Alzheimer Disease: Weintraub S

Weintraub S, Salmon D, Mercaldo N, Ferris S, Graff-Radford NR, Chui H, Cummings J, DeCarli C, Foster NL, Galasko D, Peskind E, Dietrich W, Beekly DL, Kukull WA, Morris JC. · Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, 320 E. Superior, Searle 11-467, Chicago, IL 60611, USA. · Alzheimer Dis Assoc Disord. · Pubmed #19474567 No free full text.

Abstract: The neuropsychologic test battery from the Uniform Data Set (UDS) of the Alzheimer's Disease Centers (ADC) program of the National Institute on Aging consists of brief measures of attention, processing speed, executive function, episodic memory, and language. This paper describes development of the battery and preliminary data from the initial UDS evaluation of 3268 clinically cognitively normal men and women collected over the first 24 months of utilization. The subjects represent a sample of community-dwelling, individuals who volunteer for studies of cognitive aging. Subjects were considered "clinically cognitively normal" based on clinical assessment, including the Clinical Dementia Rating scale and the Functional Assessment Questionnaire. The results demonstrate performance on tests sensitive to cognitive aging and to the early stages of Alzheimer disease in a relatively well-educated sample. Regression models investigating the impact of age, education, and sex on test scores indicate that these variables will need to be incorporated in subsequent normative studies. Future plans include: (1) determining the psychometric properties of the battery; (2) establishing normative data, including norms for different ethnic minority groups; and (3) conducting longitudinal studies on cognitively normal subjects, individuals with mild cognitive impairment, and individuals with Alzheimer disease and other forms of dementia.

Rösler A, Mapstone M, Hays-Wicklund A, Gitelman DR, Weintraub S. · Cognitives Neurology and Alzheimer's Disease Center, Northwestern University Medical School, Chicago, IL, USA. · Cortex. · Pubmed #16042027 No free full text.

Abstract: Visual search for a target in an array of distractors relies upon flexible shifts between global and local modes of attentional processing. Visual search is slowed in patients with Alzheimer's disease (AD), in part due to an increase in the number and duration of eye fixations made en route to a target (Rösler et al., 2000). This phenomenon may represent a compensatory adaptation to a narrowing of the zone of focal attention, necessitating more shifts of gaze in order to attend to the global workspace. Eye fixations were analyzed in two regions of interest (ROIs, central fixation and peripheral target locations) in 9 patients with mild AD, 9 cognitively intact age-matched control subjects, and 9 young controls, while they searched for a target object in a radial array that contained from 1 to 6 stimuli. Contrasted with young subjects, the search strategy of older controls and, to a greater extent, AD patients showed an increase in the average number and duration of peripheral fixations. Reduced efficiency of visual search in AD may be contributed to by reduced ability to dynamically adjust the attentional zoom, coupled with the inability to disengage attention from peripheral targets.

Rösler A, Mapstone ME, Hays AK, Mesulam MM, Rademaker A, Gitelman DR, Weintraub S. · Department of Psychiatry, University Hospital, Basel, Switzerland. · Neuropsychology. · Pubmed #10928743 No free full text.

Abstract: Visual search, characterized by eye fixation patterns, was examined in 8 patients with Alzheimer's disease (AD), 8 cognitively intact, age-matched individuals, and 8 young control participants as they searched for a number among a nonlinear array of letters on a large computer screen. Among the 3 groups, target detection accuracy differed and detection time increased linearly. There were more fixations, and fixation duration was significantly longer in the AD patients than in the other 2 groups. These factors contributed to the lengthening of target detection time. This qualitative difference in the architecture of visual search between AD and aging may reflect a specific deficit in the disengagement of visual spatial attention, a prolongation of saccade initiation, or inefficiency in planning a search strategy.

Weintraub S, Peavy GM, O'Connor M, Johnson NA, Acar D, Sweeney J, Janssen I. · Northwestern Alzheimer's Disease Center, Northwestern University Medical School, Chicago, IL 60611, United States of America. · J Clin Exp Neuropsychol. · Pubmed #10779840 No free full text.

Abstract: Three Words - Three Shapes was designed as an easy "bedside" test for elderly patients that assesses verbal and nonverbal memory within the same modality. In the present study, it was administered to patients with probable Alzheimer's disease (PRAD), a control group of non-demented older subjects (NC) and a group of patients with Korsakoff's amnesia (KA). Incidental recall and several other measures of learning, retention and recognition differentiated control from PRAD and KA subjects. PRAD and KA subjects' performance was similar, but there were some material-specific interactions. This test is relatively easy and some of the derived measures could prove useful in staging amnesia progression beyond the earliest stages of PRAD when more difficult tests yield floor effects.

