 100%., Interpretation: Selected features at presentation reliably identified patients with potentially treatment-responsive causes of RPD. Adaptation of the STAM 3 P screening score in clinical practice may minimize diagnostic delays and missed opportunities for treatment in patients with suspected RPD. ANN NEUROL 2024;95:237-248., (© 2023 American Neurological Association.)

Objective: This study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment-responsive causes of RPD., Methods: Biomarkers of Alzheimer disease neuropathology (amyloid-β 42/40 ratio, phosphorylated tau [p-tau181, p-tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin-like protein-1 [VILIP-1], total tau), neuroinflammation (chitinase-3-like protein [YKL-40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein-1 [MCP-1]), and synaptic dysfunction (synaptosomal-associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age- and sex-matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease., Results: Alzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL-40 and low VILIP-1 identified patients with autoimmune/inflammatory diseases. MCP-1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP-1, p-tau181, and sTREM2 identified the 44 patients with treatment-responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease., Interpretation: Selected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross-sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2024;95:299-313., (© 2023 American Neurological Association.)

Background/objective: The AD8 informant-based screening instrument has been validated with molecular biomarkers of Alzheimer disease (AD) but not with the gold standard of neuropathologic AD. The objective of this study was to validate the AD8 with neuropathologic AD and compare its predictive performance with that of the Mini-Mental State Examination and both participant-derived and informant-derived subjective memory complaint (SMC) regarding the participant., Methods: This longitudinal cohort study at the Knight Alzheimer Disease Research Center at Washington University included 230 participants, ages 50 to 91 years, who later had a neuropathologic examination. Four dementia screening instruments from their baseline assessment were evaluated: the AD8, Mini-Mental State Examination, participant SMC, and informant SMC. The primary outcome was a neuropathologic diagnosis of AD., Results: The average participant age at baseline was 80.4 years, 48% were female. All 4 dementia screening tests were predictive of neuropathologic AD. There was no significant difference in the predictive performance of the AD8 compared with the other instruments, but the AD8 had superior sensitivity and combined positive and negative predictive values., Conclusion: The AD8 is a brief and sensitive screening instrument that may facilitate earlier and more accurate AD diagnosis in a variety of care settings.

Introduction: Spatial navigation deficits are observed in Alzheimer's disease cross-sectionally, but prediction of longitudinal clinical decline has been less examined., Methods: Cognitive mapping (CM) was assessed in 95 participants and route learning (RL) was assessed in 65 participants at baseline. Clinical progression over an average of 4 to 5 years was assessed using the clinical dementia rating (CDR) scale. Relative predictive ability was compared to episodic memory, hippocampus, and cerebrospinal fluid biomarkers (phosphorylated tau/amyloid β 42 (ptau 181 /Aβ 42 ) ratio)., Results: CM and RL were predictors of clinical progression (P's < 0.032). All measures, except RL-Learning remained predictors with episodic memory in models (P's < 0.048). Only RL-Retrieval remained a predictor when ptau 181 /Aβ 42 was included (P < 0.001). CM interacted with hippocampus and ptau 181 /Aβ 42 in prediction (P's < 0.013). CM, RL, and episodic memory evidenced strong diagnostic accuracy (area under the curve (AUC) = 0.894, 0.794, and 0.735, respectively); CM tended to perform better than episodic memory (P = 0.056)., Discussion: Baseline spatial navigation performance may be appropriate for assessing risk of clinical progression., (© 2019 the Alzheimer's Association.)

Driving is a complex, multifaceted instrumental activity of daily living that has an independent influence on multiple health and well-being outcomes among older adults. Therefore, the benefits of driving to the individual must be balanced, through careful assessment and diagnosis, with the potential risk to self and others posed by a medically impaired driver. The influence of dementia changes substantially during the disease progression from very mild to mild, and driving is not advised for those who have progressed to the moderate stage of Alzheimer disease. Fortunately, validated high-quality screening instruments, including modern simulators and other technology aids, can help clinicians trichotomize risk (i.e., high, moderate, or low) and determine which patients need further evaluation by a driving specialist (e.g., those in the moderate range). Moreover, a body of evidence is building regarding the efficacy of certain intervention pathways to maintain current levels of driving performance among individuals with dementia, or at least slow its decline. Even with the progression of advanced driving technologies, understanding driving ability of patients with dementia will remain a critical challenge to clinicians for the foreseeable future., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: With 36 million older adult U.S. drivers, safety is a critical concern, particularly among those with dementia. It is unclear at what stage of Alzheimer's disease (AD) older adults stop driving and whether preclinical AD affects driving cessation., Methods: Time to driving cessation was examined based on Clinical Dementia Rating (CDR) and AD cerebrospinal fluid biomarkers. 1795 older adults followed up to 24 years received CDR ratings. A subset (591) had cerebrospinal fluid biomarker measurements and was followed up to 17 years. Differences in CDR and biomarker groups as predictors of time to driving cessation were analyzed using Kaplan-Meier curves and Cox proportional models., Results: Higher CDR scores and more abnormal biomarker measurements predicted a shorter time to driving cessation., Discussion: Higher levels of AD biomarkers, including among individuals with preclinical AD, lead to earlier driving cessation. Negative functional outcomes of preclinical AD show a nonbenign phase of the disease., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

