Christopher M. Clark

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer's disease

Reliable information on rate of progression of cognitive impairment in probable Alzheimers disease (AD) is important for evaluating possible beneficial effects of therapeutic agents and in planning long-term care for patients with this chronic illness. However, wide variability exists in published rates of change for psychometric measures of the dementing process, and there is need for an accurate analysis of large numbers of persons with the disorder studied over long periods. Utilizing the large, well-characterized sample of the Consortium to Establish a Registry for Alzheimers Disease and employing a least squares regression method to adjust for different levels of impairment and periods of observation, we report rates of change on the Short Blessed Test, Mini-Mental State Examination, Blessed Dementia Scale, Clinical Dementia Rating, and other cognitive measures in 430 patients with probable AD (mean age at entry = 70.9 ± 8.0 SD years) studied for up to 4 years. We found that rate-of-change determinations are less reliable when the observation period is 1 year or less, that dementia progression may be nonlinear when described by certain measures, and that simple change scores do not accurately characterize the rate of decline. We also found that rate of progression in AD is determined by the severity of cognitive impairment: the less severe the dementia, the slower the rate of decline.

Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease.

Background Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the ‘preclinical’ stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome. Methods and Findings CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (nu200a=u200a24) and cognitively normal controls (CDR 0) (nu200a=u200a24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (nu200a=u200a292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85–0.94 95% confidence interval [CI]) and 0.88 (0.81–0.94 CI), respectively. Conclusions Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions.

Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer's disease

Article abstract-CSF levels of tau protein are increased in many patients with Alzheimers disease (AD). Studies disagree on whether the increase is found in moderate or severe AD to a greater extent than in mild AD, and in two reports there was an inverse correlation between tau levels and cognitive scores. To readdress this question, we measured CSF tau in a group of mildly impaired patients with AD (Mini-Mental State Examination [MMSE] scores >or=to20/30) and compared their tau levels with those in age-comparable normal and neurologic controls. We found that the mean level of CSF tau was significantly increased in the AD group compared with the controls, and 29 of 36 patients with AD had levels that exceeded a cutoff determined in a previous study. CSF tau levels did not correlate with MMSE scores. These findings and those of previous studies show that elevated CSF tau levels are found in most patients with AD, occur early in the course of dementia, and may be useful in supporting the diagnosis of AD. NEUROLOGY 1997;48: 632-635

Neurodegeneration Across Stages of Cognitive Decline in Parkinson Disease

OBJECTIVEnTo assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).nnnDESIGNnImages were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.nnnSETTINGnThe Parkinsons Disease and Movement Disorders Center at the University of Pennsylvania.nnnSUBJECTSnEighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.nnnRESULTSnThe PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β = -0.37; P = .001), and PDD patients demonstrated hippocampal (β = -0.32; P = .004) and additional medial temporal lobe atrophy (β = -0.36; P = .003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P = .04) and a similar pattern to that of PDD patients (P = .81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.nnnCONCLUSIONSnHippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.

Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer's disease: A CERAD analysis, part XII

Article abstract-To determine whether the age of onset of Alzheimers disease (AD) is related to the expression and rate of decline of this disorder, we examined the clinical and neuropsychological performance of 421 patients entered into the Consortium to Establish a Registry for Alzheimers Disease and followed annually for up to 4 years. Statistical analyses were based on multivariable logistic regression analysis for dichotomous clinical measures and multivariable linear regression analysis for psychometric measures. All analyses examined the effect of age after controlling for gender, education, and stage of dementia. Clinical information obtained on entry into the study indicated that younger patients performed more poorly on measures of language and concentration, and older patients performed more poorly on measures of memory and orientation. On neuropsychological measures at entry, younger patients performed more poorly on praxis and had significantly higher scores on confrontation naming. Younger age predicted a significantly faster rate of progression for all neuropsychological measures. These findings support the concept of age-related clinical subtypes of AD. NEUROLOGY 1996;46: 136-141

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part XI. Clinical milestones in patients with Alzheimer's disease followed over 3 years

The rate of cognitive decline, measured by psychometric testing, is widely used to track the progression of Alzheimers disease (AD).As an alternative approach, we studied clinical measures as markers of the progression of dementia in 343 community-dwelling patients with probable AD enrolled in the multi-center Consortium to Establish a Registry for Alzheimers Disease (CERAD) project. Subjects received standardized evaluations at entry and at annual follow-up. Decline on the Clinical Dementia Rating, loss of instrumental activities of daily living, failure to recall three words on the Mini-Mental State Examination (MMSE), and decline of the total MMSE score to below 10 were high-risk milestones, with cumulative frequencies exceeding 50% at 3 years. Loss of dressing and toileting activities occurred at intermediate rates, while loss of eating ability was rare. The risk of reaching clinical milestones and the annual rate of cognitive decline on the MMSE were directly correlated. Clinical milestones are useful indices of the progression of dementia in patients with AD.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part IX. A prospective cliniconeuropathologic study of Parkinson's features in Alzheimer's disease.