Acevedo A, Krueger KR, Navarro E, Ortiz F, Manly JJ, Padilla-Vélez MM, Weintraub S, López OL, Mungas D. · Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, MRI Building, 2nd Floor, 4300 Alton Road, Miami Beach, FL 33140, USA. · Alzheimer Dis Assoc Disord. · Pubmed #19474568 No free full text.

Abstract: Researchers from Alzheimer's Disease Centers (ADCs) across the United States with expertise in the assessment of Spanish-speaking elderly collaborated to create the official Spanish version of measures in the Uniform Data Set of the National Institute on Aging Alzheimer's Disease Center Program. The present article describes this project, whose primary goal was to create Spanish instruments with cultural and linguistic equivalence to the English versions. The resulting Spanish versions make provisions for variations among Spanish-speaking groups in the United States of different nationalities, socio-cultural, linguistic, and educational backgrounds. A consensus-based translation and adaptation approach was used, and guiding principles and specific components of this process are summarized. The Spanish translation and adaptation of the Uniform Data Set measures became available online to ADCs in April 2007. Its creation is important, as the resulting effort provides standardized measures for the collection of cross-sectional and longitudinal data on a large cohort of Spanish-speaking elders across the country and facilitates collaborative research among ADCs.

Schaffer BA, Bertram L, Miller BL, Mullin K, Weintraub S, Johnson N, Bigio EH, Mesulam M, Wiedau-Pazos M, Jackson GR, Cummings JL, Cantor RM, Levey AI, Tanzi RE, Geschwind DH. · Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 2506 Gonda, 695 Charles E. Young Dr S, Los Angeles, CA 90095-1761, USA. · Arch Neurol. · Pubmed #18852354 No free full text.

Abstract: BACKGROUND: Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found. OBJECTIVE: To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease. Design, Setting, and PARTICIPANTS: Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer's Genetics Study). RESULTS: Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2-68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer's Genetics sample showed the same direction of association as the case-control sample. CONCLUSIONS: To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets.

Mesulam M, Wicklund A, Johnson N, Rogalski E, Léger GC, Rademaker A, Weintraub S, Bigio EH. · Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. · Ann Neurol. · Pubmed #18412267 No free full text.

Abstract: OBJECTIVE: To identify predictors of Alzheimer's disease (AD) versus frontotemporal lobar degeneration pathology in primary progressive aphasia (PPA), and determine whether the AD pathology is atypically distributed to fit the aphasic phenotype. METHODS: Neuropsychological and neuropathological analyses of 23 consecutive PPA autopsies. All had qualitative determination of neurofibrillary tangle (NFT) density. Additional quantitation was done in four of the PPA/AD cases and four AD cases with the typical amnestic dementia of the Alzheimer type. RESULTS: The sample contained mostly logopenic, agrammatic, and mixed forms of PPA. All six agrammatics had frontotemporal lobar degeneration (five of six with tauopathy). Seven of the 11 logopenics had AD. In logopenics, lower memory scores increased the probability of AD, but there were exceptions. The PPA/AD group showed predominance of entorhinal NFT typical of the amnestic dementia of the Alzheimer type. In the small subgroup examined quantitatively, neocortical NFTs were more numerous in the left hemisphere of PPA/AD. However, the asymmetry was low and inconsistent. Neuritic plaques did not display consistent asymmetry. Apolipoprotein E4, a major risk factor for typical AD, did not predict AD pathology in PPA. INTERPRETATION: Subtyping PPA helps to predict AD versus frontotemporal lobar degeneration pathology at the group level. However, our results and the literature also indicate that no clinical predictor is completely reliable in individual patients. The inconsistent concordance of NFT distribution with the asymmetric atrophy and the nonamnestic phenotype also raises the possibility that the AD markers encountered at autopsy in PPA may not always reflect the nature of the initiating neurodegenerative process.