Cognitive and physical aspects of functionality are closely related. However, whether physical decline differs by dementia type and progression rate is debatable. To address these issues, we conducted a longitudinal study of 766 older adults whose physical performance and cognitive status were assessed annually with standard assessment tools [eg, Physical Performance Test, Clinical Dementia Rate (CDR)] for 8 years. Compared with participants who remained cognitively normal, those progressing to later-stage dementia (CDR=1) declined in their mobility by a factor of 2.82 (P<0.001), followed by those who maintained a later-stage diagnosis (slope=-1.84, P<0.001), those progressing from early-stage to later-stage (CDR=0.5 to CDR=1) dementia (slope=-1.20, P<0.001), and those who progressed to early-stage dementia (slope=-0.39, P=0.038) suggesting a steeper physical decline with dementia progression, particularly in those with the fastest disease progression. Although all types of dementia experienced mobility decline, those progressing to non-Alzheimer disease (AD) dementias, especially vascular dementia declined faster than those who remained normal (slope=-2.70, P<0.001) or progressed to AD (slope=-2.18, P<0.001). These associations were better captured by the gait/balance component of physical functionality. Our findings suggest that rapidly progressing dementia patients particularly those with non-AD subtypes should be targeted for interventions to maintain or improve gait/balance and prevent functional decline and disability although AD patients may also benefit.

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., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

To assess the directionality of the association between physical and cognitive decline in later life, we compared patterns of decline in performance across groups defined by baseline presence of cognitive and/or physical impairment [none (n = 217); physical only (n = 169); cognitive only (n = 158), or both (n = 220)] in a large sample of participants in a cognitive aging study at the Knight Alzheimer's Disease Research Center at Washington University in St. Louis who were followed for up to 8 years (3,079 observations). Rates of decline reached 20% for physical performance and varied across cognitive tests (global, memory, speed, executive function, and visuospatial skills). We found that physical decline was better predicted by baseline cognitive impairment (slope = -1.22, p<0.001), with baseline physical impairment not contributing to further decline in physical performance (slope = -0.25, p = 0.294). In turn, baseline physical impairment was only marginally associated with rate of cognitive decline across various cognitive domains. The cognitive-functional association is likely to operate in the direction of cognitive impairment to physical decline although physical impairment may also play a role in cognitive decline/dementia. Interventions to prevent further functional decline and development of disability and complete dependence may benefit if targeted to individuals with cognitive impairment who are at increased risk.

The value of screening for cognitive impairment, including dementia and Alzheimer's disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimer's Foundation of America and the Alzheimer's Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient-centered management of dementia., (Published by Elsevier Inc.)

A diagnosis of dementia is challenging to deliver and to hear; yet, agreement on diagnosis is essential for effective treatment for dementia. We examined consensus on the results of an evaluation of dementia in 90 patients assessed at an Alzheimer's Disease Research Center. Diagnostic impressions were obtained from 5 sources: (1) the physician's chart; (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 with that between physicians and patients, although it was imperfect between physicians and video raters and the written summary. Agreement among sources varied by dementia severity, with the 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 diagnosis of dementia and decisions regarding future planning and care.

Objective: To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a work group sponsored by the National Institute on Aging and the Alzheimer's Association, on the diagnosis of very mild and mild Alzheimer disease (AD)dementia., Design: Retrospective review of ratings of functional impairment across diagnostic categories., Setting: Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center., Participants: Individuals (N=17 535) with normal cognition,MCI, or AD dementia., Main Outcome Measures: The functional ratings of individuals with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer's Disease Centers and submitted to the National Alzheimer's Coordinating Center were assessed in accordance with the definition of "functional independence" allowed by the revised criteria. Pairwise demographic differences between the 3 diagnostic groups were tested using t tests for continuous variables and 2 for categorical variables., Results: Almost all (99.8%) individuals currently diagnosed with very mild AD dementia and the large majority(92.7%) of those diagnosed with mild AD dementia could be reclassified as having MCI with the revised criteria,based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home.Large percentages of these individuals with AD dementia also meet the revised "functional independence" criterion for MCI as measured by the Functional Assessment Questionnaire., Conclusions: The categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that "MCI due to AD" represents the earliest symptomatic stage of AD.

The AD8 questionnaire developed by Washington University in St Louis is a screening tool with 8 questions to reliably differentiate nondemented from demented individuals even at the very mild stage. We recruited 239 participants, including 114 cognitively normal, 73 very mild dementia, and 52 mild dementia to validate its application in Taiwanese. The cut-off value of AD8 was 2 in discriminating cognitively normal from demented individuals with the area under curve (AUC) = 0.961, sensitivity = 97.6%, specificity = 78.1%, positive likelihood ratio (PLR) = 4.5, and negative likelihood ratio (NLR) = 0.03. The cut-off value also was 2 in discriminating nondemented from very mild dementia with the AUC = 0.948, sensitivity = 95.9%, specificity = 78.1%, PLR = 4.4, and NLR = 0.05. The Chinese AD8 is effective in discriminating individuals with dementia, even at its mildest stages from those without dementia with properties identical to the original English version. The cAD8 is a quick dementia screening tool that can be applied across cultures.

