| 1. |
- Besga, A., et al.
(författare)
-
Differences in brain cholesterol metabolism and insulin in two subgroups of patients with different CSF biomarkers but similar white matter lesions suggest different pathogenic mechanisms
- 2012
-
Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 510:2, s. 121-126
-
Tidskriftsartikel (refereegranskat)abstract
- Investigate possible associations of white matter hyperintensities (WMHs) with the metabolism of cholesterol and insulin in two subgroups of patients with memory complaints and different CSF A beta 42 and CSF tau levels. 59 patients from the memory clinic at Karolinska Hospital were included. Degree of WMHs was rated using the ARWMC scale and the following biomarkers were measured in CSF and plasma: insulin, cholesterol, lanosterol, lathosterol, and oxidized cholesterol metabolites. The WMHs in CSF control-like group correlated with increased brain cholesterol synthesis and reduced efflux of oxysterols and insulin in CSF. In the CSF AD-like group, the WMHs correlated with increased peripheral cholesterol metabolism. Despite having similar appearance on FLAIR images, the pathogenic mechanisms of WMHS are likely to be different in the two groups investigated.
|
|
| 2. |
- Caracciolo, B, et al.
(författare)
-
The symptom of low mood in the prodromal stage of mild cognitive impairment and dementia : a cohort study of a community dwelling elderly population
- 2011
-
Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 82:7, s. 788-793
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate the symptom of low mood as a predictor of mild cognitive impairment (MCI) and its progression to dementia, taking into account: (i) MCI severity, (ii) time of assessment and (iii) interaction with other factors.Methods 764 cognitively healthy elderly subjects living in the community, from the Kungsholmen Project. Participants were assessed by direct interview to detect low mood. Subjects were then followed for 6 years to identify those who developed MCI. People with incident MCI were followed for a further 3 years to assess progression to dementia.Results People with low mood at baseline had a 2.7-fold (95% CI 1.9 to 3.7) increased risk of developing MCI at follow-up. The association was stronger for amnestic MCI (aMCI: HR 5.8; 95% CI 3.1 to 10.9) compared with global cognitive impairment (other cognitive impairment no dementia, oCIND: HR 2.2; 95% CI 1.5 to 3.3). ApoE-ε4 interacted with low mood in a synergistic fashion, increasing the risk of aMCI, while no interaction with psychiatric, vascular, frailty related or psychosocial factors was observed. Low mood at baseline, as opposed to low mood co-occurring with MCI, was associated with a 5.3-fold (95% CI 1.2 to 23.3) increased risk of progression to dementia in aMCI. In contrast, no association was found in oCIND.Conclusion Low mood was more strongly associated with aMCI than with global cognitive impairment. Progression towards dementia was predicted only by low mood manifest in the prodromal stage of MCI. These findings indicate that low mood is particularly prominent in the very early stages of cognitive decline.
|
|
| 3. |
- Enache, D., et al.
(författare)
-
Antidepressants and mortality risk in a dementia cohort : data from SveDem, the Swedish Dementia Registry
- 2016
-
Ingår i: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 134:5, s. 430-440
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The association between mortality risk and use of antidepressants in people with dementia is unknown. Objective: To describe the use of antidepressants in people with different dementia diagnoses and to explore mortality risk associated with use of antidepressants 3 years before a dementia diagnosis. Methods: Study population included 20 050 memory clinic patients from the Swedish Dementia Registry (SveDem) diagnosed with incident dementia. Data on antidepressants dispensed at the time of dementia diagnosis and during 3-year period before dementia diagnosis were obtained from the Swedish Prescribed Drug Register. Cox regression models were used. Results: During a median follow-up of 2 years from dementia diagnosis, 25.8% of dementia patients died. A quarter (25.0%) of patients were on antidepressants at the time of dementia diagnosis, while 21.6% used antidepressants at some point during a 3-year period before a dementia diagnosis. Use of antidepressant treatment for 3 consecutive years before a dementia diagnosis was associated with a lower mortality risk for all dementia disorders and in Alzheimer's disease. Conclusion: Antidepressant treatment is common among patients with dementia. Use of antidepressants during prodromal stages may reduce mortality in dementia and specifically in Alzheimer's disease.
|
|
| 4. |
- Hooshmand, Babak, et al.
