Alzheimer Disease: Small BJ

Bäckman L, Small BJ. · Karolinska Institutet, Aging Research Center, S-113 30 Stockholm, Sweden. · Physiol Behav. · Pubmed #17573076 No free full text.

Abstract: Using data from the Kungsholmen Project (KP), we describe a program of research that focuses on preclinical cognitive markers of dementia. A large number of KP studies convincingly demonstrate that there is a preclinical period that spans several years in both Alzheimer's disease (AD) and vascular dementia (VaD), during which cognitive deficits are possible to detect. In AD, the preclinical impairment generalizes across a variety of cognitive domains, including episodic memory, executive functioning, perceptual speed, attention, verbal ability, and visuospatial skill. Although less research has been directed at cognition in preclinical VaD, the emerging evidence suggests a rather broad prodromal impairment in this disease as well. Thus, the nature of the cognitive impairment appears to be largely similar in preclinical AD and VaD. Despite the fact that average group differences in cognitive performance between incident dementia cases and controls are large several years before diagnosis, the distribution of scores in these groups overlap greatly. In order to improve group classification, future research should consider combining cognitive markers with preclinical indicators from other domains (e.g., biological, clinical, social, genetic) into multivariate prediction models.

Small BJ, Gagnon E, Robinson B. · School of Aging Studies, University of South Florida, Tampa, USA. · Geriatrics. · Pubmed #17408315 No free full text.

Abstract: With the projected dramatic increase in the number of people who will be diagnosed with Alzheimer's disease (AD) in the coming years, interest is growing in identifying and treating adults at high risk for developing the disorder. Recent research suggests that individuals who will go on to receive a diagnosis of AD exhibit deficits in cognitive performance years beforehand. Those with mild cognitive impairment (MCI), for example, have characteristic cognitive deficits, such as memory loss, and convert to a diagnosis of AD at a faster rate than cognitively healthy controls. MCI has thus become a focus of research because it may help identify high-risk individuals for whom prophylactic treatments designed to slow the progress toward AD can be prescribed. After describing the diagnostic criteria and dementia outcomes associated with MCI, this article discusses several challenges to the study of cognitive impairment before the diagnosis of AD.

Bäckman L, Jones S, Berger AK, Laukka EJ, Small BJ. · Department of Geriatric Epidemiology, Aging Research Center, Neurotec, Karolinska Institute, Stockholm, Sweden. · J Intern Med. · Pubmed #15324363 No free full text.

Abstract: The literature on cognitive markers in preclinical AD is reviewed. The findings demonstrate that impairment in multiple cognitive domains is typically observed several years before clinical diagnosis. Measures of executive functioning, episodic memory and perceptual speed appear to be most effective at identifying at-risk individuals. The fact that these cognitive domains are most implicated in normal cognitive aging suggests that the cognitive deficit observed preclinically is not qualitatively different from that observed in normal aging. The degree of cognitive impairment prior to the diagnosis of Alzheimer's disease (AD) appears to generalize relatively well across major study characteristics, including sample ascertainment procedures, age and cognitive status of participants, as well as time to diagnosis of dementia. In episodic memory, there is evidence that the size of the preclinical deficit increases with increasing cognitive demands. The global cognitive impairment observed is highly consistent with observations that multiple brain structures and functions are affected long before the diagnosis of AD. However, there is substantial overlap in the distribution of cognitive scores between those who will and those who will not be diagnosed with AD, hence limiting the clinical utility of cognitive markers for early identification of cases. Future research should consider combining cognitive indicators with other types of markers (i.e. social, somatic, genetic, brain-based) in order to increase prediction accuracy.

Small BJ, Mobly JL, Laukka EJ, Jones S, Bäckman L. · Department of Gerontology, University of South Florida, Tampa, FL 33620, USA. · Acta Neurol Scand Suppl. · Pubmed #12603248 No free full text.

Abstract: We review the literature on cognitive functioning during the transition from normal aging to clinical Alzheimer's disease (AD). There is ample empirical evidence that deficits across multiple cognitive domains are apparent years to decades before the AD diagnosis, with impairments in episodic memory representing a common cognitive manifestation of the preclinical phase of the disease. Interestingly, the magnitude of the preclinical cognitive deficits appears to be relatively stable until a few years before clinical diagnosis. The behavioural deficits associated with preclinical AD are consistent with the neural changes that appear many years before eventual diagnosis. In addition to increasing our theoretical understanding of AD development, research on cognition in preclinical AD contributes to the identification of persons at risk of developing AD for purposes of intervention.