The Open Access Series of Imaging Studies is a series of neuroimaging data sets that are publicly available for study and analysis. The present MRI data set consists of a longitudinal collection of 150 subjects aged 60 to 96 years all acquired on the same scanner using identical sequences. Each subject was scanned on two or more visits, separated by at least 1 year for a total of 373 imaging sessions. Subjects were characterized using the Clinical Dementia Rating (CDR) as either nondemented or with very mild to mild Alzheimer's disease. Seventy-two of the subjects were characterized as nondemented throughout the study. Sixty-four of the included subjects were characterized as demented at the time of their initial visits and remained so for subsequent scans, including 51 individuals with CDR 0.5 similar level of impairment to individuals elsewhere considered to have "mild cognitive impairment." Another 14 subjects were characterized as nondemented at the time of their initial visit (CDR 0) and were subsequently characterized as demented at a later visit (CDR > 0). The subjects were all right-handed and include both men (n = 62) and women (n = 88). For each scanning session, three or four individual T1-weighted MRI scans were obtained. Multiple within-session acquisitions provide extremely high contrast to noise, making the data amenable to a wide range of analytic approaches including automated computational analysis. Automated calculation of whole-brain volume is presented to demonstrate use of the data for measuring differences associated with normal aging and Alzheimer's disease.

Background: Since 1979, our clinicians have used an autobiographical memory task testing for events that occurred over the most recent week and most recent month in their semistructured interview when assessing for dementia., Objective: To examine correlations between scores on the autobiographical memory task and on 2 other commonly used brief memory tasks with results of a clinical assessment for dementia., Design: Correlation study., Setting: Academic research., Participants: Participants were enrolled in Washington University Alzheimer Disease Research Center studies, were 60 years or older, and participated in assessments between May 29, 2002, and August 15, 2005 (N = 425)., Main Outcome Measures: Nonparametric Spearman rank correlations, adjusted for age and education status, between the Clinical Dementia Rating sum of boxes (CDR-SB) and scores on the autobiographical memory task and on 2 clinical brief memory tasks obtained from the Mini-Mental State Examination and the Short Blessed Test., Results: Scores on the autobiographical memory task and on each of the other 2 memory tasks correlated significantly with the CDR-SB (P < .001). Scores on the autobiographical memory task had a significantly higher correlation with results of the CDR-SB than the other 2 memory tasks (P < .001)., Conclusion: Clinicians may find the autobiographical memory task an important indicator of memory function and the autobiographical query a useful tool when assessing for dementia.

The aim was to develop a brief physical performance assessment tool that can be reliably used to detect physical impairment in older adults with and without mild dementia. Scores on the 9-item physical performance test (PPT) from non-demented participants were used to develop and validate the 4-item mini-PPT. The validated mini-PPT was then used to predict total PPT score and functional physical status in participants with mild dementia. Receiver operating curve (ROC) analyses were used to generate a cutoff score that classifies participants as functional vs. not functional. The setting was in the Alzheimer's Disease Research Center (Washington University). A total of 1199 participants met inclusion criteria: 574 non-demented participants, 436 with very mild dementia, measured by the clinical dementia rating (CDR)=0.5 and 189 with mild dementia (CDR=1). The mean age of the sample was 76.4 years, mean educational attainment was 14 years, 58% were women, and 11% were African American. A 4-item scale, the mini-PPT, was developed (based on the results of multiple regression analyses and clinical meaningfulness) that highly correlated with total PPT score (r=0.917, p<0.0001) in the non-demented sample. The correlation of the mini-PPT with total PPT was 0.90 among those with very mild, and 0.91 among those with mild dementia. Using the ROCs, a cutoff score of 12 correctly classified at least 85% of non-demented and demented persons. The 4-item mini-PPT is highly correlated with the 9-item PPT in non-demented and mildly demented persons. This brief tool may be useful in detecting early physical impairment in the clinical setting.

Objective: To examine dementia severity as determined by the Clinical Dementia Rating (CDR) over time., Design: Secondary analysis of data from longitudinal studies of aging and dementia., Setting: Alzheimer's Disease Research Center, where a variety of clinicians contributed CDR ratings during the study., Participants: Adults aged 63 to 83 years with no (CDR 0), very mild (CDR 0.5), or mild (CDR 1) dementia enrolled in the Alzheimer's Disease Research Center at any time from August 13, 1979, through May 30, 2007., Main Outcome Measures: Within each CDR group, changes in scores on standardized psychometric tests with time were examined using multiple linear regression analyses. These tests included the Mini-Mental State Examination, Short Blessed Test, Logical Memory IA-Immediate from the Wechsler Memory Scale-Revised, and Blessed Dementia Scale, and a psychometric composite score., Results: A total of 1768 participants met the inclusion criteria. With time, participants were older, more educated, and more likely to be nonwhite and less likely to be men. Statistically significant change in psychometric test performance with time occurred only within the CDR 1 group for Logical Memory and the psychometric composite, but the degree of change was minimal., Conclusion: Despite changes in participant characteristics, the CDR demonstrates general stability for assessment of dementia for almost 3 decades.

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 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.