Rogalski E, Johnson N, Weintraub S, Mesulam M. · Neurological Sciences, Rush University Medical Center, 1735 W. Harrison Street, Chicago, IL 60612, USA. · Arch Neurol. · Pubmed #18268195 links to  free full text

Abstract: BACKGROUND: Although risk factors for Alzheimer disease have been well studied, much less is known about risk factors for primary progressive aphasia (PPA). OBJECTIVE: To demonstrate that learning disabilities (LDs) are more common in patients with PPA and their first-degree family members. DESIGN, SETTING, AND PATIENTS: Self-report endorsement of an individual and family history of an LD in a sample of 699 subjects from the Northwestern Alzheimer's Disease Center registry. We compared 3 dementia groups (PPA, typical amnestic Alzheimer disease, and the behavioral variant of frontotemporal dementia) and 1 elderly control group. A retrospective medical record review in the PPA probands was used to obtain additional information. MAIN OUTCOME MEASURE: Prevalence of LDs among probands and their first-degree relatives. RESULTS: The patients with PPA and their first-degree family members had a significantly higher frequency of LD compared with the other dementia groups and the controls. Some of the families of patients with PPA displayed unusual concentrations of LD, especially dyslexia. CONCLUSION: These results suggest that LD may constitute a risk factor for PPA, providing additional clues concerning the determinants for the selective vulnerability of the language network in this syndrome.

Banks S, Weintraub S. · Northwestern University, Feinberg School of Medicine, Cognitive Neurology and Alzheimer's Disease Center, Chicago, IL, USA. · Brain Cogn. · Pubmed #18194832 links to  free full text

Abstract: Lack of insight is a core diagnostic criterion for behavioral variant frontotemporal dementia (bvFTD), and is believed to be intact in the early stages of primary progressive aphasia (PPA). In other neurological conditions, symptom-specific insight has been noted, with behavioral symptoms appearing especially vulnerable to reduced insight. Different components of insight, self-awareness and self-monitoring, are also often considered separate phenomena. The current study compared insight in patients with PPA, bvFTD, and probable Alzheimer's disease (PrAD) and a group of cognitively intact control subjects. Additionally, differences in insight for the domains primarily affected by the three types of dementia, namely, Behavior, Naming, and Memory, were assessed, and self-awareness and self-monitoring were compared. A total of 55 participants were enrolled. Participants were asked to complete self-estimate scales demonstrating their perceived ability immediately prior to, and immediately following a test in each domain of interest. Results indicated that PPA and normal control groups performed very similarly on control (Weight and Eyesight) and cognitive domains, whereas bvFTD and PrAD patients were unable to accurately assess Memory. All three diagnostic groups failed to accurately assess their behavioral symptoms, suggesting that this domain is vulnerable to loss of insight across diagnoses. Naming ability, in contrast, was either accurately assessed or underestimated in all groups. Finally, there were no notable differences between self-awareness and self-monitoring, potential explanations for this are examined.

Wicklund AH, Rademaker A, Johnson N, Weitner BB, Weintraub S. · Department of Psychiatry and Behavioral Sciences, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, IL 60611, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18090428 No free full text.

Abstract: Progressive decline in cognition is a hallmark feature of dementia, and the rate and profile of cognitive decline has been well characterized in Alzheimer disease (AD). Less is known about decline in cognition over time in other forms of dementia such as the behavioral variant of frontotemporal dementia (FTD) and primary progressive aphasia (PPA). The present study examined rate of cognitive decline across domains of memory, language, and executive function measured by neuropsychologic tests, in AD (n=84), FTD (n=66), and PPA (n=44). Patients were in the mild stages of dementia, with comparable duration of illness at the baseline evaluation. A best linear unbiased predictor (BLUP) analysis was used in which the slope of the relationship between a cognitive measure and time was estimated for each person. AD subjects demonstrated a floor effect on measures of memory at baseline and a decline on measures of language and executive functioning over time. FTD showed the greatest decline over time on the Mini-Mental State Examination, executive functioning, and naming. PPA patients demonstrated prominent decline on language measures, verbal memory measures, and attention. Results suggest that the profile of rate of change over time has unique features on the basis of the type of dementia syndrome. However, there is overlap in the profiles of decline likely influenced by the overlap in cognitive constructs measured by neuropsychologic tests. The comparison of the rate of decline in FTD and PPA may also reflect the neuroanatomic overlap in these syndromes over time.

Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. · Lancet Neurol. · Pubmed #17826340 No free full text.

Abstract: BACKGROUND: The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. METHODS: We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT). FINDINGS: Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele. INTERPRETATION: Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.