Jones S, Small BJ, Fratiglioni L, Backman L. · No affiliation provided · Brain Cogn. · Pubmed #15259392 No free full text.

Abstract: We examined individual-difference variables in relation to the rate of change in global cognitive performance, measured by the MMSE, from 3 years prior to diagnosis of Alzheimer's disease (AD) to the time of diagnosis. The population-based sample consisted of 230 incident AD persons who were followed over a 3-year interval. The average annual decline in MMSE was 1.81 points. Being older and acquiring additional diseases during the 3 years preceding diagnosis predicted a faster rate of decline in global cognitive functioning. However, other individual difference variables such as sex, education, depression, vitamin levels (vitamin B12 and folic acid), apolipoprotein status, and social network did not precipitate the rate of decline in the preclinical phase of AD.

Small BJ, Fratiglioni L, Viitanen M, Winblad B, Bäckman L. · Department of Gerontology, Mailbox SOC 107, University of South Florida, 4202 E Fowler Ave, Tampa, FL 33620, USA. · Arch Neurol. · Pubmed #10867781 links to  free full text

Abstract: OBJECTIVES: To examine the ability of the total score and individual items from the Mini-Mental State Examination in predicting the development of Alzheimer disease (AD) across a 3- and 6-year period in a population-based sample, and to describe the longitudinal changes in these measures across the same follow-up periods. DESIGN: Prospective follow-up of a community-based cohort, with 3 times of testing across a 6-year period. At each time of measurement, participants were clinically examined by physicians to identify demented and nondemented participants according to Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria. PARTICIPANTS: The study population consisted of all participants who were nondemented at the first follow-up and participated in the second follow-up examination. Among those, 459 remained nondemented and 73 developed AD during the second follow-up period. RESULTS: Baseline differences in the total Mini-Mental State Examination score and the delayed memory item were seen 6 years before eventual dementia diagnosis (P<.01). Analysis of the longitudinal changes showed no differences in the rate of decline for the incident AD or nondemented group between time 1 and time 2 (P>.10). However, the incident AD group exhibited precipitous declines in 8 of the 10 subscales between time 2 and time 3, the point at which they were clinically diagnosed (P<.01). Logistic regression analyses showed that only the delayed memory item was a significant predictor of who would develop AD, independent of age, sex, and years of education, at both of the first 2 times of measurement (P<.001). CONCLUSIONS: The diagnosis of AD is preceded by a long preclinical phase in which deficits in memory performance are most common. These deficits remain relatively stable up until the time that a dementia diagnosis can be rendered. Arch Neurol. 2000.

Small BJ, Bäckman L. · School of Aging Studies, University of South Florida, Tampa, FL 33620, USA. · Cortex. · Pubmed #17941341 No free full text.

Abstract: Preclinical Alzheimer's disease (AD) refers to a period of time prior to diagnosis during which cognitive deficits among individuals who will go on to receive a diagnosis of AD are present. There is great interest in describing the nature of cognitive change during the preclinical period, in terms of whether persons decline in a linear fashion to diagnosis, or exhibit some stability of functioning, followed by rapid losses in performance. In the current study we apply Growth Mixture Modeling to data from The Kungsholmen Project to evaluate whether decline in Mini Mental State Examination (MMSE) scores during the preclinical period of AD follows a linear or quadratic function. At the end of a 7-year follow-up period, some individuals would be diagnosed with AD (n=71), whereas others would remain free of dementia (n=457). The results indicated that a two-group quadratic model of decline provided the best statistical fit measures, as well as the greatest estimates of sensitivity (67%) and specificity (86%). Differences in MMSE scores were apparent at baseline, but the preclinical AD group began to experience precipitous declines three years prior to diagnosis. Finally, persons who were misclassified as preclinical AD had fewer years of education and poorer MMSE scores at baseline.

McArdle JJ, Small BJ, Bäckman L, Fratiglioni L. · Department of Psychology, University of Southern California, Los Angeles 90089, USA. · J Geriatr Psychiatry Neurol. · Pubmed #16306246 No free full text.