The prevention of neurodegenerative dementias, such as Alzheimer's disease, is a public health priority. Due to the large numbers of affected patients, even interventions bringing about a relatively small delay in disease onset could have large public health effects. Randomized controlled trials (RCTs) are required to demonstrate the effectiveness of preventive interventions, but such trials raise specific methodological questions because they are new in the field of neurodegenerative diseases, and require large numbers of elderly subjects and lengthy follow-up periods. We performed a literature search to identify primary prevention RCTs for neurodegenerative dementia. The methodology of the trials was summarized and discussed during two expert meetings. Overall, 39 trials were identified that assessed dementia incidence or cognitive decline as a primary or secondary study outcome. Age was the most common selection criteria for target populations. Follow-up periods ranged from one month to nine years and were longest in studies measuring dementia incidence as an outcome. Results of RCTs have so far been generally negative and conflicting with those of observational studies, perhaps due to methodological issues. Future trials must therefore carefully consider the target population, outcomes and duration of follow-up to be used, and should assess the problem of attrition.

Objective: To re-examine proposed models of cognitive test performance that concluded separate factor structures were required for people with Alzheimer disease (AD) and older adults without dementia., Methods: Five models of cognitive test performance were compared using multistep confirmatory factor analysis in 115 individuals with autopsy-confirmed AD and 191 research participants without clinical dementia from longitudinal studies at the Washington University AD Research Center. The models were then cross-validated using independent samples of 323 people with clinically diagnosed dementia of the Alzheimer type and 212 cognitively healthy older adults., Results: After controlling for Alzheimer-specific changes in episodic memory, performance on the battery of tests used here was best represented in people both with and without dementia by a single model of one general factor and three specific factors (verbal memory, visuospatial ability, and working memory). Performance by people with dementia was lower on the general factor than it was by those without dementia. Larger variances associated with the specific factors in the group with dementia indicated greater individual differences in the pattern of cognitive deficits in the stage of AD., Conclusions: A hybrid model of general and specific cognitive domains simplifies cognitive research by allowing direct comparison of normal aging and Alzheimer disease performance. The presence of a general factor maximizes detection of the dementia, whereas the specific factors reveal the heterogeneity of dementia's associated cognitive deficits.

TAR DNA-binding protein 43 (TDP-43) is a major component of the inclusions in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). We studied TDP-43 pathology in the hippocampus and frontal cortex of autopsy brains from patients with FTLD-U (n = 68), dementia lacking distinctive histopathology (n = 4), other neurodegenerative diseases (n = 23), and controls (n = 12) using a sensitive immunohistochemistry protocol. Marked enhancement of staining of TDP-43-positive dystrophic neurites (DNs) was obtained, and we observed 2 previously unrecognized pathologic patterns (i.e. frequent long DNs in the CA1 region and frequent dot-like DNs in the neocortical layer 2) in 39% and 15% of the FTLD-U cases, respectively. Frequent long DNs, but not dot-like DNs, were significantly associated with progranulin mutations. Based on this evaluation, 4 FTLD-U cases showed no TDP-43 pathology and were reclassified as "FTLD-U, non-TDP-43 proteinopathy," and 3 cases of dementia lacking distinctive histopathology were reclassified as FTLD-U. Of the cases with other neurodegenerative diseases, 43% showed TDP-43 pathology in the hippocampus, but only 4% showed TDP-43 pathology in the frontal cortex. No TDP-43 pathology was seen in controls. These results indicate that the sensitivity of the TDP-43 immunohistochemistry method affects both the extent and type of abnormalities detected. Moreover, assessment of abnormalities in both the hippocampus and frontal cortex may be diagnostically important in FTLD-U.

Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3' splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency., (Copyright 2008 Wiley-Liss, Inc.)

The Open Access Series of Imaging Studies is a series of magnetic resonance imaging data sets that is publicly available for study and analysis. The initial data set consists of a cross-sectional collection of 416 subjects aged 18 to 96 years. One hundred of the included subjects older than 60 years have been clinically diagnosed with very mild to moderate Alzheimer's disease. The subjects are all right-handed and include both men and women. For each subject, three or four individual T1-weighted magnetic resonance imaging scans obtained in single imaging sessions are included. Multiple within-session acquisitions provide extremely high contrast-to-noise ratio, making the data amenable to a wide range of analytic approaches including automated computational analysis. Additionally, a reliability data set is included containing 20 subjects without dementia imaged on a subsequent visit within 90 days of their initial session. Automated calculation of whole-brain volume and estimated total intracranial volume are presented to demonstrate use of the data for measuring differences associated with normal aging and Alzheimer's disease.

TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FTDs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and familial FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FTD with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis.

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.

Background: A proportion of patients who meet the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Associations criteria for Alzheimer disease (AD) have frontotemporal lobar degeneration (FTLD) confirmed at autopsy, with or without concomitant AD. Thus, the clinical phenotypes of the 2 disorders may overlap., Objective: To identify clinical and psychometric indicators that distinguish AD from FTLD at initial presentation., Design: Longitudinal study of memory and aging., Setting: Alzheimer's Disease Research Center, Washington University School of Medicine., Participants: Forty-eight clinically well-characterized cases of autopsy-confirmed FTLD (27 with psychometric testing results) were compared with 27 autopsy-confirmed AD cases., Results: Behavioral abnormalities, particularly impulsivity (P<.001), disinhibition (P<.001), social withdrawal (P = .01), and progressive nonfluent aphasia, distinguished individuals with FTLD from those with AD. The individuals with FTLD performed better than those with AD on a visual test of episodic memory (P = .01), but worse on word fluency (P = .02) (performance correlated with aphasic features). Other cognitive and clinical features, including executive dysfunction and memory impairment, were comparable between the FTLD and AD groups. Concomitant histopathological AD was present in 11 of the 48 individuals with FTLD., Conclusions: Clinical and cognitive features of FTLD may overlap with AD, although behavioral and language difficulties distinguish those with FTLD. Memory loss in those with FTLD may in part reflect word-finding difficulties stemming from language dysfunction. Compounding the overlap of FTLD and AD clinical phenotypes is the presence of histopathological AD in almost one fourth of individuals with FTLD.

