Criteria for mild cognitive impairment (MCI) include impairment of cognitive function, ascertained by performance on objective cognitive tests. The diagnosis of MCI thus is based on standardized cutoff scores for these measures and represents interindividual differences in performance. Use of normative values for MCI diagnosis has limitations, however, as psychometric performance can be influenced by factors including literacy, education, and culture. The Clinical Dementia Rating utilizes a semi-structured informant interview and participant assessment to detect cognitive change. This informant-based instrument determines intraindividual cognitive decline, and previous work by our group (Storandt et al., 2006) demonstrates its ability to identify clinically meaningful cognitive change at the pre-MCI level (i.e. before cognitive test performance reaches an impaired level). The current study extends this approach to a community sample of African American older adults. To compare CDR detection of cognitive change with psychometric performance in African American elderly. 147 participants (mean age 61±4.5 years) from the population-based African American Health project were screened for dementia using brief informant-based instruments and with the Short Blessed Test and Mini Mental State Examination. A purposive sample of 61 subjects returned for a follow up clinical assessment. For 22 participants rated CDR 0.5 (uncertain/very mild dementia), performance on Wechsler Memory Scale Logical Memory Delayed Recall (WMS LM) was compared with original and revised MCI criteria. MMSE scores were not significantly different for CDR 0 (n=39) and CDR 0.5 (n=22) participants (27.7±2.3 and 27.7±1.5). Participants rated as CDR 0.5 differed significantly from CDR 0 participants on WMS LM (21.7±12.5 vs. 27.4±10.0, p<0.05). However, the scores for CDR 0.5 participants were insufficient to meet criteria for MCI. In a population-based sample of African American participants, the CDR detects cognitive decline at the pre-MCI level. This study demonstrates the utility of an informant-based interview to detect the earliest stages of clinically relevant cognitive change in a population-based sample that is historically underrepresented in dementia research.
Cerebrospinal fluid (CSF) protein values of amyloid-β (Aβ 42), tau, and phosphorylated tau 181 (ptau 181) are becoming accepted biomarkers for Alzheimer's disease (AD) pathology in research settings. The extent of their use and perceived utility in clinical settings, however, is less well studied, and it is unclear how these biomarkers influence clinicians when making a diagnosis of AD. In this study, we evaluated how clinicians consider CSF biomarkers in the diagnosis and treatment of patients with possible dementia. Participants (N = 193) were physicians and other medical professionals who evaluate older adults for neurodegenerative dementing diseases. In this within-subjects clinical vignette study, participants were randomized to view normal, borderline, AD-consistent, or no CSF information in two vignettes portraying patients with borderline and mild AD symptoms. In addition, clinicians reported on the use and perceived utility of CSF laboratory results in clinical practice. Clinicians reported current infrequent use and limited perceived utility of CSF biomarkers in clinical practice, yet CSF biomarkers affected clinical decision making. Viewing AD-consistent CSF values made clinicians 6-12 times more likely to make an AD-related diagnosis (p < .01), increased diagnostic confidence (p < .05), and led clinicians to initiate treatment more often than clinicians who had no CSF information (p = .004). CSF biomarkers can influence clinical decisions and have different effects depending on the extent to which biomarkers reflect AD pathology, consistency between clinical-pathological information, and ambiguity or clarity of protein values. Clinicians should consider potential biases when integrating CSF biomarker values in clinical decisions.
Several genome-wide association studies (GWAS) have associated variants in late-onset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes.Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education.Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (β = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (β = -0.44, SE = 0.09, p = 0.009 and β = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (β = 0.26, SE = 0.10, p = 0.010).MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease.