Although extrapyramidal signs such as rigidity, bradykinesia, and postural impairment frequently occur in patients with Alzheimers disease (AD), the correlation of these parkinsonian manifestations with the neuro-pathologic changes of Parkinsons disease (PD) has not been well estabiished. Previous clinicopathologic studies addressing this issue have been largely retrospective or have consisted of relatively small numbers of cases. We examined the neuropathologic correlates of clinical parkinsonism in 78 cases with autopsy-confirmed AD prospectively enrolled in the Consortium to Establish a Registry for Alzheimers Disease. Sixteen (20.5%) of the 78 AD cases showed concomitant PD pathology (AD/PD) as evidenced by the presence of nigral degeneration and Lewy bodies at any site. There were neocortical Lewy bodies in eight of these 16 cases. Two or more clinical manifestations of extrapyramidal dysfunction were present in eight (50.0%) of the 16 cases of ADPD versus 11 (17.7%) of the 62 cases of AD alone (p < 0.01). Although semiquantitative ratings of the frequency of neuritic plaques showed no differences between the two groups, neurofibrillary tangles in the AD/PD group were less frequent in the midfrontal (p < 0.001) and superior temporal cortex (p < 0.05). These findings support previous reports that ADPD cases are more likely to manifest extrapyramidal dysfunction and show plaque predominance at autopsy.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part VI. Family history assessment: A multicenter study of first-degree relatives of Alzheimer's disease probands and nondemented spouse controls

Although familial factors in Alzheimers disease (AD) are well established, uniform family-history assessment in genetic and epidemiologic studies of AD is needed to reconcile the divergent estimates of the cumulative risk of this illness among relatives of AD probands. To answer the need, the Consortium to Establish a Registry for Alzheimers Disease (CERAD) has developed a standardized Family History Assessment of AD to identify the presence of AD, Parkinsons disease (PD), and Downs syndrome (DS) in family members. This paper describes the use of this new assessment instrument in 118 patients with AD (estimated mean age at onset [± SD] = 64.5 ± 7.7 years) and their nondemented spouses who were enrolled in 11 different CERAD sites in the U.S. The first-degree relatives of the probands with AD had a significantly greater cumulative risk (p < 0.005) of AD or primary progressive dementia (24.8%) than did the relatives of spouse controls (15.2%). Furthermore, the cumulative risk for this disorder among female relatives of probands was significantly greater than that among male relatives. There were no differences between the families of probands and controls for the numbers of affected first-degree relatives with PD or DS. This is the first reported multicenter family-history study of AD, and it supports earlier reports of familial factors in AD and indicates a higher risk to female relatives of AD probands. The CERAD Family History Assessment instrument may be useful for further multicenter and epidemiologic studies designed to delineate familial factors associated with AD.

A videotaped CIBIC for dementia patients Validity and reliability in a simulated clinical trial

BackgroundThe global impression of a clinician is an Food and Drug Administration–mandated primary outcome measure for clinical trials in dementia. Reliability and validity of these measures are not well established. MethodsA videotaped version of the Clinician’s Interview Based Impression of Change (CIBIC) was evaluated. Raters were informed that the videotaped interviews were taken at baseline and 6 to 12 months later, when in fact half of the interviews were shown in reverse order. Ratings on “true order” interviews were compared with ratings on “reverse order” interviews. In addition, ratings by neurologists experienced in dementia were compared with those of less experienced raters. ResultsInter-rater reliability of the neurologists was poor when measured by absolute agreement on a 7-point scale (kappa = 0.18). With a less stringent 3-point scale (better, worse, or unchanged), inter-rater reliability was significantly better for the true order videos (kappa = 0.51) than for the reversed order videos (kappa = 0.12). Validity also was reduced in the reverse order group: neurologists rated 90% of subjects correctly in the “true order” group and 63% correctly in the “reversed order” group. The inter-rater reliability of the neurologists was greater than the less experienced raters, but the validity of the neurologists’ ratings was only marginally better. ConclusionsThe reliability and validity of the videotape CIBIC are reasonable when patients follow the expected course of gradual decline, but are poor when patients appear to improve. These findings suggest that global assessments should be modified as outcome measures in clinical trials with patients with dementia.

Growth and survival relationships of 71 tree species with nitrogen and sulfur deposition across the conterminous U.S.

Atmospheric deposition of nitrogen (N) influences forest demographics and carbon (C) uptake through multiple mechanisms that vary among tree species. Prior studies have estimated the effects of atmospheric N deposition on temperate forests by leveraging forest inventory measurements across regional gradients in deposition. However, in the United States (U.S.), these previous studies were limited in the number of species and the spatial scale of analysis, and did not include sulfur (S) deposition as a potential covariate. Here, we present a comprehensive analysis of how tree growth and survival for 71 species vary with N and S deposition across the conterminous U.S. Our analysis of 1,423,455 trees from forest plots inventoried between 2000 and 2016 reveals that the growth and/or survival of the vast majority of species in the analysis (n = 66, or 93%) were significantly affected by atmospheric deposition. Species co-occurred across the conterminous U.S. that had decreasing and increasing relationships between growth (or survival) and N deposition, with just over half of species responding negatively in either growth or survival to increased N deposition somewhere in their range (42 out of 71). Averaged across species and conterminous U.S., however, we found that an increase in deposition above current rates of N deposition would coincide with a small net increase in tree growth (1.7% per Δ kg N ha-1 yr-1), and a small net decrease in tree survival (-0.22% per Δ kg N ha-1 yr-1), with substantial regional and among-species variation. Adding S as a predictor improved the overall model performance for 70% of the species in the analysis. Our findings have potential to help inform ecosystem management and air pollution policy across the conterminous U.S., and suggest that N and S deposition have likely altered forest demographics in the U.S.