Background: Individuals with no cognitive impairment during life but with neuropathologic Alzheimer disease (AD) may represent cases of presymptomatic, or unrecognized early symptomatic, AD. The cognitive reserve hypothesis suggests that at a particular level of AD pathology, highly educated individuals are less likely to manifest clinical symptoms of dementia vs less-educated individuals., Objective: To investigate whether education can help explain a clinical diagnosis of no dementia within 1 year of death among individuals with neuropathologic diagnoses of AD., Methods: Samples of participants (age 65+ years at last clinical assessment) meeting each of three neuropathologic criteria for AD were constructed using data from the National Alzheimer's Coordinating Center Minimum and Neuropathology Data Sets. Generalized linear mixed models (using the logit link function) were used in each sample to examine whether years of education was associated with dementia within 1 year of death, adjusting for other relevant variables., Results: Twelve percent of individuals meeting Khachaturian (122/1,009), 19% meeting low, intermediate, or high likelihood for National Institute on Aging/Reagan Institute (320/1,704), and 14% meeting possible, probable, or definite Consortium to Establish a Registry for Alzheimer's Disease (265/1,835) neuropathologic criteria for AD were nondemented at their final clinical assessment. Persons with more education were less likely to have a dementia diagnosis in each sample., Conclusions: Regardless of the neuropathologic criteria used, education is predictive of dementia status among individuals with neuropathologic Alzheimer disease. These results support the theory that individuals with greater cognitive reserve, as reflected in years of education, are better able to cope with AD brain pathology without observable deficits in cognition.

Objective: To establish the validity, reliability, and discriminative properties of the AD8, a brief informant interview to detect dementia, in a clinic sample., Methods: We evaluated 255 patient-informant dyads. We compared the number of endorsed AD8 items with an independently derived Clinical Dementia Rating (CDR) and with performance on neuropsychological tests. Construct and concurrent validity, test-retest, interrater and intermodal reliability, and internal consistency of the AD8 were determined. Receiver operator characteristic curves were used to assess the discriminative properties of the AD8., Results: Concurrent validity was strong with AD8 scores correlating with the CDR (r = 0.75, 95% CI 0.63 to 0.88). Construct validity testing showed strong correlation between AD8 scores, CDR domains, and performance on neuropsychological tests. The Cronbach alpha of the AD8 was 0.84 (95% CI 0.80 to 0.87), suggesting excellent internal consistency. The AD8 demonstrated good intrarater reliability and stability (weighted kappa = 0.67, 95% CI 0.59 to 0.75). Both in-person and phone administration showed equal reliability (weighted kappa = 0.65, 95% CI 0.57 to 0.73). Interrater reliability was very good (Intraclass correlation coefficient = 0.80, 95% CI 0.55 to 0.92). The area under the curve was 0.92 (95% CI 0.88 to 0.95), suggesting excellent discrimination between nondemented individuals and those with cognitive impairment regardless of etiology., Conclusion: The AD8 is a brief, sensitive measure that validly and reliably differentiates between nondemented and demented individuals. It can be used as a general screening device to detect cognitive change regardless of etiology and with different types of informants.

Objective: To determine which clinical features best characterize Parkinson disease dementia (PDD), compared with Alzheimer disease (AD) and dementia with Lewy bodies (DLB), and to determine the pathologic basis for PDD., Methods: We examined 103 participants enrolled in a longitudinal study (nondemented control = 10, PD = 42, DLB = 20, AD = 31) who were followed to autopsy using standardized protocols. We characterized the features of PDD using published criteria for AD and DLB as a framework. Statistical analysis was performed using chi(2) and Fisher exact tests, Kaplan-Meier curves, and logistic regression models., Results: The sample's mean age was 74.0 years (range 53 to 91 years), and individuals were followed for a mean of 3.4 visits (range 1 to 12 visits). During longitudinal follow-up, 83% of subjects with PD developed dementia, defined as a Clinical Dementia Rating score of >or=0.5. Features that distinguished PDD from AD included cognitive fluctuations (p = 0.001), visual (p < 0.001) and auditory (p = 0.006) hallucinations, depression (p = 0.003), and sleep disturbance (p = 0.003). These PDD features were identical to those observed for DLB. The pathologic substrates for PDD included DLB (38%), AD (32%), and nigral LB alone (24%). Clinical predictors of PDD were visual hallucinations (odds ratio [OR] 21.3; 95% CI: 1.5 to 309.6) and male gender (OR 9.6; 95% CI: 1.3 to 71.4)., Conclusions: Parkinson disease dementia (PDD) shares identical clinical features with dementia with Lewy bodies (DLB); both entities can be distinguished from Alzheimer disease. The presence of PDD/DLB features at any time during the course of PD is highly predictive of dementia and the presence of LB at autopsy; in particular, male gender and visual hallucinations in PD predict dementia.