(författare)
-
Homocysteine and holotranscobalamin and the risk of Alzheimer disease : a longitudinal study
- 2010
-
Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 75:16, s. 1408-1414
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the relation between serum levels of homocysteine (tHcy) and holotranscobalamin (holoTC), the active fraction of vitamin B12, and risk of incident Alzheimer disease (AD) in a sample of Finnish community-dwelling elderly. METHODS: A dementia-free sample of 271 subjects aged 65-79 years derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study was followed up for 7 years to detect incident AD. The association between serum tHcy and holoTC with AD was analyzed with multiple logistic regression after adjusting for several potential confounders, including common vascular risk factors. RESULTS: The odds ratios (ORs) (95% confidence interval [CI]) for AD were 1.16 (1.04-1.31) per increase of 1 μmol/L of tHcy at baseline and 0.980 (0.965-0.995) for each increase of 1 pmol/L baseline holoTC. Adjustment for several potential confounders including age, sex, education, APOE ε4 allele, body mass index, Mini-Mental State Examination, smoking, stroke, and blood pressure did not alter the associations: ORs (95% CI) for AD became 1.19 (1.01-1.39) for tHcy and 0.977 (0.958-0.997) for holoTC. Adjusting for holoTC attenuated the tHcy-AD link (OR changed from 1.16 to 1.10, 95% CI 0.96-1.25). The holoTC-AD relationship was less influenced by controlling for tHcy (OR changed from 0.980 to 0.984, 95% CI 0.968-1.000). Addition of folate did not change any of the results. CONCLUSIONS: This study suggests that both tHcy and holoTC may be involved in the development of AD. The tHcy-AD link may be partly explained by serum holoTC. The role of holoTC in AD should be further investigated.
|
|
| 5. |
- Iacono, D., et al.
(författare)
-
Neuropathologic Assessment of Dementia Markers in Identical and Fraternal Twins
- 2014
-
Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 24:4, s. 317-333
-
Tidskriftsartikel (refereegranskat)abstract
- Twin studies are an incomparable source of investigation to shed light on genetic and non-genetic components of neurodegenerative diseases, as Alzheimer's disease (AD). Detailed clinicopathologic correlations using twin longitudinal data and post-mortem examinations are mostly missing. We describe clinical and pathologic findings of seven monozygotic (MZ) and dizygotic (DZ) twin pairs. Our findings show good agreement between clinical and pathologic diagnoses in the majority of the twin pairs, with greater neuropathologic concordance in MZ than DZ twins. Greater neuropathologic concordance was found for -amyloid than tau pathology within the pairs. ApoE4 was associated with higher -amyloid and earlier dementia onset, and importantly, higher frequency of other co-occurring brain pathologies, regardless of the zygosity. Dementia onset, dementia duration, difference between twins in age at dementia onset and at death, did not correlate with AD pathology. These clinicopathologic correlations of older identical and fraternal twins support the relevance of genetic factors in AD, but not their sufficiency to determine the pathology, and consequently the disease, even in monozygotic twins. It is the interaction among genetic and non-genetic risks which plays a major role in influencing, or probably determining, the degeneration of those brain circuits associated with pathology and cognitive deficits in AD.
|
|
| 6. |
|
|
| 7. |
- Kramberger, Milica Gregoric, et al.
