Cerebral white matter changes : Differentiating vascular and degenerative cognitive impairment

Different types of dementia are difficult to identify in vivo, especially at early stages and partly due to the frequent co-existence of various etiologies. Recent techniques, including examination of biomarkers in cerebrospinal fluid (CSF) and advanced brain imaging techniques facilitate a more precise diagnosis of a given type of dementia. As previous diagnostic criteria for the Alzheimer type of dementia (AD) only captured the disease after dementia occured, new criteria involving recent biomarkers aim to arrive at a diagnosis at early stages, even prior to the onset of overt dementia. Along with episodic memory impairment, neuroimaging and CSF analysis have been proposed as reliable and important tools to make an accurate AD diagnosis possible, including forms of AD with co-existing cerebrovascular disease. The objective of this thesis aims to exploit the posssibilities of CSF analysis and neuroimaging in order to better understand the relationship between cerebrovascular and degenerative changes and cognition. To do so, measures of cerebral white matter changes from magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were studied in cognitively impaired patients and compared to levels of CSF biomarkers and cognition. In degenerative and vascular cognitive impairment, risk factors and pathological disease processes have been well mapped. However, it remains unclear which exact mechanisms trigger these processes and in which way white matter changes and cortical events are connected. Improved early diagnostic specificity and better knowledge of interaction between vascular and degenerative changes may give rise to specific approaches to prevention and therapy, based upon individual risk-profiles

Cerebrospinal fluid markers in Creutzfeldt-Jakob disease

<p>Abstract</p> <p>Background</p> <p>The objective was to assess the utility of total tau protein (tTau), the ratio of (tTau)/181 phosphorylated tau protein (P-Tau) and 14-3-3 protein, as diagnostic markers in cerebrospinal fluid (CSF) for Creutzfeldt-Jakob disease (CJD).</p> <p>Methods</p> <p>CSF samples received from Norwegian hospitals between August 2005 and August 2007 were retrospectively selected from consecutive patients with tTau values > 1200 ng/L (n = 38). The samples from patients clinically diagnosed with CJD (n = 12) were compared to those from patients with other degenerative neurological diseases: Alzheimer's/vascular dementia (AD/VaD, n = 21), other neurological diseases (OND, n = 5). Total Tau, P-Tau, and β-Amyloid (Aβ₄₂) were measured with commercial kits. Additionally, 14-3-3 protein was measured semi-quantitatively by immunoblot.</p> <p>Results</p> <p>The minimum cut-off limits for diagnosis of CJD were chosen from the test results. For tTau the lower limit was fixed at 3000 ng/L, for the tTau/P-Tau ratio it was 60, and for 14-3-3 protein it was 0.75 arbitrary units. For tTau and tTau/P-Tau ratio, all but three CJD patients had levels above the minimum, whereas almost all of the other patients were below. For the 14-3-3 protein, two CJD patients were below the minimum and five were above. Only one of the other patients was higher than the limit. The sensitivities, specificities and diagnostic efficiencies were: tTau 75%, 92%, and 87%; tTau/P-Tau 75%, 96%, and 89%; and 14-3-3 protein 80%, 96%, and 91%.</p> <p>Conclusion</p> <p>The results suggest that 14-3-3 protein may be the better marker for CJD, tTau/P-Tau ratio and tTau are also efficient markers, but showed slightly inferior diagnostic properties in this study, with tTau/P-Tau marginally better than tTau.</p

Impact of White Matter Lesions on Cognition in Stroke Patients Free from Pre-Stroke Cognitive Impairment: A One-Year Follow-Up Study

Background/Aim: Post-stroke cognitive impairment and dementia may be caused by pure vascular, pure degenerative or mixed disease. The relation between post-stroke cognitive impairment and the combination of vascular pathology and degenerative changes is less evaluated. We aimed to evaluate the associations between white matter lesions (WMLs) and patient performance 1 year after stroke on tests of executive functioning, memory and visuospatial function, adjusted for the effects of lifestyle and disease-related factors, including medial temporal lobe atrophy (MTLA). Methods: Patients with a first-ever stroke or transient ischemic attack were invited to participate in the study. The associations between the cognitive test performances and WMLs were studied using linear regression [Trail Making Test B (TMT B) and 10-word test] and logistic regression (Clock Drawing Test). Results: In total, 199 patients completed the follow-up. The TMT B (p = 0.029) and the 10-word test (p = 0.014) were significantly associated with WMLs; however, the Clock Drawing Test (p = 0.19) was not. The TMT B (p = 0.018) and the 10-word test (p ≤ 0.001) were both significantly associated with MTLA. Conclusion: Impaired executive functioning and memory are significantly associated with WMLs and MTLA. The mechanisms explaining post-stroke cognitive impairment are multifactorial, including different types of vascular pathology and coexisting vascular and degenerative changes

Effects of cerebrovascular disease on amyloid precursor protein metabolites in cerebrospinal fluid