Purpose: We aimed to develop and evaluate a multimedia workshop curriculum to educate physicians and other health professionals about (a) driving-related assessment in older adults with dementia, and (b) strategies to encourage driving retirement for impaired individuals., Design and Methods: A curriculum developed by the Older Drivers Project of the American Medical Association was expanded for presentation by a multidisciplinary team. One pilot and seven test workshops were offered. A program evaluation method-testing knowledge, confidence, attitudes, and practice behaviors-was employed at four points in time: T1 (Time 1; pretest focusing on the previous 12 months), T2 (Time 2; same-day post-test), T3 (Time 3; post-test at 3 months), and T4 (Time 4; post-test at 12 months)., Results: At T1, participants (N = 147) expressed high agreement that an assessment of driving ability is an important issue in clinical dementia care, but they reported low knowledge of assessment strategies, resources, and state reporting requirements. Modest gains in knowledge and confidence were demonstrated at both T3 (n = 93) and T4 (n = 63). In addition, the frequency of driving-related practice behaviors (i.e., incorporation of driving-related questions into clinical evaluation, chart documentation, reporting of impaired drivers) had increased significantly by T3 and T4., Implications: The results indicate that a focused workshop curriculum, with practical and immediate applications to care, can motivate measurable changes in clinical practice. Once they are informed, health professionals can address issues of driving ability in older patients with dementia and, with the support of available resources, encourage impaired individuals to retire from driving for the safety of everyone on the road.

Objective: Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques., Methods: In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred., Results: Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds, which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum critical region for FTLD-U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation, Ala-9 Asp, within the signal peptide., Interpretation: HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay.

Background: Brief measures that accurately discriminate normal cognitive aging from very mild dementia are lacking. Cognitive tests often are insensitive to very mild dementia. Informant-based measures may be more sensitive in detecting early dementia., Objective: To identify informant-reported clinical variables that differentiate cognitively normal individuals from those with very mild dementia., Methods: A 55-item battery of informant queries regarding an individual's cognitive status was derived from a semistructured interview and a consensus panel of dementia experts. The battery was evaluated with informants for 189 consecutive participants of a longitudinal study of memory and aging and compared with an independently obtained Clinical Dementia Rating (CDR) score for the participant. Multiple regression and receiver operator characteristic curves assessed subsets of the items to discriminate between CDR 0 (no dementia) and CDR 0.5 (very mild dementia)., Results: The final version (AD8) querying memory, orientation, judgment, and function was administered to an additional sample of 112 CDR 0 and 68 CDR 0.5 participants. Using a cut-off of two items endorsed, the area under the curve was 0.834, suggesting good to excellent discrimination, sensitivity was 74%, and specificity was 86% (prevalence of 0.38 for very mild dementia). Inclusion of 56 additional individuals with mild to severe dementia (increasing dementia prevalence to 0.53) increased sensitivity to 85%., Conclusions: The AD8 is a brief, sensitive measure that reliably differentiates between nondemented and demented individuals. Use of the AD8 in conjunction with a brief assessment of the participant could improve diagnostic accuracy in general practice.

Objectives: To determine the validity and reliability of clinician ratings of the driving competence of patients with mild dementia., Design: Observational study of a cross-section of drivers with mild dementia based on chart review by clinicians with varying types of expertise and experience., Setting: Outpatient dementia clinic., Participants: Fifty dementia subjects from a longitudinal study of driving and dementia., Measurements: Each clinician reviewed information from the clinic charts and the first study visit. The clinician then rated the drivers as safe, marginal, or unsafe. A professional driving instructor compared these ratings with total driving scores on a standardized road test and categorical ratings of driving competence. Clinicians also completed a visual analog scale assessment of variables that led to their determinations of driving competence., Results: Accuracy of clinician ratings ranged from 62% to 78% for the instructor's global rating of safe versus marginal or unsafe. In general, there was moderate accuracy and interrater reliability. Accuracy could have been improved in the least-accurate raters by greater attention to dementia duration and severity ratings, as well as less reliance on the history and physical examination. The most accurate predictors were clinicians specially trained in dementia assessment, who were not necessarily the most experienced in their years of clinical experience., Conclusion: Although a clinician may be able to identify many potentially hazardous drivers, accuracy is insufficient to suggest that a clinician's assessment alone is adequate to determine driving competence in those with mild dementia.