Rogalski E, Rademaker A, Weintraub S. · Cognitive Neurology and Alzheimer's Disease Center Department of Preventive Medicine, Northwestern University, Chicago, IL, USA. · Cogn Behav Neurol. · Pubmed #17356343 No free full text.

Abstract: BACKGROUND/AIMS: Factors influencing the course and severity of symptoms in primary progressive aphasia (PPA), a language-based dementia, have not been fully elucidated. The current study examined the influence of gender on performance on tests of naming and verbal fluency in patients with PPA. Comparisons were also made within a group of probable Alzheimer disease (AD) patients to determine whether gender differences were present in the most common form of neurodegenerative dementia. METHODS: Performance was compared by gender within each diagnostic group on 3 language measures: the Boston Naming Test, category fluency (animals), and lexical fluency (FAS). Scores were compared at baseline (Visit 1) and in a subset of participants 6 to 15 months later (Visit 2). RESULTS: Compared to men, women with PPA demonstrated significantly greater impairment on word fluency tests at both visits and also had a more aggressive rate of decline between visits. AD patients showed no differences by gender on any measure. CONCLUSIONS: The results suggest gender-based vulnerability in PPA where women express more severe language impairments than men given a similar duration of illness.

Wicklund AH, Johnson N, Rademaker A, Weitner BB, Weintraub S. · Department of Psychiatry and Behavioral Sciences, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, 320 E. Superior, Chicago, IL 60611, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17334267 No free full text.

Abstract: Assessment of functional ability is an essential component in the clinical diagnosis of dementia. Most studies have primarily focused on disability due to Alzheimer disease (AD), and less is known about profiles of functional impairment in other dementia syndromes. Functional ability was assessed in individuals in the early stages of AD (N=100), the behavioral variant of frontotemporal dementia (FTD) (N=57), and primary progressive aphasia (PPA) (N=61), using the activities of daily living questionnaire (Johnson et al, 2004). The average duration of illness for the 3 groups ranged from 3.4 to 3.9 years. Overall level of functional impairment and the profile of abilities across subscales of Self-Care, Household Care, Employment and Recreation, Shopping and Money, Travel, and Communication were examined. Results showed that overall functional ability was moderately impaired in AD and FTD, and mildly impaired in PPA. For all groups, more complex ADLs were impaired early on, with relative preservation of self-care activities. The Communication score was the least impaired next to Self-Care for FTD and AD, and the most impaired for PPA patients. The activities of daily living questionnaire may capture aspects of preserved functioning that are not apparent from patients' scores on cognitive tests, especially for those with aphasia.

Morris JC, Weintraub S, Chui HC, Cummings J, Decarli C, Ferris S, Foster NL, Galasko D, Graff-Radford N, Peskind ER, Beekly D, Ramos EM, Kukull WA. · Washington University, St. Louis, MO 63108, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17132964 No free full text.

Abstract: A Clinical Task Force, composed of clinical leaders from Alzheimer's Disease Centers (ADC), was convened by the National Institute on Aging to develop a uniform set of assessment procedures to characterize individuals with mild Alzheimer disease and mild cognitive impairment in comparison with nondemented aging. The resulting Uniform Data Set (UDS) defines a common set of clinical observations to be collected longitudinally on ADC participants in accordance with standard methods. The UDS was implemented at all ADCs on September 1, 2005. Data obtained with the UDS are submitted to the National Alzheimer's Coordinating Center and represent a unique and valuable source of data to support and stimulate collaborative research.

Schrauf RW, Weintraub S, Navarro E. · Department of Linguistics and Applied Language Studies, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. · J Int Neuropsychol Soc. · Pubmed #16903131 No free full text.

Abstract: Adaptations of the National Adult Reading Test (NART) for assessing premorbid intelligence in languages other than English requires (a) generating word-items that are rare and do not follow grapheme-to-phoneme mappings common in that language, and (b) subsequent validation against a cognitive battery normed on the population of interest. Such tests exist for Italy, France, Spain, and Argentina, all normed against national versions of the Wechsler Adult Intelligence Scale. Given the varieties of Spanish spoken in the United States, the adaptation of the Spanish Word Accentuation Test (WAT) requires re-validating the original word list, plus possible new items, against a cognitive battery that has been normed on Spanish-speakers from many countries. This study reports the generation of 55 additional words and revalidation in a sample of 80 older, Spanish-dominant immigrants. The Batería Woodcock-Muñoz Revisada (BWM-R), normed on Spanish speakers from six countries and five U.S. states, was used to establish criterion validity. The original WAT word list accounted for 77% of the variance in the BWM-R and 58% of the variance in Ravens Colored Progressive Matrices, suggesting that the unmodified list possesses adequate predictive validity as an indicator of intelligence. Regression equations are provided for estimating BWM-R and Ravens scores from WAT scores.

