| 51. |
- Forsell, Charlotte, et al.
(författare)
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Genetic association to the amyloid plaque associated protein gene COL25A1 in Alzheimer's disease
- 2010
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Ingår i: Neurobiology of Aging. - Fayetteville, N.Y. : Ankho International. - 0197-4580 .- 1558-1497. ; 31:3, s. 409-415
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Tidskriftsartikel (refereegranskat)abstract
- The COL25A1 gene, located in 4q25, encodes the CLAC protein, which has been implicated in Alzheimer's disease (AD) pathogenesis. CLAC was originally identified in amyloid preparations from AD brain and has been shown to be associated with amyloid plaques, inhibition of Abeta-fibril elongation and increased protease resistance of Abeta-fibrils through direct binding to Abeta. These biochemical data as well as the genomic location of the COL25A1 gene in chromosome 4q25 where we previously have reported a weak linkage-signal in Swedish AD families encouraged us to perform a case-control association study of two LD blocks in COL25A1 using 817 AD cases and 364 controls. The LD blocks cover a putative Abeta-binding motif and the variable 3' end of the gene. The analyses indicated association to three of eight analysed SNPs. We found further support for the association by replication in a Swedish population-based longitudinal sample set (n=926). Thus, in addition to the biochemical data, there is now genetic evidence of association between COL25A1 and risk for Alzheimer's disease.
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| 52. |
- Fratiglioni, Laura, et al.
(författare)
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Prevention of Alzheimer's disease and dementia : Major findings from the Kungsholmen Project
- 2007
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Ingår i: Physiology and Behavior. - : Elsevier. - 0031-9384 .- 1873-507X. ; 92:1-2, s. 98-104
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Tidskriftsartikel (refereegranskat)abstract
- The aging of the population is a worldwide phenomenon, and studying age-related diseases has become a relevant issue from both a scientific and a public health perspective. This review summarises the major findings concerning prevention of Alzheimer's disease (AD) and other dementias from a population-based study, the Kungsholmen Project. The study addresses risk- and protective factors for AD and dementia from a lifetime perspective: at birth, during childhood, in adult life, and in old age. Although many aspects of the dementias are still unclear, some risk factors have been identified and interesting hypotheses have been suggested for other putative risk or protective factors. At the moment it is also possible to delineate some preventative strategies for dementia.
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| 53. |
- Fratiglioni, Laura, et al.
(författare)
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Åldrandets epidemiologi med fokus på fysisk och mental funktionsförmåga
- 2001
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Ingår i: Läkartidningen. - Stockholm : Sveriges läkarförbund. - 0023-7205 .- 1652-7518. ; 98:6, s. 552-558
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Tidskriftsartikel (refereegranskat)abstract
- In the past decades, the »graying« of the population has emerged as a world-wide phenomenon, leading to an increased interest in research on aging. Many population-based studies have been initiated in several countries, such as the Kungsholmen Project in Stockholm, Sweden. These studies have shown that older adults can be recruited to participate in intensive physiological and clinical evaluations, and that longitudinal surveys are well accepted by the elderly. Comorbidity and physical and mental functioning have emerged as important variables for describing health status and identifying risk factors. Dementia arose as one of the most common diseases in the very old, as dementia prevalence nearly doubles every fifth year. Some risk factors for Alzheimer’s disease have been identified and interesting working hypotheses have been suggested. The natural history of the dementias have been sufficiently outlined for allocating medical and social resources, and for counseling patients and relatives.
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| 54. |
- Frisoni, Giovanni B, et al.
(författare)
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The pilot European Alzheimer's Disease Neuroimaging Initiative of the European Alzheimer's Disease Consortium.
- 2008
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 4:4, s. 255-64
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In North America, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has established a platform to track the brain changes of Alzheimer's disease. A pilot study has been carried out in Europe to test the feasibility of the adoption of the ADNI platform (pilot E-ADNI). METHODS: Seven academic sites of the European Alzheimer's Disease Consortium (EADC) enrolled 19 patients with mild cognitive impairment (MCI), 22 with AD, and 18 older healthy persons by using the ADNI clinical and neuropsychological battery. ADNI compliant magnetic resonance imaging (MRI) scans, cerebrospinal fluid, and blood samples were shipped to central repositories. Medial temporal atrophy (MTA) and white matter hyperintensities (WMH) were assessed by a single rater by using visual rating scales. RESULTS: Recruitment rate was 3.5 subjects per month per site. The cognitive, behavioral, and neuropsychological features of the European subjects were very similar to their U.S. counterparts. Three-dimensional T1-weighted MRI sequences were successfully performed on all subjects, and cerebrospinal fluid samples were obtained from 77%, 68%, and 83% of AD patients, MCI patients, and controls, respectively. Mean MTA score showed a significant increase from controls (left, right: 0.4, 0.3) to MCI patients (0.9, 0.8) to AD patients (2.3, 2.0), whereas mean WMH score did not differ among the three diagnostic groups (between 0.7 and 0.9). The distribution of both MRI markers was comparable to matched US-ADNI subjects. CONCLUSIONS: Academic EADC centers can adopt the ADNI platform to enroll MCI and AD patients and older controls with global cognitive and structural imaging features remarkably similar to those of the US-ADNI.
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| 55. |
- Frykman, Susanne, et al.