(författare)
-
Association between EEG abnormalities and CSF biomarkers in a memory clinic cohort
- 2013
-
Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger. - 1420-8008 .- 1421-9824. ; 36:5-6, s. 319-328
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of the study was to describe distinct electroencephalogram (EEG) phenotypes defined after routine visual EEG analysis in a large memory clinic cohort and to investigate their relationship to cerebrospinal fluid (CSF) biomarkers. Methods: Patients with Alzheimer's disease (n = 131), mild cognitive impairment (n = 285), subjective cognitive impairment (n = 310), and mixed dementia (n = 29) were assessed clinically with neuroimaging, EEG and CSF investigations. EEG phenotypes were based on frequency of background activity (BA) and presence and degree of episodic abnormalities (EA). Results: BA and EA differed significantly (p < 0.001) between diagnostic groups. A lower CSF amyloid β42/phospho-tau ratio and higher total tau were associated with slower BA (p < 0.01) and a higher degree of EA (p < 0.04). Conclusions: Slowing of BA in combination with EA seems to be related to biological markers of neurodegeneration
|
|
| 8. |
- Olomon, A. S., et al.
(författare)
-
Serum total cholesterol, statins and cognition in non-demented elderly
- 2009
-
Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 30:6, s. 1006-1009
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The association between serum total cholesterol (TC), lipid-lowering drugs and cognition in the elderly is currently controversial. Objective: To investigate the relationship between TC, lipid-lowering drugs and cognitive functions in non-demented elderly. Design and Setting: Participants of the Cardiovascular risk factors, aging and dementia (CAIDE) study were derived from random, population-based samples previously studied in 1972, 1977, 1982 or 1987. Analyses are based on 1382 non-demented participants re-examined in 1998 after an average follow-up of 21 years. Results: High midlife TC was associated with poorer late-life episodic memory and category fluency. TC decreased in most individuals over time. A more pronounced decrease was related to poorer late-life episodic memory and psychomotor speed, but not if subjects used statins. Conclusions: The TC-cognition relationship seems bidirectional. High midlife TC is associated with poorer late-life cognition, but decreasing TC after midlife may reflect poorer cognitive status. Statins may be beneficial for cognition in non-demented elderly.
|
|
| 9. |
- Schneider, L. S., et al.
(författare)
-
Clinical trials and late-stage drug development for Alzheimer's disease : an appraisal from 1984 to 2014
- 2014
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 275:3, s. 251-283
-
Tidskriftsartikel (refereegranskat)abstract
- The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.
|
|
| 10. |
- Solomon, A., et al.
(författare)
-
Serum cholesterol changes after midlife and late-life cognition : Twenty-one-year follow-up study
- 2007
-
Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 68:10, s. 751-756
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Longitudinal studies have shown that high serum total cholesterol (TC) at midlife is a risk factor for dementia/Alzheimer disease. The significance of TC later in life is unclear. Objective: To investigate changes in serum TC from midlife to late life and their relationship with late-life cognition. Methods: Participants of the Cardiovascular Risk Factors, Aging and Dementia study were derived from random, population-based samples previously studied in a survey in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1,449 individuals aged 65 to 79 were reexamined in 1998. Results: Serum TC levels decreased in most individuals. High midlife TC represented a risk factor for more severe cognitive impairment later in life, and the values were significantly different between the control, mild cognitive impairment, and dementia groups. There were no significant differences in serum TC at reexamination. A moderate decrease in serum TC from midlife to late life (0.5 to 2 mmol/L) was significantly associated with the risk of a more impaired late-life cognitive status, even after adjusting for age, follow-up time, sex, years of formal education, midlife cholesterol, changes in body mass index, APOE epsilon 4 genotype, history of myocardial infarction/stroke/diabetes, and lipid-lowering treatment. Conclusions: The relationship between serum total cholesterol (TC) and dementia seems to be bidirectional. High midlife serum TC is a risk factor for subsequent dementia/Alzheimer disease, but decreasing serum TC after midlife may reflect ongoing disease processes and may represent a risk marker for late-life cognitive impairment.
|
|