Abstract: This article explores new statistical methodologies for using longitudinal data in the early prediction of Alzheimer's disease (AD). Specifically, the authors examine some new techniques that allow the joint or "shared" estimation of longitudinal components based on both duration (survival) and quantitative changes (growth curves). These new shared growth-survival parameter models may be used to characterize the declining functions that anticipate the onset of AD. The authors apply these models to data from the Kungsholmen Project, a longitudinal study of aging in Stockholm, Sweden. They examine age-based survival-frailty models for the onset of AD, latent growth-decline curve models for changes in cognition over age, and 3 alternative forms of models for the shared relationships of survival and early cognitive decline. The accuracy and reliability of this approach is considered for a better understanding of the developmental course of AD in these data, including the potential removal of biases due to subject selection.

White L, Small BJ, Petrovitch H, Ross GW, Masaki K, Abbott RD, Hardman J, Davis D, Nelson J, Markesbery W. · Honolulu-Asia Aging Study, Kuakini Medical Center, Honolulu, HI, USA. · J Geriatr Psychiatry Neurol. · Pubmed #16306244 No free full text.

Abstract: In this study, we compare neuropathological findings at autopsy with clinical dementia diagnoses, such as Alzheimer's disease and vascular dementia. Participants consisted of 363 aged Japanese-American men from the Honolulu-Asia Aging Study. Results indicated that the correspondence between clinical and neuropathologic diagnosis was not great, with 56% of patients diagnosed with probable or possible Alzheimer's disease during life but with only 19% having neuritic plaques and/or neurofibrillary tangles as the sole or dominant dementia-related lesions in the brain at autopsy. Although 16% of cases were attributed to mixed causes during life, almost 40% were found to have significant mixtures of dementia-related lesions at autopsy. Finally, both Alzheimer's disease and non-Alzheimer's disease neuropathologic lesions contributed independently to the explanation of variance on a test of overall cognitive performance. The results suggest that clinical diagnosis of dementia made during life may fail to reflect the pathogenic complexity of this condition in very elderly persons.

Wiltshire K, Foster S, Kaye JA, Small BJ, Camicioli R. · University of Alberta, Edmonton, Canada. · Dement Geriatr Cogn Disord. · Pubmed #16192724 No free full text.

Abstract: Corpus callosum area has been examined in neurodegenerative diseases as a marker for cortical pathology and for differential diagnosis; however, it has not been examined in Parkinson's disease (PD). We compared callosal area in patients with PD and PD with dementia (PDD) to healthy controls and patients with Alzheimer's disease (AD). We subsequently compared our results to a meta-analysis of studies examining callosal area in AD, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). For the imaging study, midsagittal T1-weighted MRIs were analyzed and the callosal area was determined in patients with PD (n = 24), PDD (n = 25), AD (n = 16) and controls (n = 27). The meta-analysis combined results from all publications (Medline or PubMed) representing unique samples and measuring callosal area in AD, FTD, PSP, and CBD. We found that PD and PDD patients did not show statistically significant callosal atrophy compared to controls (effect size d, 95% CI, d = 0.13, -0.26 to 0.52, and d = 0.05, -0.44 to 0.33, respectively) or AD. The AD patients had a significant loss of callosal area compared to controls (d = -0.58, -1.01 to -0.15). Dementia severity was correlated with total callosal atrophy in AD (R = 0.66, p < 0.01) but not in PDD patients (R = 0.18, p > 0.1). The meta-analysis revealed significant combined effect sizes for callosal atrophy of: AD (d = -1.03, -1.13 to -0.93), FTD (d = -1.21, -1.56 to -0.86), PSP (d = -1.09, -1.38 to -0.81), and CBD (d = -1.80, -2.18 to -1.43). We conclude that PD and PDD patients do not have callosal atrophy in contrast to other neurodegenerative diseases, including AD. Callosal atrophy was correlated with dementia severity in patients with AD but not PDD.

Bäckman L, Jones S, Berger AK, Laukka EJ, Small BJ. · Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institute, Stockholm, Sweden. · Neuropsychology. · Pubmed #16060827 No free full text.

