| 1. |
- Eriksdotter-Jönhagen, Maria, et al.
(author)
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Encapsulated cell biodelivery of nerve growth factor to the Basal forebrain in patients with Alzheimer's disease.
- 2012
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In: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 33:1, s. 18-28
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Journal article (peer-reviewed)abstract
- Degeneration of cholinergic neurons in the basal forebrain correlates with cognitive decline in patients with Alzheimer's disease (AD). Targeted delivery of exogenous nerve growth factor (NGF) has emerged as a potential AD therapy due to its regenerative effects on the basal forebrain cholinergic neurons in AD animal models. Here we report the results of a first-in-man study of encapsulated cell (EC) biodelivery of NGF to the basal forebrain of AD patients with the primary objective to explore safety and tolerability.
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| 2. |
- Blom, Elin S., et al.
(author)
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Rapid progression from mild cognitive impairment to Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE epsilon4/epsilon4 genotype.
- 2009
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In: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 27:5, s. 458-64
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Journal article (peer-reviewed)abstract
- BACKGROUND/AIMS: Increased cerebrospinal fluid (CSF) tau, decreased CSF amyloid-beta42 (Abeta42) and the apolipoprotein E gene (APOE) epsilon4 allele predict progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Here, we investigated these markers to assess their predictive value and influence on the rate of disease progression. METHODS: Using ELISA, we measured the CSF biomarkers in 47 AD patients, 58 patients with MCI and 35 healthy control subjects. Twenty-eight MCI patients revisited the clinic and half of them progressed to AD during a period of 3-12 years. RESULTS: The expected changes in CSF total (T)-tau, phosphorylated (P)-tau and Abeta42 levels were found in AD, confirming the diagnostic value of these biomarkers. We were also able to corroborate an increased risk for progression from MCI to AD with elevated CSF T-tau and P-tau and with the presence of the APOE epsilon4/epsilon4 genotype, but not with decreased Abeta42. Finally, for the first time we demonstrated that MCI subjects with high CSF T-tau or P-tau and APOE epsilon4 homozygosity progressed faster from MCI to AD. CONCLUSIONS: CSF T-tau and P-tau as well as the APOE epsilon4/epsilon4 genotype are robust predictors of AD and are also associated with a more rapid progression from MCI to AD.
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| 3. |
- Ferreira, Daniel, et al.
(author)
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Brain changes in Alzheimer's disease patients with implanted encapsulated cells releasing nerve growth factor
- 2015
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 43, s. 1059-1072
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Journal article (peer-reviewed)abstract
- © 2015-IOS Press and the authors. New therapies with disease-modifying effects are urgently needed for treating Alzheimer's disease (AD). Nerve growth factor (NGF) protein has demonstrated regenerative and neuroprotective effects on basal forebrain cholinergic neurons in animal studies. In addition, AD patients treated with NGF have previously shown improved cognition, EEG activity, nicotinic binding, and glucose metabolism. However, no study to date has analyzed brain atrophy in patients treated with NGF producing cells. In this study we present MRI results of the first clinical trial in patients with AD using encapsulated NGF biodelivery to the basal forebrain. Six AD patients received the treatment during twelve months. Patients were grouped as responders and non-responders according to their twelve-months change in MMSE. Normative values were created from 131 AD patients from ADNI, selecting 36 age-and MMSE-matched patients for interpreting the longitudinal changes in MMSE and brain atrophy. Results at baseline indicated that responders showed better clinical status and less pathological levels of cerebrospinal fluid (CSF) Aβ1-42. However, they showed more brain atrophy, and neuronal degeneration as evidenced by higher CSF levels of T-tau and neurofilaments. At follow-up, responders showed less brain shrinkage and better progression in the clinical variables and CSF biomarkers. Noteworthy, two responders showed less brain shrinkage than the normative ADNI group. These results together with previous evidence supports the idea that encapsulated biodelivery of NGF might have the potential to become a new treatment strategy for AD with both symptomatic and disease-modifying effects.
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| 4. |
- Karami, Azadeh, et al.
(author)
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Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease
- 2015
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:11, s. 1316-1328
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Journal article (peer-reviewed)abstract
- Introduction: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase. Method: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed. Results: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-beta, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures. Discussion: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.
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| 5. |
- Skillbäck, Tobias, et al.
(author)
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Sex differences in CSF biomarkers for neurodegeneration and blood-brain barrier integrity.
- 2021
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In: Alzheimer's & dementia. - : Wiley. - 2352-8729. ; 13:1
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Journal article (peer-reviewed)abstract
- As cerebrospinal fluid (CSF) neurofilament light protein (NfL) and the CSF/serum albumin ratio (QAlb) are used in the clinical routine, the impact of demographic factors on these biomarkers is important to understand.Participants were derived from two Swedish samples: the population-based H70 Study (n = 308, age 70) and a clinical routine cohort (CSF NfL, n = 8995, QAlb, n = 39252, age 0 to 95). In the population-based study, QAlb and NfL were examined in relation to sex, cardiovascular risk factors, and cerebral white matter lesions (WMLs). In the clinical cohort, QAlb and NfL sex differences were tested in relation to age.Men had higher QAlb and NfL concentrations and had higher QAlb and NfL concentrations from adolescence throughout life. NfL was not related to WML, but QAlb correlated positively with WMLs.The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.