Wicklund AH, Johnson N, Rademaker A, Weitner BB, Weintraub S. · Department of Psychiatry and Behavioral Sciences, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16772743 No free full text.

Abstract: Memory impairment, characterized by a pattern of rapid forgetting, is the hallmark deficit in Alzheimer's disease (AD). Memory deficits have also been reported in frontotemporal dementia (FTD), and are thought to reflect diminished organizational and attentional abilities leading to a pattern of decreased acquisition of new information. The present study compared patients with AD, the behavioral variant of FTD, and cognitively intact elderly control subjects on two types of memory tests: story memory and word list recall. The percent of information recalled immediately (encoded), after a delay, and the percent retention between these conditions was calculated for both tests. The results showed that FTD patients encoded and recalled more information from the story than AD patients. No difference was found between FTD and AD patients for encoding of the word list. However, FTD patients recalled more words after a delay than AD patients. Percent retention on both tasks was also greater for the FTD group. The results suggest that patterns of performance on different tests of memory, and, in particular, measures of retention, can be useful in differentiating memory impairment in AD from that of FTD on cognitive testing.

Westerberg CE, Paller KA, Weintraub S, Mesulam MM, Holdstock JS, Mayes AR, Reber PJ. · Northwestern University, Evanston, IL 60208, USA. · Neuropsychology. · Pubmed #16594780 No free full text.

Abstract: Recognition can be guided by familiarity, a restricted form of retrieval devoid of contextual recall, or by recollection, which occurs when retrieval is sufficient to support the full experience of remembering an episode. Recollection and familiarity were disentangled by testing recognition memory using silhouette object drawings, high target-foil resemblance, and both yes-no and forced-choice procedures. Theoretically, forced-choice recognition could be mediated by familiarity alone. Alzheimer's disease and its preclinical stage, mild cognitive impairment (MCI), were associated with memory impairments that were greater on the yes-no test. Remarkably, forced-choice recognition was unequivocally normal in patients with MCI compared with age-matched controls. Neuropathology in hippocampus and entorhinal cortex, known to be present in MCI, presumably disrupted recollection while leaving familiarity-based recognition intact.

Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM. · Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Feinberg School of Medicine, 320 East Superior Street, Searle 11-453, Chicago, IL 60611, USA. · Neurobiol Aging. · Pubmed #16574280 No free full text.

Abstract: Neurofibrillary degeneration in the nucleus basalis and a loss of its cortical cholinergic projections are prominent components of the neuropathology in Alzheimer's disease (AD). The AD brain is also associated with a degeneration of the noradrenergic projections arising from the nucleus locus coeruleus (LC), but the time course of this lesion is poorly understood. To determine whether the LC displays neurofibrillary abnormalities early in the course of events leading to AD, we examined tissue specimens from seven cognitively normal controls and five subjects at the stages of mild cognitively impairment (MCI) or early AD. Tyrosine hydroxylase immunochemistry was used as a marker of LC neurons while AT8 immunolabeling visualized abnormal tau associated with neurofibrillary tangles and their precursors. Thioflavine-S was used as a marker for fully developed tangles. We found that AT8-positive labeling and thioflavine-S positive tangles were present in both groups of specimens. However, the percentage of neurons containing each of these markers was significantly higher in the cognitively impaired group. The MMSE scores displayed a negative correlation with both markers of cytopathology. These results indicate that cytopathology in the LC is an early event in the age-MCI-AD continuum and that it may be listed among the numerous factors that mediate the emergence of the cognitive changes leading to dementia.

Li X, Rowland LP, Mitsumoto H, Przedborski S, Bird TD, Schellenberg GD, Peskind E, Johnson N, Siddique T, Mesulam MM, Weintraub S, Mastrianni JA. · Department of Neurology, Pritzker School of Medicine and Center for Comprehensive Care and Research on Memory Disorders, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA. · Ann Neurol. · Pubmed #16315279 No free full text.