Abstract: To determine the size of the impairment across different cognitive domains in preclinical Alzheimer's disease (AD), a meta-analysis based on 47 studies involving 9,097 controls and 1,207 preclinical AD cases was conducted. There were marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; somewhat smaller deficits in verbal ability, visuospatial skill, and attention; and no preclinical impairment in primary memory. Younger age (< 75 years) and shorter follow-up intervals (< 3 years) were associated with larger effect sizes for both global cognitive ability and episodic memory. For global cognitive ability, studies that used population-based sampling yielded larger effect sizes; for episodic memory, larger differences were seen in studies that preidentified groups in terms of baseline cognitive impairment. Within episodic memory, delayed testing and recall-based assessment resulted in the largest effect sizes. The authors conclude that deficits in multiple cognitive domains are characteristic of AD several years before clinical diagnosis. The generalized nature of the deficit is consistent with recent observations that multiple brain structures and functions are affected long before the AD diagnosis.

Small BJ, Rosnick CB, Fratiglioni L, Bäckman L. · School of Aging Studies, University of South Florida, Tampa, FL 33620, USA. · Psychol Aging. · Pubmed #15584785 No free full text.

Abstract: The epsilon4 allele of the apolipoprotein E (APOE) gene is a known risk factor for Alzheimer's disease and may also affect cognitive performance in normal aging. Evidence of the presence and magnitude of epsilon4-related cognitive deficits was examined with a meta-analysis of the available literature. Thirty-eight studies were included, and cognitive performance was collapsed into 8 domains. Results indicated significant APOE-epsilon4 group differences for global cognitive functioning, episodic memory, and executive functioning, in favor of non-epsilon4 carriers. In addition, older age and APOE-epsilon4 heterozygosity was associated with smaller epsilon4-related impairments. The meta-analysis results suggest that APOE-epsilon4 genotype does affect cognitive performance in healthy aging, although the influence is relatively small and specific to certain domains of cognitive performance.

Bunce D, Fratiglioni L, Small BJ, Winblad B, Bäckman L. · Department of Psychology, Goldsmiths College, University of London, London SE14 6NW, UK. · Neurology. · Pubmed #15365129 No free full text.

Abstract: OBJECTIVE: To investigate whether presence of the APOE epsilon4 allele is related to the pathologic progression of preclinical Alzheimer disease (AD), as reflected by change in Mini-Mental State Examination (MMSE) scores among persons in the preclinical phase of AD, and cognitively intact adults confirmed as dementia-free during the 6-year assessment period. METHOD: In a population-based sample, participants were stratified according to APOE genotype (epsilon4 or non-epsilon4) and whether they received a diagnosis of AD at the end of either a 3- or 6-year assessment period. Participants were aged 75 years and older, and were nondemented at baseline. At the end of the 3-year period, 17.2% of non-epsilon4 and 26.7% of epsilon4 carriers became demented. For the 6-year period those percentages were 11.2% for non-epsilon4 carriers and 16.9% for epsilon4-carriers. RESULTS: Individuals in the preclinical phase of AD showed greater decline on the MMSE as compared to nondemented adults. However, the decline was most marked in the 3 years prior to clinical diagnosis. Further, APOE-epsilon4 genotype did not modify the rate of decline among to-be-demented participants, as well as individuals who would remain free of AD. CONCLUSIONS: Although possession of the APOE epsilon4 allele is a risk factor for AD in old age, it does not modify the progression of the disease during the preclinical period. Further, in the absence of preclinical dementia, APOE did not influence global cognitive change in nondemented persons.

Jones S, Laukka EJ, Small BJ, Fratiglioni L, Bäckman L. · Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institutet, and Stockholm Gerontology Research Center, Stockholm, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #15286452 No free full text.

Abstract: Alzheimer's disease (AD) and vascular dementia (VaD) patients exhibit similar patterns of deficits in many cognitive tasks in the early clinical stages. Considering that preclinical cognitive deficits are well documented in AD, the purpose of the present study was to investigate if such deficits are also present in VaD. The cognitive outcome measure was the Mini-Mental State Examination (MMSE). The sample was taken from a population-based study and consisted of 699 persons who were nondemented at baseline, but out of whom 35 persons were diagnosed with VaD and 170 with AD at a 3-year follow-up. Both the incident VaD and AD cases exhibited baseline deficits on the total score of the MMSE and three of the subscales: orientation to time, orientation to place, and delayed memory. Further, both dementia groups exhibited precipitous decline on most MMSE subscales during the 3-year follow-up period. Logistic regression analyses showed that all subscales that revealed deficits at baseline predicted dementia status at follow-up. Delayed memory was the best predictor in both preclinical VaD and preclinical AD. Thus, these results demonstrate preclinical cognitive deficits in VaD in a measure of global cognitive functioning, which closely resemble those observed in AD. This observation suggests that circulatory disturbance is associated with cognitive problems several years before the actual VaD diagnosis.