Background: To understand the earliest signs of cognitive decline caused by Alzheimer disease (AD) and other illnesses causing dementia, information is needed from well-characterized individuals without dementia studied longitudinally until autopsy., Objective: To determine clinical and cognitive features associated with the development of AD or other dementias in older adults., Design: Longitudinal study of memory and aging., Setting: Alzheimer's Disease Research Center, St Louis, Mo., Main Outcome Measures: Clinical Dementia Rating, its sum of boxes, and neuropathologic diagnosis of dementia., Participants: Eighty control participants who eventually came to autopsy., Results: Individuals who did not develop dementia showed stable cognitive performance. Entry predictors of dementia were age, deficits in problem solving as well as memory, slowed psychomotor performance, and depressive features. Minimal cognitive decline occurred prior to dementia diagnosis, after which sharp decline was noted. Even individuals who were minimally cognitively impaired (Clinical Dementia Rating = 0.5) typically had neuropathologic AD at autopsy. Histopathologic AD also was present in 34% of individuals who did not have dementia at death; these individuals without dementia showed an absence of practice effects on cognitive testing., Conclusions: Increased age, depressive features, and even minimal cognitive impairment, as determined clinically by Clinical Dementia Rating sum of boxes and by slowed psychomotor performance, identify older individuals without dementia who develop dementia. Older adults who do not develop dementia have stable cognitive performance. The absence of practice effects may denote the subset of older adults without dementia with histopathologic AD, which may reflect a preclinical stage of the illness.

Dementia is a common and under-diagnosed problem among the elderly. An accurate screening test would greatly aid the ability of physicians to evaluate dementia and memory problems in clinical practice. We sought to determine whether simple and brief psychometric tests perform similarly to the Mini-Mental State Examination (MMSE) in screening for dementia. Using a retrospective analysis, a series of standard, brief, psychometric tests were compared with each other and to the MMSE as screening tests for very mild dementia, using DSM-III-R criterion as the gold standard. Two independent cohorts from the Baltimore Longitudinal Study of Aging and the Washington University Alzheimer's Disease Research Center were evaluated. We found that two brief and simple-to-administer tests appear to offer similar degrees of sensitivity and specificity to the MMSE. These are the recall of a five-item name and address, "John Brown 42 Market Street Chicago" and the one-minute verbal fluency for animals. Combining these two tests further improves sensitivity and specificity, surpassing the MMSE, to detect dementia in individuals with memory complaints.

Individuals with semantic dementia (SD) were differentiated neuropsychologically from individuals with dementia of the Alzheimer type (DAT) at very mild-to-mild stages (clinical dementia rating 0.5 or 1). A picture naming and recognition memory experiment provided a particularly useful probe for early identification, with SD individuals showing preserved picture recognition memory and impaired naming, and DAT individuals tending to show the reverse dissociation. The identification of an early SD group provided the opportunity to inform models of reading by exploring the influence of isolated lexical semantic impairment on reading regular words. Results demonstrated prolonged latency in both SD and DAT group reading compared to a control group but exaggerated influence of frequency and length only for the SD group. The SD reading pattern was associated with focal atrophy of the left temporal pole. These cognitive-neuroanatomical findings suggest a role for the left temporal pole in lexical/semantic components of reading and demonstrate that cortical thickness differences in the left temporal pole correlate with prolonged latency associated with increased reliance on sublexical components of reading.

Background: Atypical presentations of neurodegenerative dementing disorders include the syndrome of progressive posterior cortical dysfunction (PPCD) involving selective higher order visuospatial deficits. The neuropathologic correlates of PPCD remain poorly defined., Methods: This is a retrospective case series of 27 individuals (14 men, 13 women) diagnosed clinically with PPCD. Participants were either enrolled in the Alzheimer's Disease Research Center (ADRC) or referred to the memory diagnostic center of an urban academic medical center. Clinical evaluations included physical and neurologic examinations, the Clinical Dementia Rating (CDR), and psychometric measures. Neuropathologic examinations were completed in 21 individuals with PPCD. Psychometric measures from 65 individuals with mild dementia of the Alzheimer type (DAT) enrolled in the ADRC were used for comparison., Results: Neuropathologic etiologies of PPCD were Alzheimer disease (AD) (n = 13), AD plus Parkinson disease (n = 1), AD-Lewy body variant (n = 2), dementia with Lewy bodies plus progressive subcortical gliosis of Neumann (n = 1), corticobasal degeneration (n = 2), and prion-associated diseases: Creutzfeldt-Jakob disease (n = 1) and fatal familial insomnia (n = 1). Confirming the clinical impression, psychometric profiles for individuals with PPCD differed from those of people with DAT alone and revealed disproportionate deficits on measures of visuospatial ability., Conclusions: AD was the most frequent cause of PPCD in this series, although non-Alzheimer's dementing disorders also should be considered.

Atlas normalization, as commonly used by functional data analysis, provides an automated solution to the widely encountered problem of correcting for head size variation in regional and whole-brain morphometric analyses, so long as an age- and population-appropriate target atlas is used. In the present article, we develop and validate an atlas normalization procedure for head size correction using manual total intracranial volume (TIV) measurement as a reference. The target image used for atlas transformation consisted of a merged young and old-adult template specifically created for cross age-span normalization. Automated atlas transformation generated the Atlas Scaling Factor (ASF) defined as the volume-scaling factor required to match each individual to the atlas target. Because atlas normalization equates head size, the ASF should be proportional to TIV. A validation analysis was performed on 147 subjects to evaluate ASF as a proxy for manual TIV measurement. In addition, 19 subjects were imaged on multiple days to assess test-retest reliability. Results indicated that the ASF was (1) equivalent to manual TIV normalization (r = 0.93), (2) reliable across multiple imaging sessions (r = 1.00; mean absolute percentage of difference = 0.51%), (3) able to connect between-gender head size differences, and (4) minimally biased in demented older adults with marked atrophy. Hippocampal volume differences between nondemented (n = 49) and demented (n = 50) older adults (measured manually) were equivalent whether corrected using manual TIV or automated ASF (effect sizes of 1.29 and 1.46, respectively). To provide normative values, ASF was used to automatically derive estimated TIV (eTIV) in 335 subjects aged 15-96 including both clinically characterized nondemented (n = 77) and demented (n = 90) older adults. Differences in eTIV between nondemented and demented groups were negligible, thus failing to support the hypothesis that large premorbid brain size moderates Alzheimer's disease. Gender was the only robust factor that influenced eTIV. Men showed an approximately approximately 12% larger eTIV than women. These results demonstrate that atlas normalization using appropriate template images provides a robust, automated method for head size correction that is equivalent to manual TIV correction in studies of aging and dementia. Thus, atlas normalization provides a common framework for both morphometric and functional data analysis.

