Alzheimers Disease Research Center

Stockholm, Sweden

Alzheimers Disease Research Center

Stockholm, Sweden

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Steenland K.,Alzheimers Disease Research Center | Steenland K.,Emory University | Levey A.,Alzheimers Disease Research Center | Levey A.,Emory University
Neuroepidemiology | Year: 2010

Background: Survival varies widely among different neurodegenerative diseases. Data on the role of the Mini Mental State Examination (MMSE) and apolipoprotein E (APOE) in survival are sparse except for Alzheimer's disease (AD). Methods: We studied mortality of 3,581 patients in an academic clinic from 1993 to 2004. Average follow-up was 4.1 years. We studied patients with amyotrophic lateral sclerosis (ALS) (n = 174), possible AD (n = 206), probable AD (n = 1,175), Parkinson's disease (PD) (n = 661), mild cognitive impairment (MCI) (n = 357), frontotemporal dementia (FTD) (n = 94), Lewy body disease (LBD) (n = 64), and controls (n = 850). We compared patients' mortality to the US population and to controls. Results: Mortality ranged from 7% for controls to 58% for ALS patients. The median survival times from initial visit for PD, FTD, probable AD, possible AD, LBD, and ALS were 8.9, 7.0, 5.9, 5.6, 5.3, and 2.7 years, respectively. Mortality rate ratios comparing each disease to controls were 39.43, 7.25, 3.70, 3.51, 2.47, 2.73, and 1.61 for ALS, FTD, LBD, PD, probable AD, possible AD, and MCI, respectively. A lower initial MMSE score was associated with higher mortality for probable AD, PD, and MCI, while APOE4 predicted mortality for PD and LBD. Non-whites had 20% lower mortality rates than whites for all dementias combined, adjusting for education. Conclusions: All neurologic diseases, including MCI, had increased mortality versus controls. A lower MMSE score and APOE4 presence predicted higher mortality for some patient groups. © 2010 S. Karger AG, Basel.


Mielke M.M.,Mayo Medical School | Roberts R.O.,Mayo Medical School | Cha R.,Mayo Medical School | Drubach D.I.,Alzheimers Disease Research Center | And 4 more authors.
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2013

Background.The association between gait speed and cognition has been reported; however, there is limited knowledge about the temporal associations between gait slowing and cognitive decline among cognitively normal individuals.Methods.The Mayo Clinic Study of Aging is a population-based study of Olmsted County, Minnesota, United States, residents aged 70-89 years. This analysis included 1,478 cognitively normal participants who were evaluated every 15 months with a nurse visit, neurologic evaluation, and neuropsychological testing. The neuropsychological battery used nine tests to compute domain-specific (memory, language, executive function, and visuospatial skills) and global cognitive z-scores. Timed gait speed (m/s) was assessed over 25 feet (7.6 meters) at a usual pace. Using mixed models, we examined baseline gait speed (continuous and in quartiles) as a predictor of cognitive decline and baseline cognition as a predictor of gait speed changes controlling for demographics and medical conditions.Results.Cross-sectionally, faster gait speed was associated with better performance in memory, executive function, and global cognition. Both cognitive scores and gait speed declined over time. A faster gait speed at baseline was associated with less cognitive decline across all domain-specific and global scores. These results were slightly attenuated after excluding persons with incident mild cognitive impairment or dementia. By contrast, baseline cognition was not associated with changes in gait speed.Conclusions.Our study suggests that slow gait precedes cognitive decline. Gait speed may be useful as a reliable, easily attainable, and noninvasive risk factor for cognitive decline. © The Author 2012.


Burack M.A.,University of Rochester | Taylor-Reinwald L.,Alzheimers Disease Research Center | Perlmutter J.S.,University of Washington | Cairns N.J.,Alzheimers Disease Research Center
Neurology | Year: 2010

OBJECTIVE: To investigate the specificity of in vivo amyloid imaging with [C]-Pittsburgh Compound B (PIB) in Parkinson disease dementia (PDD). METHODS: We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death. RESULTS: We observed elevated cortical uptake of [C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse Aβ plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden. CONCLUSIONS: [C]-Pittsburgh Compound B (PIB) PET is specific for fibrillar Aβ molecular pathology but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease dementia. The ability to specifically identify fibrillar Aβ amyloid in the setting of α-synucleinopathy makes [C]-PIB PET a valuable tool for prospectively evaluating how the presence of Aβ amyloid influences the clinical course of dementia in patients with Lewy body disorders. © 2010 by AAN Enterprises, Inc.