Abstract: The prion protein (PrP) is central to the prion diseases, although a role in other neurodegenerative diseases has been postulated. A common polymorphism (Met or Val) at codon 129 of the PrP gene (PRNP) features prominently in the risk and phenotype, of prion disease, and an abnormality in its distribution frequency may signal a role for PrP in other diseases. We conducted a case-control study to compare the PRNP codon 129 genotype distribution in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and primary progressive aphasia (PPA), including 281 AD, 256 ALS, 39 PPA, and 415 healthy control subjects. Statistical analysis was applied to determine the presence or absence of disease-specific genotype associations. The distribution of codon 129 genotypes was similar among healthy control, AD, and ALS subjects, although the heterozygous state was significantly overrepresented (age-adjusted odds ratio, 8.47) in PPA, a rare condition of unknown cause. Although these findings do not entirely exclude a role for PrP in AD or ALS, they do not support the codon 129 genotype as a risk factor for either disease. However, the strong association between heterozygosity and PPA raises new questions about its cause and the role of PrP in other neurodegenerative diseases.

Vandenberghe RR, Vandenbulcke M, Weintraub S, Johnson N, Porke K, Thompson CK, Mesulam MM. · Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Medical School, Chicago, IL, USA. · Ann Neurol. · Pubmed #15668969 No free full text.

Abstract: Impaired word retrieval is a main symptom of primary progressive aphasia (PPA). The cognitive features of this impairment in PPA are poorly understood. We studied 12 patients with PPA (6 English-speaking and 6 Dutch-speaking), 7 patients with early-stage clinically probable Alzheimer's disease (PRAD), 5 patients with mild cognitive impairment (MCI), and 15 age-matched, cognitively intact, control subjects. Subjects had to name a picture (the probe), which was preceded by a written word (the prime) that could be the correct name of the picture, a noun belonging to the same semantic subcategory (related prime), a semantically unrelated noun (unrelated prime), or a pseudoword (neutral control). Naming latencies were longer in PPA and PRAD patients than in control subjects. Critically, the interaction between group and prime type was highly significant. PPA patients named the probe more slowly after a related compared with an unrelated prime. In contrast, PRAD patients, mild cognitive impairment patients, and healthy control subjects tended to name the probe faster when it was preceded by a related prime. The semantic interference effect in PPA generalized across languages and PPA subtypes. Selection among competing word forms sharing a same semantic field is abnormal in PPA. The semantic interference effect constitutes a positive distinguishing feature between PPA and PRAD.

Johnson N, Barion A, Rademaker A, Rehkemper G, Weintraub S. · Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. · Alzheimer Dis Assoc Disord. · Pubmed #15592135 No free full text.

Abstract: This study describes the development and validation of the Activities of Daily Living Questionnaire (ADLQ), an informant-based assessment of functional abilities, in patients with probable Alzheimer disease and other forms of dementia. The ADLQ measures functioning in six areas: self-care, household care, employment and recreation, shopping and money, travel, and communication. The ADLQ was administered to 140 caregivers followed longitudinally in the Northwestern Alzheimer's Disease Center. In a subset of 28 participants, the total ADLQ score and each of the subscales were found to be highly reproducible, with average concordance coefficients of 0.86. Concurrent validity was established by comparing the ADLQ with the Record of Independent Living, a previously validated measure of level of dependency in daily living activities. The ADLQ was also compared with other measures of dementia severity on the initial and annual follow-up visits and was found to be significantly and negatively correlated with the Mini-Mental State Examination and positively correlated with the Clinical Dementia Rating Scale. The ADLQ has high test-retest and concurrent validity and is consistent with other measures of temporal decline in patients with probable Alzheimer disease and other forms of dementia.

Wicklund AH, Johnson N, Weintraub S. · Department of Psychiatry and Behavioral Sciences, Division of Psychology, Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. · J Clin Exp Neuropsychol. · Pubmed #15512925 No free full text.

Abstract: Primary Progressive Aphasia (PPA) is a clinical dementia syndrome characterized by the gradual dissolution of language without impairment of other cognitive domains for at least the first 2 years of illness (M.-M. Mesulam, 1982, 2001). It is difficult to demonstrate the integrity of nonlanguage domains in PPA because most neuropsychological tests of memory, reasoning, and attention require language competence for their performance. In the present study, reasoning and cognitive flexibility were tested nonverbally in patients with PPA using a modified ten-item version of the Visual Verbal Test (Feldman & Drasgow, 1959). This test measures the ability to detect similarities among objects and to sort a single set of objects according to two different principles. The performance of PPA patients (n = 20) was compared with that of patients with dementia of the Alzheimer type (AD) (n = 20), patients with the comportmental/executive dysfunction variant of frontotemporal dementia (FTD) (n = 16), and cognitively intact controls (n = 20). Patients with PPA and controls performed similarly, detecting commonalities among objects and shifting from one sorting principle to another. In contrast, both AD and FTD subjects were significantly impaired on both measures. These results provide evidence of preserved reasoning in PPA, further differentiating this syndrome from other behaviorally focal dementia syndromes.

