| 31. |
- Höglund, Kina, 1976, et al.
(författare)
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Effect of statins on beta-amyloid metabolism in humans: potential importance for the development of senile plaques in Alzheimer's disease.
- 2006
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Ingår i: Acta neurologica Scandinavica. Supplementum. - : Hindawi Limited. - 0065-1427 .- 0001-6314 .- 1600-0404. ; 185, s. 87-92
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Tidskriftsartikel (refereegranskat)abstract
- According to the amyloid cascade hypothesis, both familial and sporadic Alzheimer's disease (AD) is caused by the toxic effect of over-production and/or aggregation of beta-amyloid (Abeta). Recent cell and animal studies have linked the production of Abeta to high levels of cholesterol and the use of statins, compounds inhibiting the de novo synthesis of cholesterol. Epidemiological studies have also supported such linkage by showing a reduced prevalence of AD for subjects taking statins. A limited number of clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in AD in humans and this review focuses on the current state of these clinical studies. The results are contradictory, but the overall interpretation suggests that statin treatment probably does not have a direct impact through lowering of cholesterol on the APP processing and Abeta production in humans. To confirm this, further clinical studies needs to be performed with extended treatment periods and where several parameters (lipid profile, lipoproteins, sterols, biomarkers related to AD and APP metabolites) are analyzed, both in the cerebrospinal fluid and plasma. The pleiotropic effects of statins should be investigated further. One approach is presented in this review.
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| 32. |
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| 33. |
- Höglund, Kina, 1976, et al.
(författare)
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The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer's disease
- 2005
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 19:5-6, s. 256-265
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Tidskriftsartikel (refereegranskat)abstract
- During the last years, several clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in Alzheimer’s disease (AD) in humans. We present an open biochemical study where 19 patients with AD have been treated with simvastatin (20 mg/day) for 12 months. The aim was to further investigate the effect of simvastatin treatment on cerebrospinal fluid (CSF) biomarkers of APP processing, AD biomarkers as total tau and tau phosphorylated at threonine 181, brain cholesterol metabolism as well as on cognitive decline in patients with AD. Despite biochemical data suggesting that treatment with 20 mg/day of simvastatin for 12 months does affect the brain cholesterol metabolism, we did not find any change in CSF or plasma levels of β-amyloid (Aβ)<sub>1–42</sub>. However, by analysis of APP isoforms, we found that statin treatment may favor the nonamyloidogenic pathway of APP processing. The relevance and mechanism between statin treatment and AD has to be further elucidated by using statins of different lipophility in different dosages over a longer period of time.
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| 34. |
- Jansen, Willemijn J, et al.
(författare)
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
- 2018
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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| 35. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
- 2015
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Ingår i: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 313:19, s. 1924-38
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.
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| 36. |
- Jeppsson, Anna, et al.
(författare)
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Shared CSF Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus and Subcortical Small Vessel Disease.
- 2022
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Ingår i: Frontiers in neurology. - : Frontiers Media SA. - 1664-2295. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we examine similarities and differences between 52 patients with idiopathic normal pressure hydrocephalus (iNPH) and 17 patients with subcortical small vessel disease (SSVD), in comparison to 28 healthy controls (HCs) by a panel of cerebrospinal fluid (CSF) biomarkers.We analyzed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ isoforms -38, -40, and -42, neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), matrix metalloproteinases (MMP -1, -2, -3, -9, and -10), and tissue inhibitors of metalloproteinase 1 (TIMP1). Radiological signs of white matter damage were scored using the age-related white matter changes (ARWMC) scale.All amyloid fragments were reduced in iNPH and SSVD (p < 0.05), although more in iNPH than in SSVD in comparison to HC. iNPH and SSVD showed comparable elevations of NFL, MBP, and GFAP (p < 0.05). MMPs were similar in all three groups except for MMP-10, which was increased in iNPH and SSVD. Patients with iNPH had larger ventricles and fewer WMCs than patients with SSVD.The results indicate that patients with iNPH and SSVD share common features of subcortical neuronal degeneration, demyelination, and astroglial response. The reduction in all APP-derived proteins characterizing iNPH patients is also present, indicating that SSVD encompasses similar pathophysiological phenomena as iNPH.
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| 37. |
- Jiang, Hong, et al.
(författare)
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Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease.
- 2011
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: We recently reported that expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer's disease (AD). Moreover, we also found that, in an Alzheimer's mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.
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| 38. |
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| 39. |
- Johansson, Per, 1966, et al.
(författare)
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Cerebrospinal fluid substance P concentrations are elevated in patients with Alzheimer's disease.
- 2015
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Ingår i: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 609, s. 58-62
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Tidskriftsartikel (refereegranskat)abstract
- The neuropeptides substance P, orexin A (hypocretin-1) and neurotensin are signaling molecules that influence brain activity. We examined their cerebrospinal fluid (CSF) levels in a study population consisting of Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n=32), stable MCI (SMCI, n=13), other dementias (n=15), and healthy controls (n=20). CSF substance P level was increased in AD patients compared to patients with other dementias and healthy controls (P<0.05 and P<0.01, respectively). Patients with other dementia or SMCI had lower CSF orexin A level than AD patients (both P<0.05) and marginally lower level than healthy controls (both P=0.05). CSF neurotensin level was similar in all groups. In the total study population (n=80), CSF substance P level correlated positively with CSF levels of T-tau and P-tau, and in AD patients (n=32), CSF substance P level correlated positively with CSF Aβ1-42 level. In conclusion, CSF substance P level was elevated in AD patients and correlated with CSF Aβ1-42 level, a well established marker of senile plaque pathology. The role of low CSF orexin A level in other dementias or SMCI needs to be explored in further studies.
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| 40. |
- Johansson, Per, 1966, et al.
(författare)
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Mild dementia is associated with increased adrenal secretion of cortisol and precursor sex steroids in women.
- 2011
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Ingår i: Clinical endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 75:3, s. 301-308
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Tidskriftsartikel (refereegranskat)abstract
- Context Sex steroid levels decrease with increasing age, but little is known whether this is of importance for the age-related decline in cognitive function. Design and patients A cross-sectional study of 50 (26 men) consecutive patients under primary evaluation of cognitive impairment (D group) and 18 (9 men) matched healthy controls (C group). Measurements Sex steroid and precursor levels were determined in serum and, when measurable, in cerebrospinal fluid (CSF) using gas chromatography/mass spectroscopy (GC-MS) or liquid chromatography/mass spectroscopy (LC-MS). Sex hormone binding globulin (SHBG) and cortisol concentrations were measured using conventional assays. Results Patients in the D group had higher 24-h urine cortisol levels and increased serum levels of dehydroepiandrosterone (DHEA) and its sulphate ester dihydroepiandrosterone sulphate (DHEAS), androsterone (ADT), and oestrone (E1) and its sulphate ester E1S, compared with the controls. When men and women were analysed separately, increased serum concentrations of E1 and E1S were observed in both D men and D women, whereas increased levels of other sex steroids and cortisol were seen only in D women. Conclusions In both D men and women, serum E1 and E1S levels were increased, whereas other changes were gender specific and only seen in D women. Further studies are needed to determine whether these changes are a cause of, or merely a consequence of, cognitive impairment in elderly subjects.
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