Petersen R.C.,Rochester College | Petersen R.C.,Alzheimers Disease Research Center | Petersen R.C.,Mayo Medical School | Aisen P.,University of California at San Diego | And 16 more authors.
Annals of Neurology | Year: 2013

Objective The newly proposed National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) due to Alzheimer disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known. Methods The Mayo Clinic Study of Aging (MCSA) is a population-based longitudinal study of nondemented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) to assess the applicability of the criteria in both settings and to assess their outcomes. Results Fourteen percent of MCSA and 16% of ADNI-1 of subjects were biomarker negative. In addition, 14% of MCSA and 12% of ADNI-1 subjects had evidence for amyloid deposition only, whereas 43% of MCSA and 55% of ADNI-1 subjects had evidence for amyloid deposition plus neurodegeneration (magnetic resonance imaging atrophy, fluorodeoxyglucose positron emission tomography hypometabolism, or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model; for example, 29% of MCSA subjects and 17% of ADNI-1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone. Interpretation The NIA-AA criteria apply to most MCI subjects in both the community and clinical trials settings; however, a sizeable proportion of subjects had conflicting biomarkers, which may be very important and need to be explored. © 2013 American Neurological Association.


Armstrong R.A.,Aston University | Carter D.,Alzheimers Disease Research Center | Carter D.,University of Washington | Cairns N.J.,Alzheimers Disease Research Center | Cairns N.J.,University of Washington
Neuropathology and Applied Neurobiology | Year: 2012

Aims: To further characterize the neuropathology of the heterogeneous molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP). Methods: We quantified the neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe using a phosphorylation-independent TDP-43 antibody in 32 cases of FTLD-TDP comprising sporadic and familial cases, with associated pathology such as hippocampal sclerosis (HS) or Alzheimer's disease (AD), and four neuropathological subtypes using TDP-43 immunohistochemistry. Analysis of variance (anova) was used to compare differences between the various groups of cases. Results: These data from FTLD-TDP cases demonstrate quantitative differences in pathological features between: (i) regions of the frontal and temporal lobe; (ii) upper and lower cortex; (iii) sporadic and progranulin (GRN) mutation cases; (iv) cases with and without AD or HS; and (v) between assigned subtypes. Conclusions: The data confirm that the dentate gyrus is a major site of neuropathology in FTLD-TDP and that most laminae of the cerebral cortex are affected. GRN mutation cases are quantitatively different from sporadic cases, while cases with associated HS and AD have increased densities of dystrophic neurites and abnormally enlarged neurones respectively. There is little correlation between the subjective assessment of subtypes and the more objective quantitative data. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.


Johnell K.,Karolinska Institutet | Religa D.,Alzheimers Disease Research Center | Religa D.,Karolinska University Hospital | Eriksdotter M.,Karolinska Institutet | Eriksdotter M.,Karolinska University Hospital
Dementia and Geriatric Cognitive Disorders | Year: 2013

Background/Aims: We aimed to study whether there are differences between dementia disorders and the use of anti-dementia drugs and antipsychotics (neuroleptics) in a large population of dementia patients. Methods: Information about dementia disorders was obtained from the national Swedish Dementia Registry (SveDem) 2007-2010 (n = 7,570). Multivariate logistic regression analysis was performed to investigate the association between dementia disorders and the use of anti-dementia drugs and antipsychotics, after adjustment for age, sex, residential setting, living alone, MMSE score and number of other drugs (a proxy for overall co-morbidity). Results: More than 80% of the Alzheimer's disease (AD) and 86% of dementia with Lewy bodies (DLB) patients used anti-dementia drugs. Women were more likely than men to be treated with cholinesterase inhibitors. A higher MMSE score was positively associated with the use of cholinesterase inhibitors, but negatively associated with NMDA receptor antagonists and antipsychotics. Use of antipsychotics was 6% overall; however, it was 16% in DLB patients with an adjusted odds ratio of 4.2 compared to AD patients. Conclusion: Use of anti-dementia drugs in AD was in agreement with Swedish guidelines. However, use of antipsychotics in DLB patients was high, which might be worrying given the susceptibility of DLB patients to antipsychotics. Copyright © 2013 S. Karger AG, Basel.


