| 1. |
- Brodaty, Henry, et al.
(författare)
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The World of Dementia Beyond 2020
- 2011
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Ingår i: Journal of The American Geriatrics Society. - : Wiley. - 0002-8614 .- 1532-5415. ; 59:5, s. 923-927
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Tidskriftsartikel (refereegranskat)abstract
- Counterpoised against dire projections of the tripling of the prevalence of dementia over the next 40 years are major developments in diagnostic biomarkers, neuroimaging, the molecular biology of Alzheimer's disease (AD), epidemiology of risk and protective factors, and drug treatments—mainly targeting the amyloid pathway, tau protein, and immunotherapy—that may have the potential to modify the progression of AD. Drug combinations and presymptomatic treatments are also being investigated. Previous trials of dementia-modifying drugs have not shown benefit, and even if current Phase III trials prove successful, these drugs will not eradicate other dementias, could (if not curative) increase dementia duration and prevalence, and are unlikely to come onto the market before 2020. In the meantime, delaying the onset of dementia by even 2 years would have significant economic and societal effects. This article provides an overview of current achievements and potentials of basic and clinical research that might affect the development of dementia prevalence and care within the near future.
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| 2. |
- Damian, Marinella, et al.
(författare)
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Single-Domain Amnestic Mild Cognitive Impairment Identified by Cluster Analysis Predicts Alzheimer's Disease in the European Prospective DESCRIPA Study
- 2013
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 36:1-2, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). Methods: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e. g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE >= 28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. Results: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (A beta(42), t-tau, APOE epsilon 4, and medial temporal atrophy), compared to SCI or naMCI. Conclusion: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings. Copyright (C) 2013 S. Karger AG, Basel
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| 3. |
- Hooshmand, Babak, et al.
(författare)
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Plasma homocysteine, Alzheimer and cerebrovascular pathology : a population-based autopsy study
- 2013
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 136, s. 2707-2716
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Tidskriftsartikel (refereegranskat)abstract
- Elevated plasma total homocysteine is associated with increased risk of dementia/Alzheimer's disease, but underlying pathophysiological mechanisms are not fully understood. This study investigated possible links between baseline homocysteine, and post-mortem neuropathological and magnetic resonance imaging findings up to 10 years later in the Vantaa 85+ population including people aged epsilon 85 years. Two hundred and sixty-five individuals had homocysteine and autopsy data, of which 103 had post-mortem brain magnetic resonance imaging scans. Methenamine silver staining was used for amyloid-beta and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, cerebral amyoloid angiopathy, and alpha-synuclein pathology. Magnetic resonance imaging was used for visual ratings of the degree of medial temporal lobe atrophy, and periventricular and deep white matter hyperintensities. Elevated baseline homocysteine was associated with increased neurofibrillary tangles count at the time of death: for the highest homocysteine quartile, odds ratio (95% confidence interval) was 2.60 (1.28-5.28). The association was observed particularly in people with dementia, in the presence of cerebral infarcts, and with longer time between the baseline homocysteine assessment and death. Also, elevated homocysteine tended to relate to amyloid-beta accumulation, but this was seen only with longer baseline-death interval: odds ratio (95% confidence interval) was 2.52 (0.88-7.19) for the highest homocysteine quartile. On post-mortem magnetic resonance imaging, for the highest homocysteine quartile odds ratio (95% confidence interval) was 3.78 (1.12-12.79) for more severe medial temporal atrophy and 4.69 (1.14-19.33) for more severe periventricular white matter hyperintensities. All associations were independent of several potential confounders, including common vascular risk factors. No relationships between homocysteine and cerebral macro- or microinfarcts, cerebral amyoloid angiopathy or alpha-synuclein pathology were detected. These results suggest that elevated homocysteine in adults aged epsilon 85 years may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology. Randomized controlled trials are needed to determine the impact of homocysteine-lowering treatments on dementia-related pathology.
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| 4. |
- Kivipelto, Miia, et al.
(författare)
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World-Wide FINGERS Network : A global approach to risk reduction and prevention of dementia
- 2020
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:7, s. 1078-1094
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Tidskriftsartikel (refereegranskat)abstract
- Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
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| 5. |
- Le Guen, Yann, et al.
(författare)
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Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
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Tidskriftsartikel (refereegranskat)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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