Context: The Clinical Dementia Rating (CDR) is quickly becoming a criterion standard in multicenter clinical trials in Alzheimer disease. An abbreviated version, with formal monitoring for consistency across sites and raters, is currently used in the Alzheimer's Disease Cooperative Study (ADCS)., Objective: To demonstrate the degree of agreement on CDR scoring of clinical monitors working independently from ADCS-CDR worksheets., Design: Three members of the ADCS who are experienced and highly trained with respect to the CDR independently reviewed the ADCS-CDR worksheets of 15 subjects, assigning box and global CDR scores according to the prescribed algorithm., Setting: The ratings were assigned during a single, 3-hour session in a closed room., Participants: Two clinical monitors and one project director/clinical monitor supervisor., Main Outcome Measures: Percent agreement, Kendall's tau-b, and Cohen's kappa were used to assess the degree of agreement of the raters with the previously established gold standard assessment on global and box scores for the 15 subjects., Results: Raters, blinded to patient groupings, were in agreement with the Gold Standard global CDR assessment on 87% of ratings. Kappa values indicated good (kappa = 0.66, orientation and judgment & problem solving boxes) to excellent (kappa = 0.83, global CDR) agreement., Conclusions: The ADCS-CDR worksheets were reliably and consistently scored by clinical monitors, who may be considered proxy gold standards for CDR assessment.

Given the remarkable similarities between the genetics of tau diseases and the genetics of alpha-synuclein diseases, and given the fact that we have recently found a triplication of the alpha-synuclein locus in a family in which we had shown linkage to the alpha-synuclein locus, we determined to test whether some of the several families with autosomal dominant frontal temporal dementia which show genetic linkage to the tau locus but in which tau mutations have not been found could be caused by similar structural mutations. We did not find any such mutations.

Background: The informed consent process is central to the conduct of research but may be difficult for cognitively impaired participants to understand. The authors developed a brief test addressing the elements of informed consent for a specific minimum-risk nontreatment research protocol., Objective: To evaluate and document understanding of informed consent by elderly research participants across a range of dementia severity., Methods: The elements of informed consent regarding participation in a longitudinal study of healthy aging and dementia were reviewed with both demented (n = 250) and nondemented (n = 165) participants who then completed a short test requiring yes-no responses to assess understanding of these elements. Demented participants had very mild, mild, or moderate dementia as staged by the Clinical Dementia Rating., Results: After adjusting for education, performance on the test varied with dementia severity in mean differences and by correlation. All nondemented and very mildly demented participants and 92% of mildly demented participants provided correct answers for at least 8 of 10 true-false items, whereas only 67% of the moderately demented participants achieved this level of accuracy., Conclusions: Demented individuals, very mild and mild, understood informed consent information for this nontreatment research study. Understanding notably declined in the moderate stage of dementia. Brief tests may be useful as one method to assess understanding of the consent process for specific studies.

Background: Tau and beta-amyloid (Abeta) are proposed diagnostic biomarkers for Alzheimer disease (AD). Previous studies report their relationship to clinical diagnoses of AD and other dementias. To understand their value as predictors of disease-specific pathology, levels determined during life must be correlated with definitive diagnoses in mixed dementia groups and cognitively normal subjects., Objectives: To correlate antemortem cerebrospinal fluid (CSF) tau and Abeta levels with definitive dementia diagnosis in a diverse group of patients; to calculate statistics for CSF tau and Abeta., Design: Prospective study., Setting: Ten clinics experienced in the diagnosis of neurodegenerative dementias. Patients One hundred six patients with dementia and 4 cognitively normal subjects with a definitive diagnosis, and 69 clinically diagnosed cognitively normal subjects., Main Outcome Measures: Correlation of CSF tau and Abeta with final diagnosis., Results: Mean tau level was 612 pg/mL for the 74 patients with AD, 272 pg/mL for 10 patients with frontal dementia, 282 pg/mL for 3 patients with dementia with Lewy bodies, and 140 pg/mL for 73 cognitively normal control subjects. Tau was less than 334 pg/mL for 20 patients with AD. Abeta42 was reduced in patients with AD (61 fmol/mL) compared with patients with frontal dementia (133 fmol/mL) and control subjects (109 fmol/mL), but not compared with patients with dementia with Lewy bodies (14 fmol/mL) or prion disease (60 fmol/mL)., Conclusions: Elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other dementing disorders. However, some patients with AD have a level less than the mean +/- 2 SDs of the cognitively normal cohort.