Lane R.F.,Mount Sinai School of Medicine | Gatson J.W.,Southwestern University | Small S.A.,Columbia University | Ehrlich M.E.,Mount Sinai School of Medicine | And 3 more authors.
Molecular Neurodegeneration | Year: 2010

Background: Generation of the amyloid (A) peptide of Alzheimer's disease (AD) is differentially regulated through the intracellular trafficking of the amyloid precursor protein (APP) within the secretory and endocytic pathways. Protein kinase C (PKC) and rho-activated coiled-coil kinases (ROCKs) are two "third messenger" signaling molecules that control the relative utilization of these two pathways. Several members of the Vps family of receptors (Vps35, SorL1, SorCS1) play important roles in post-trans-Golgi network (TGN) sorting and generation of APP derivatives, including A at the TGN, endosome and the plasma membrane. We now report that Vps10-domain proteins are candidate substrates for PKC and/or ROCK2 and act as phospho-state-sensitive physiological effectors for post-TGN sorting of APP and its derivatives. Results: Analysis of the SorL1 cytoplasmic tail revealed multiple consensus sites for phosphorylation by protein kinases. SorL1 was subsequently identified as a phosphoprotein, based on sensitivity of its electrophoretic migration pattern to calf intestine alkaline phosphatase and on its reaction with anti-phospho-serine antibodies. Activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. ROCK2, the neuronal isoform of another protein kinase, was found to form complexes with SorL1, and both ROCK2 inhibition and ROCK2 knockdown enhanced generation of both soluble APP and A. Conclusion: These results highlight the potential importance of SorL1 in elucidating phospho-state sensitive mechanisms in the regulation of metabolism of APP and A by PKC and ROCK2. © 2010 Lane et al; licensee BioMed Central Ltd.


Wimo A.,Alzheimers Disease Research Center | Winblad B.,Alzheimers Disease Research Center | Jonsson L.,i3 Innovus
Alzheimer's and Dementia | Year: 2010

Background: The purpose of this study was to update the previous estimate of the worldwide cost of dementia in 2005 to 2009. Methods: The cost model is based on prevalence estimates, country and region-specific data on Gross Domestic Product per person and average wage, with results from previously published cost-of-illness studies in different countries. Prevalence figures are updated to 2009 and costs were adjusted to 2009 constant US dollars ($). Results: The total worldwide societal cost of dementia, based on a dementia population of 34.4 million demented persons, was estimated to $422 billion in 2009, including $142 billion for informal care (34%). Conclusions: The worldwide cost of dementia has increased by 34% (18% in fixed prices) between 2005 and 2009. © 2010.


Gil-Bea F.J.,Alzheimers Disease Research Center | Solas M.,University of Navarra | Solomon A.,Alzheimers Disease Research Center | Mugueta C.,University of Navarra | And 4 more authors.
Journal of Alzheimer's Disease | Year: 2010

Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1-42 (Aβ1-42) levels and cognitive score. Furthermore, total-tau/(Aβ1-42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1-42 ratio for early AD diagnosis in women. © 2010 - IOS Press and the authors. All rights reserved.


Knopman D.S.,Alzheimers Disease Research Center
Neurology: Clinical Practice | Year: 2012

Donepezil 10 mg/day has been a modestly successful therapeutic agent for the palliative treatment of Alzheimer disease dementia. In 2011, seeking greater efficacy and an extension of the Aricept brand, a 23-mg formulation of donepezil was introduced. A large-scale trial, organized by Eisai, the sponsor, failed to show superiority in their primary analyses of donepezil 23 mg/day in patients with moderate to severe Alzheimer disease dementia vs 10 mg, but the published report used post hoc analyses to claim "statistically significant benefits." There was greater than a 3 times higher rate of gastrointestinal side effects with 23 mg of donepezil compared to 10 mg. Thus, not only does donepezil 23 mg/day increase the likelihood of unacceptable gastrointestinal side effects, it provides no clinical benefits. Aricept 23 mg is about 10 times more costly per pill than donepezil 10 mg. Copyright © 2012 American Academy of Neurology.

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