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Effect of physical exercise on markers of neuronal dysfunction in cerebrospinal fluid in patients with Alzheimer's disease.

ABSTRACT: INTRODUCTION:Physical exercise has gained increasing focus as a potential mean to maintain cognitive function in patients with Alzheimer's disease (AD). Alongside the markers of specific AD pathology (amyloid ? and tau), other pathologies such as neuronal damage and synaptic loss have been proposed as markers of the disease. Here, we study the effect of physical exercise on biomarkers of neuronal and synaptic integrity. METHODS:Cerebrospinal fluid (CSF) from 51 AD subjects who participated in the randomized controlled trial Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) was analyzed for the concentration of neurofilament light (NFL), neurogranin (Ng), visinin-like protein-1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Participants were subjected to either 16 weeks of moderate- to high-intensity exercise (n = 25) or treatment as usual (control group, n = 26), and CSF was collected before and after intervention. RESULTS:No significant differences in CSF concentrations of VILIP-1, YKL-40, NFL, and Ng were observed when comparing mean change from baseline between the exercise and control groups. Similarly, when classifying subjects based on their exercise levels, no significant changes were observed for the biomarkers in the control group compared with the high-exercise group (attending 80% of the exercise sessions with an intensity of 70% of maximum heart rate or above). DISCUSSION:These results are not supportive of a modulatory effect of physical exercise on the selected biomarkers of neuronal and synaptic integrity in patients with AD.

SUBMITTER: Jensen CS

PROVIDER: S-EPMC5651430 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Effect of physical exercise on markers of neuronal dysfunction in cerebrospinal fluid in patients with Alzheimer's disease.

Jensen Camilla Steen CS Portelius Erik E Høgh Peter P Wermuth Lene L Blennow Kaj K Zetterberg Henrik H Hasselbalch Steen Gregers SG Simonsen Anja Hviid AH

Alzheimer's & dementia (New York, N. Y.) 20170417 2

<h4>Introduction</h4>Physical exercise has gained increasing focus as a potential mean to maintain cognitive function in patients with Alzheimer's disease (AD). Alongside the markers of specific AD pathology (amyloid β and tau), other pathologies such as neuronal damage and synaptic loss have been proposed as markers of the disease. Here, we study the effect of physical exercise on biomarkers of neuronal and synaptic integrity.<h4>Methods</h4>Cerebrospinal fluid (CSF) from 51 AD subjects who par ...[more]

PMID: 29067334

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Project description:BACKGROUND:Neuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer's disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD. METHODS:From a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time. RESULTS:Cerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories. CONCLUSIONS:Basic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability.

Project description:A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsynytenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages (n = 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold (p < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, p = 0.04) in an independent cohort (n = 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8-fold, p < 0.04), a finding that was replicated (0.7 to 0.8-fold, p < 0.05) for 6 proteins in a third cohort (n = 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold (p < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD.

Project description:Lobar cerebral microbleeds (CMBs) in Alzheimer's disease (AD) are associated with cerebral amyloid angiopathy (CAA) due to vascular amyloid beta (Aβ) deposits. However, the relationship between lobar CMBs and clinical subtypes of AD remains unknown. Here, we enrolled patients with early- and late-onset amnestic dominant AD, logopenic variant of primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA) who were compatible with the AD criteria. We then examined the levels of cerebrospinal fluid (CSF) biomarkers [Aβ1-42, Aβ1-40, Aβ1-38, phosphorylated tau 181 (P-Tau), total tau (T-Tau), neurofilament light chain (NFL), and chitinase 3-like 1 protein (YKL-40)], analyzed the number and localization of CMBs, and measured the cerebral blood flow (CBF) volume by 99mTc-ethyl cysteinate dimer single photon emission computerized tomography (99mTc ECD-SPECT), as well as the mean cortical standard uptake value ratio by 11C-labeled Pittsburgh Compound B-positron emission tomography (11C PiB-PET). Lobar CMBs in lvPPA were distributed in the temporal, frontal, and parietal lobes with the left side predominance, while the CBF volume in lvPPA significantly decreased in the left temporal area, where the number of lobar CMBs and the CBF volumes showed a significant inversely correlation. The CSF levels of NFL in lvPPA were significantly higher compared to the other AD subtypes and non-demented subjects. The numbers of lobar CMBs significantly increased the CSF levels of NFL in the total AD patients, additionally, among AD subtypes, the CSF levels of NFL in lvPPA predominantly were higher by increasing number of lobar CMBs. On the other hand, the CSF levels of Aβ1-38, Aβ1-40, Aβ1-42, P-Tau, and T-Tau were lower by increasing number of lobar CMBs in the total AD patients. These findings may suggest that aberrant brain hypoperfusion in lvPPA was derived from the brain atrophy due to neurodegeneration, and possibly may involve the aberrant microcirculation causing by lobar CMBs and cerebrovascular injuries, with the left side dominance, consequently leading to a clinical phenotype of logopenic variant.

Dataset Information

Effect of physical exercise on markers of neuronal dysfunction in cerebrospinal fluid in patients with Alzheimer's disease.

Publications

Effect of physical exercise on markers of neuronal dysfunction in cerebrospinal fluid in patients with Alzheimer's disease.

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