(författare)
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Synaptic and Endosomal Localization of Active gamma-Secretase in Rat Brain
- 2010
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:1, s. e8948-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundA key player in the development of Alzheimer's disease (AD) is the gamma-secretase complex consisting of at least four components: presenilin, nicastrin, Aph-1 and Pen-2. gamma-Secretase is crucial for the generation of the neurotoxic amyloid beta-peptide (A beta) but also takes part in the processing of many other substrates. In cell lines, active gamma-secretase has been found to localize primarily to the Golgi apparatus, endosomes and plasma membranes. However, no thorough studies have been performed to show the subcellular localization of the active gamma-secretase in the affected organ of AD, namely the brain.Principal FindingsWe show by subcellular fractionation of rat brain that high gamma-secretase activity, as assessed by production of A beta 40, is present in an endosome-and plasma membrane-enriched fraction of an iodixanol gradient. We also prepared crude synaptic vesicles as well as synaptic membranes and both fractions showed high A beta 40 production and contained high amounts of the gamma-secretase components. Further purification of the synaptic vesicles verified the presence of the gamma-secretase components in these compartments. The localization of an active gamma-secretase in synapses and endosomes was confirmed in rat brain sections and neuronal cultures by using a biotinylated gamma-secretase inhibitor together with confocal microscopy.SignificanceThe information about the subcellular localization of gamma-secretase in brain is important for the understanding of the molecular mechanisms of AD. Furthermore, the identified fractions can be used as sources for highly active gamma-secretase.
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| 56. |
- Gao, Yang, et al.
(författare)
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Live Cell FRET Imaging Reveals Amyloid beta-Peptide Oligomerization in Hippocampal Neurons
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:9
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta-peptide (A beta) oligomerization is believed to contribute to the neuronal dysfunction in Alzheimer disease (AD). Despite decades of research, many details of A beta oligomerization in neurons still need to be revealed. Forster resonance energy transfer (FRET) is a simple but effective way to study molecular interactions. Here, we used a confocal microscope with a sensitive Airyscan detector for FRET detection. By live cell FRET imaging, we detected A beta 42 oligomerization in primary neurons. The neurons were incubated with fluorescently labeled A beta 42 in the cell culture medium for 24 h. A beta 42 were internalized and oligomerized in the lysosomes/late endosomes in a concentration-dependent manner. Both the cellular uptake and intracellular oligomerization of A beta 42 were significantly higher than for A beta 40. These findings provide a better understanding of A beta 42 oligomerization in neurons.
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| 57. |
- Garcia-Ptacek, Sara, et al.
(författare)
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Subjective cognitive impairment subjects in our clinical practice
- 2014
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Ingår i: Dementia and Geriatric Cognitive Disorders Extra. - : S. Karger AG. - 1664-5464. ; 4:3, s. 419-430
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:The clinical challenge in subjective cognitive impairment (SCI) is to identify which individuals will present cognitive decline. We created a statistical model to determine which variables contribute to SCI and mild cognitive impairment (MCI) versus Alzheimer's disease (AD) diagnoses.METHODS:A total of 993 subjects diagnosed at a memory clinic (2007-2009) were included retrospectively: 433 with SCI, 373 with MCI and 187 with AD. Descriptive statistics were provided. A logistic regression model analyzed the likelihood of SCI and MCI patients being diagnosed with AD, using age, gender, Mini-Mental State Examination score, the ratio of β-amyloid 42 divided by total tau, and phosphorylated tau as independent variables.RESULTS:The SCI subjects were younger (57.8 ± 8 years) than the MCI (64.2 ± 10.6 years) and AD subjects (70.1 ± 9.7 years). They were more educated, had less medial temporal lobe atrophy (MTA) and frequently normal cerebrospinal fluid biomarkers. Apolipoprotein E4/E4 homozygotes and apolipoprotein E3/E4 heterozygotes were significantly less frequent in the SCI group (6 and 36%) than in the AD group (28 and 51%). Within the regression model, cardiovascular risk factors, confluent white matter lesions, MTA and central atrophy increased the AD likelihood for SCI subjects.CONCLUSIONS:SCI patients form a distinct group. In our model, factors suggesting cardiovascular risk, MTA and central atrophy increased the AD likelihood for SCI subjects.
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| 58. |
- George, Sonia, et al.
(författare)
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Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer's disease.
- 2014
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- The progressive development of Alzheimer's disease (AD) pathology follows a spatiotemporal pattern in the human brain. In a transgenic (Tg) mouse model of AD expressing amyloid precursor protein (APP) with the arctic (E693G) mutation, pathology spreads along anatomically connected structures. Amyloid-β (Aβ) pathology first appears in the subiculum and is later detected in interconnected brain regions, including the retrosplenial cortex. We investigated whether the spatiotemporal pattern of Aβ pathology in the Tg APP arctic mice to interconnected brain structures can be interrupted by destroying neurons using a neurotoxin and thereby disconnecting the neural circuitry.
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| 59. |
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| 60. |
- Gil-Bea, Francisco J, et al.
(författare)
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Insulin levels are decreased in the cerebrospinal fluid of women with prodomal Alzheimer's disease
- 2010
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Ingår i: Journal of Alzheimer's Disease. - Amsterdam; Washington : IOS Press. - 1387-2877 .- 1875-8908. ; 22:2, s. 405-413
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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