Laukka EJ, Jones S, Small BJ, Fratiglioni L, Bäckman L. · Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institutet and Stockholm Gerontology Research Center, Stockholm, Sweden. · J Int Neuropsychol Soc. · Pubmed #15147596 No free full text.

Abstract: We investigated whether (1) cognitive deficits are present among persons who will be diagnosed with vascular dementia (VaD) 3 years later, and (2) the pattern of such deficits is similar to that observed in preclinical Alzheimer's disease (AD). The VaD diagnosis was a diagnosis of post-stroke dementia. Population-based samples of 15 incident VaD cases, 43 incident AD cases, and 149 normal controls were compared on tests of episodic and short-term memory, verbal fluency, and visuospatial skill. Both dementia groups showed preclinical impairment relative controls on tasks assessing episodic memory 3 years before diagnosis, and there were no differences between these groups on any cognitive measure. The existence of a preclinical phase in the present VaD cases suggests that circulatory disturbance may affect cognitive performance before the occurrence of stroke that leads to clinical VaD. These results extend previous findings of similar patterns of cognitive deficits in the early clinical phases of AD and VaD to the preclinical phases of these diseases.

Bäckman L, Jones S, Small BJ, Agüero-Torres H, Fratiglioni L. · Aging Research Center at the Karolinska Institute and Stockholm Gerontology Research Center, Stockholm, Sweden. · J Gerontol B Psychol Sci Soc Sci. · Pubmed #12878651 No free full text.

Abstract: We investigated the influence of individual-difference variables implicated as risk factors for Alzheimer's disease (AD) or known to be related to cognitive performance in normal aging (e.g., age, sex, years of education, previous and recent diseases, apolipoprotein E status, social network, and substance use) on rate of cognitive change from preclinical to clinical AD. With the use of data from a population-based study, 230 persons who were nondemented at baseline and diagnosed with AD at a 3-year follow-up were examined with the Mini-Mental State Examination (MMSE). Of all predictor variables examined, only number of diseases resulting in hospital admission during the follow-up period made an independent contribution to rate of MMSE change. These results suggest that many variables affecting the onset of the degenerative process as well as cognitive functioning in normal aging exert little influence on rate of cognitive change in preclinical AD. This may reflect the fact that the emerging dementia disease overshadows the role of these variables for cognitive functioning. A possible exception to this pattern is that an increasing number of concomitant health conditions may exacerbate the rate of cognitive decline during the final portion of the preclinical phase in AD.

Small BJ, Fratiglioni L, Bäckman L. · Department of Gerontology, SOC 107, University of South Florida, 4202 E Fowler Ave, Tampa, FL 33620, USA. · Arch Gen Psychiatry. · Pubmed #11545669 No free full text.

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Bäckman L, Small BJ, Fratiglioni L. · Department of Psychology, Uppsala University, Uppsala, Sweden. · Brain. · Pubmed #11133790 links to  free full text

Abstract: We sought to determine the course of the preclinical episodic memory deficit in Alzheimer's disease. Using data from a population-based study, we compared persons who developed Alzheimer's disease n = 15) with persons who were non-demented n = 105) 6 and 3 years prior to the diagnosis of dementia. Participants were tested on tasks assessing episodic memory free recall and recognition of words) and short-term memory digit span). The incident Alzheimer's disease cases performed more poorly than their non-demented counterparts both 3 and 6 years before diagnosis on recall and recognition. There were no group differences in either forward or backward digit span. The selective impairment of episodic memory before the diagnosis of Alzheimer's disease is consistent with the view that early changes in the hippocampal complex play an important role in the memory deficit in preclinical Alzheimer's disease. On both preclinical measurement occasions, recall and recognition made independent contributions to group classification in logistic regression analyses. However, there was no evidence for accelerated decline of episodic memory in the incident Alzheimer's disease group from 6 to 3 years before diagnosis. These results indicate that Alzheimer's disease is characterized by a long preclinical period during which episodic memory deficits are detectable. The magnitude of these deficits appears to be quite stable, at least up to 3 years before diagnosis. This may reflect the fact that those biological events that eventually result in clinically diagnosed Alzheimer's disease e.g. the appearance of amyloid plaques and neurofibrillary tangles) accumulate at a relatively slow rate.