Mesulam M, Shaw P, Mash D, Weintraub S. · Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. · Ann Neurol. · Pubmed #15174015 No free full text.

Abstract: The cholinergic denervation in Alzheimer's disease (AD) provides the rationale for treatments with anticholinesterases. The presence of this cholinergic lesion is solidly established in advanced AD. Whether it also exists in early disease remains unsettled. This question was addressed with thioflavin-S histofluorescence to identify neurofibrillary tangles (NFT) and two tau antibodies (AT8, Alz-50) to identify pre-tangle cytopathology in the nucleus basalis, the source of cortical cholinergic innervation. Methods for the concurrent visualization of tauopathy and choline acetyltransferase were used to determine if the cytopathology was selectively located within cholinergic neurons. Five elderly index cases who had died at the stage of mild cognitive impairment (MCI) or early AD were identified by longitudinal neuropsychological and behavioral assessments. They were compared to 7 age-matched cognitively normal subjects. NFT and AT8 (or Alz-50) immunostaining in cholinergic nucleus basalis neurons existed even in the cognitively normal subjects. The percentage of tauopathy-containing nucleus basalis neurons was greater in the cognitively impaired and showed a significant correlation with memory scores obtained 1-18 months prior to death. These results show that cytopathology in cortical cholinergic pathways is a very early event in the course of the continuum that leads from advanced age to MCI and AD.

Salamon G, Salamon N, Johnson N, Mongkolwat P, Gitelman D, Weintraub S, Mesulam M, Russell E. · Radiology, CNADC, NWU Chicago, USA. · Rev Neurol (Paris). · Pubmed #14978395 No free full text.

Abstract: Magnetic resonance images of the brain acquired in relationship to the commissural plane have been analyzed in twenty cases classified as Probable Alzheimer's disease (Pr. AD). These examinations have been compared to normal aged matched subjects. All examinations have been made in strict correlation with the planes defined by Talairach and Tournoux (1988). The analysis of brain cortical damage was made by evaluating the sulci of the brain mainly on coronal sections correlated with simultaneous image review of the same area on the two other orthogonal planes. In Pr. AD, an asymmetric atrophic pattern was found mainly on the following areas: amygdaloid nucleus, para hippocampal gyrus, hippocampus, areas 22 and 21, temporal pole, insula, dorso frontal cortex, angular gyrus, superior parietal lobule. The primary motor and visual areas were normal in all cases.

Reber PJ, Martinez LA, Weintraub S. · Department of Psychology, Northwestern University, Evanston, Illinois 60201, USA. · Cogn Affect Behav Neurosci. · Pubmed #12943329 links to  free full text

Abstract: Patients with early Alzheimer's disease (AD) exhibit impaired declarative memory although some forms of nondeclarative memory are intact. Performance on perceptual nondeclarative memory tasks is often preserved in AD, whereas conceptual nondeclarative memory is often impaired. A conceptual nondeclarative learning task that has been studied in amnesic patients is the artificial grammar learning (AGL) task. Healthy participants and patients with impaired declarative memory both acquire information about an underlying rule structure in this task and exhibit the ability to identify rule-conforming items, despite the subjective experience of guessing at the response. In this study, 12 patients diagnosed with early AD were tested on the AGL task and a matched recognition task. The patients were able to reliably distinguish rule-conforming items from others, indicating successful AGL. Performance of the AD patients was impaired, relative to controls, on a similar recognition task, although they were found to use information about the grammaticality of study items in an attempt to improve their recognition performance. The AD patients showed a dissociation similar to that seen in anterograde amnesia: impaired recognition memory in conjunction with successful AGL. This finding suggests that the brain areas that support AGL are not compromised early in the course of AD. In addition, the nondeclarative memory of the AD patients acquired during AGL appeared to influence their performance on a declarative memory task, suggesting an interaction between this nondeclarative memory task and declarative memory.