Context Impaired physical performance may confound the clinical assessment of dementia of the Alzheimer type (DAT). Objectives Determine whether: (1) Physical Performance Test (PPT) scores are associated with the Clinical Dementia Rating (CDR), (2) PPT scores are correlated with clinical measures of health, and (3) impaired physical performance affects the clinical assessment of DAT. Design A retrospective and cross-sectional study. Setting An Alzheimer's Disease Research Center. Participants Ninety-nine research volunteers aged 85 years and older were assessed from September 1997 through July 1999; 45 had DAT (CDR = 0.5–2), and 54 were nondemented controls. Measurements Clinical health history, daily functioning, physical and neurologic status, CDR, sum of boxes, and total PPT score were obtained during clinical evaluation. Independently assessed psychometric measures of verbal and nonverbal episodic and semantic memory, visuospatial abilities, and psychometric speed yielded to a factor score representing general cognitive function. Our outcome measure was the CDR (ie, the clinical dementia rating, where higher scores indicate greater dementia severity). Results The majority (88%) of subjects in this sample of demented and nondemented older adults had some degree of physical impairment as measured by the PPT. Correlational analyses identified clinically important relationships (|τb| > 0.30, p < 0.05) between impaired PPT performance, higher CDR rating, and poor general health, including difficulty ambulating. The correlation between PPT performance and dementia severity (τb = −0.36) decreased after controlling for cognitive ability (τb = −0.19). The correlation between the cognitive factor score and dementia severity when PPT performance was controlled (τb = −0.60) was similar to the unadjusted correlation of the factor score with dementia severity (τb = −0.64). Conclusions The presence of some degree of physical impairment was common in our sample, and PPT scores correlated with both physical and cognitive impairment. Nevertheless, Alzheimer Disease Research Center clinicians appear able to successfully distinguish between physical and cognitive causes of functional impairment and assign a CDR rating that accurately reflects DAT severity in individuals with impaired physical performance.
Abstract 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.
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.
Dementia may be under–diagnosed in the community. The AD8 was developed from a longitudinal research project as a brief, informant–based measure to detect dementia. To test how well the AD8 performs as a self–rating tool, compared with both informant and clinician impression of cognitive status. 317 subject–informant dyads were evaluated from a longitudinal study of memory and aging. The number of endorsed AD8 items by the subject was compared with the number endorsed by the informant, with independently derived Clinical Dementia Rating (CDR) ratings, and with ratings of depression. Strength of association was measured with Spearman (r) and intraclass (ICC) correlation coefficients. ROC curves were used to assess the discriminative properties of the AD8 given to both subjects and informants. Mean age of subjects was 72.8 y (range 43–104) and of informants was 66.4 y (range 24 – 101). The relationship of informants included spouses (56%), children (24%), relatives (8%), friends (8%) and others (4%). 87% of subjects and 94% of informants completed the questionnaire. CDR was correlated with both informant (r=0.75, p<.0001) and subject (r=0.34, p<.0001) AD8 scores. Subjects' AD8 scores had good agreement with informants' AD8 scores (ICC=0.53, 95% CI:0.41–0.62). Subjects’ AD8 scores also correlated (p's<.0001) with subjective complaints of memory problems (r=0.47), with informants’ endorsement of DSM–IV depression features (r=0.37) and the Geriatric Depression Scale (GDS) (r=0.41); and the subjects’ endorsement DSM–IV depression features (r=0.49) and GDS (r=0.56). Subjects complaints of memory problems corresponded to the presence of both dementia (CDR 0.5, r=.25, p=.0008) and depression by DSM–IV criteria (r=0.25, p=.0008) and GDS (r=.23, p=.002). The area under the ROC curve for the informant AD8 was 0.894 (95% CI:0.86–0.93); the subject AD8 was 0.779 (95% CI:0.679–0.78). The AD8 is a brief, sensitive measure that differentiates between nondemented and demented individuals and is sensitive to depression when asked of either the subject or an informant, although informants were more observant than the subject. The AD8 can be used as a general screening device to detect dementia and depression in the older adult.
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 withPSEN1mutations. 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 thePSEN1gene, which segregates with disease.
Conclusions
A novelPSEN1mutation 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.
'%3e%3cg id='b'%3e%3cpath id='a' stroke='%23000' stroke-width='2' d='M-6-25H6m-12 3H6m-12 3H6'/%3e%3cuse xlink:href='%23a' y='44'/%3e%3c/g%3e%3cpath stroke='%23fff' d='M0 17v10'/%3e%3ccircle r='12' fill='%23cd2e3a'/%3e%3cpath fill='%230047a0' d='M0-12A6 6 0 0 0 0 0a6 6 0 0 1 0 12 12 12 0 0 1 0-24z'/%3e%3c/g%3e%3cg transform='rotate(-123.69)'%3e%3cuse xlink:href='%23b'/%3e%3cpath stroke='%23fff' d='M0-23.5v3M0 17v3.5m0 3v3'/%3e%3c/g%3e%3c/svg%3e)