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| 6. |
- Zetterberg, Henrik, 1973, et al.
(author)
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Neurochemical aftermath of amateur boxing
- 2006
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In: ARCHIVES OF NEUROLOGY. - : American Medical Association (AMA). - 0003-9942. ; 63:9, s. 1277-1280
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Journal article (peer-reviewed)
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| 7. |
- Johansson, Annica, 1969, et al.
(author)
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Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease
- 2005
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In: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 20:6, s. 367-374
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Journal article (peer-reviewed)abstract
- We have recently reported that a polymorphism in the cell division cycle <i>(CDC2) </i>gene, designated Ex6 + 7I/D, is associated with Alzheimer’s disease (AD). The <i>CDC2</i> gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, <i>CDC2 </i>is a promising candidate susceptibility gene for AD. We investigated the possible effects of the <i>CDC2</i> polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. <i>CDC2</i> genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and β-amyloid<sub>(1–42)</sub> in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The <i>CDC2</i> Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F<sub>2, 626</sub> = 7.0, p = 0.001) and the homozygous <i>CDC2</i> Ex6 + 7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13–2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD.
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| 8. |
- Leoni, Valerio, et al.
(author)
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Diagnostic Power of 24S-Hydroxycholesterol in Cerebrospinal Fluid: Candidate Marker of Brain Health
- 2013
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 36:4, s. 739-747
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Journal article (peer-reviewed)abstract
- We evaluated the diagnostic potential of 24S-hydroxycholesterol (24OHC) in cerebrospinal fluid. At a memory clinic, we investigated subjects with subjective cognitive impairment (SCI, n = 33), mild cognitive impairment (MCI) patients (n = 27), MCI patients with later progression into Alzheimer dementia at follow up (n = 10), and patients with AD (n = 24). We also had a control group of healthy volunteers who did not later develop cognitive problems (n = 13). The fraction of the population with pathological levels of 24OHC was 8% in controls, 34% in SCI, 37% in MCI, 80% in MCI with progression, and 42% in AD. The corresponding fractions for T-tau, P-tau, and A beta(42) were lower in the case of SCI and MCI but higher in the case of controls and AD. In case of MCI with progression, the fraction of pathological levels of 24OHC and A beta(42) were 80% and 63% respectively. We also studied a population of old healthy subjects age 75-99 years (n = 25). The fraction of individuals in this population with pathological levels of 24OHC was 0% whereas the fraction of individuals with pathological level of at least one of the other three biomarkers was 40%. The diagnostic power of 24OHC in cerebrospinal fluid seems to be similar to or lower than that of the established biomarkers T-tau, P-tau, and A beta(42) in the diagnosis of established AD. Our data suggest that 24OHC may be more sensitive than the classical biomarkers in an early phase of the neurodegenerative process and a better marker for "brain health" in old age.
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| 9. |
- Li, Xiaozhen, et al.
(author)
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The Effects of Gene Mutations on Default Mode Network in Familial Alzheimer’s Disease
- 2017
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 56:1, s. 327-334
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Journal article (peer-reviewed)abstract
- Familial Alzheimer’s disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel’s time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.
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| 10. |
- Buerger, Katharina, et al.
(author)
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Validation of Alzheimer's disease CSF and plasma biological markers: the multicentre reliability study of the pilot European Alzheimer's Disease Neuroimaging Initiative (E-ADNI).
- 2009
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In: Experimental gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 44:9, s. 579-85
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Journal article (peer-reviewed)abstract
- BACKGROUND: Alzheimer's Disease Neuroimaging Initiatives ("ADNI") aim to validate neuroimaging and biochemical markers of Alzheimer's disease (AD). Data of the pilot European-ADNI (E-ADNI) biological marker programme of cerebrospinal fluid (CSF) and plasma candidate biomarkers are reported. METHODS: Six academic EADC centres recruited 49 subjects (healthy controls, subjects with mild cognitive impairment (MCI) and AD). We measured CSF beta-amyloid 42 (CSF Abeta42), total tau-protein (t-tau), phosphorylated tau-proteins (P-tau181, P-tau231), plasma beta-amyloid 40 and 42 (Abeta40/Abeta42). Immediate fresh shipment was compared to freezing and later shipment on dry ice. RESULTS: CSF T-tau (fresh samples) was increased in AD versus controls (p=0.049), CSF Abeta42 (frozen samples) was decreased in MCI and AD (p=0.02), as well as plasma Abeta40 (fresh and frozen samples) in AD (p=0.049 and p=0.016). Pooled values of neurochemical parameters and ratios thereof were different between centres (p<0.005). Analysis of frozen samples yielded higher diagnostic accuracy than immediate fresh shipment with 100% (fresh: 100%) correctly classified in control subjects, 100% (78%) in MCI, 91% (91%) in AD. CONCLUSION: The use of frozen rather than fresh samples renders higher diagnostic accuracy within a multicentre context. We confirmed the feasibility of a multicentre AD biomarker programme for future clinical trials.
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