Background Alzheimer's disease (AD) and cerebrovascular disease (CVD) including chronic small vessel disease of the brain (SVD) are the most frequent causes of dementia. AD is associated with metabolism of amyloid precursor protein (APP) and low levels of amyloid-β peptide (Aβ) X-42 in the cerebrospinal fluid (CSF). CVD and SVD are established risk factors for AD, brain white matter lesions (WML) are established surrogate markers for SVD and are also associated with reduced CSF AβX-42. A cohort survey was performed to examine whether SVD or acute CVD affects APP metabolism and to explore a potential association between WML and APP metabolism in two groups; cognitively impaired patients, subjective and mild (SCI and MCI) and stroke patients. Through measurements of CSF APP metabolite levels in patients with a wide range of WML volumes, this study aimed to determine how SVD influences APP metabolism. Methods Sixty-three patients were included: 37 with subjective cognitive impairment (SCI) or mild cognitive impairment (MCI) without stroke, and 26 after acute stroke. Chronic and acute WML volume and infarct volume were determined by magnetic resonance imaging (MRI) post-scan processing, and CSF levels of α- and β-cleaved soluble APP (sAPP-α and sAPP-β, AβX-38, AβX-40 and AβX-42) were determined. The Mann-Whitney test was used to compare the patient groups. Chronic and acute WML volumes, infarct volume, age, and sex were used as predictors for CSF biomarker levels in linear regression analysis. Results CSF levels of sAPP-α and sAPP-β were strongly correlated (r = 0.95, p < 0.001) and lower levels of these biomarkers were found in the stroke group than in the SCI/MCI group; median sAPP-α 499.5 vs. 698.0 ng/mL (p < 0.001), sAPP-β 258.0 vs. 329.0 ng/mL (p < 0.005). CSF levels of sAPP-α, sAPP-β, AβX-38, AβX-40 and AβX-42 were inversely correlated with chronic WML volume (p ≤ 0.005; p ≤ 0.01; p ≤ 0.01; p ≤ 0.05; p ≤ 0.05 respectively), but not with acute WML or infarct volumes. Conclusions Lower CSF levels of sAPP-α and sAPP-β in the stroke group than in the SCI/MCI group and an inverse correlation with chronic WML indicate that ischemia lowers the levels of CSF sAPP metabolites and suggests that APP axonal transport or metabolism may be affected in SVD of the brain

Effects of cerebrovascular disease on amyloid precursor protein metabolites in cerebrospinal fluid

Abstract Background Alzheimer's disease (AD) and cerebrovascular disease (CVD) including chronic small vessel disease of the brain (SVD) are the most frequent causes of dementia. AD is associated with metabolism of amyloid precursor protein (APP) and low levels of amyloid-β peptide (Aβ) X-42 in the cerebrospinal fluid (CSF). CVD and SVD are established risk factors for AD, brain white matter lesions (WML) are established surrogate markers for SVD and are also associated with reduced CSF AβX-42. A cohort survey was performed to examine whether SVD or acute CVD affects APP metabolism and to explore a potential association between WML and APP metabolism in two groups; cognitively impaired patients, subjective and mild (SCI and MCI) and stroke patients. Through measurements of CSF APP metabolite levels in patients with a wide range of WML volumes, this study aimed to determine how SVD influences APP metabolism. Methods Sixty-three patients were included: 37 with subjective cognitive impairment (SCI) or mild cognitive impairment (MCI) without stroke, and 26 after acute stroke. Chronic and acute WML volume and infarct volume were determined by magnetic resonance imaging (MRI) post-scan processing, and CSF levels of α- and β-cleaved soluble APP (sAPP-α and sAPP-β, AβX-38, AβX-40 and AβX-42) were determined. The Mann-Whitney test was used to compare the patient groups. Chronic and acute WML volumes, infarct volume, age, and sex were used as predictors for CSF biomarker levels in linear regression analysis. Results CSF levels of sAPP-α and sAPP-β were strongly correlated (r = 0.95, p p p p ≤ 0.005; p ≤ 0.01; p ≤ 0.01; p ≤ 0.05; p ≤ 0.05 respectively), but not with acute WML or infarct volumes. Conclusions Lower CSF levels of sAPP-α and sAPP-β in the stroke group than in the SCI/MCI group and an inverse correlation with chronic WML indicate that ischemia lowers the levels of CSF sAPP metabolites and suggests that APP axonal transport or metabolism may be affected in SVD of the brain.</p

Cerebral foreign body reaction after carotid aneurysm stenting

Flow diverter stents are new important tools in the treatment of large, giant, or wide-necked aneurysms. Their delivery and positioning may be difficult due to vessel tortuosity. Common adverse events include intracranial hemorrhage and ischemic stroke, which usually occurs within the same day, or the next few days after the procedure. We present a case where we encountered an unusual intracerebral complication several months after endovascular treatment of a large left internal carotid artery aneurysm, and where brain biopsy revealed foreign body reaction to hydrophilic polymer fragments distally to the stent site. Although previously described, embolization of polymer material from intravascular equipment is rare. We could not identify any other biopsy verified case in the literature, with this particular presentation of intracerebral polymer embolization – a multifocal inflammation spread out through the white matter of one hemisphere without hemorrhage or ischemic changes

Open Access

Effects of cerebrovascular disease on amyloid precursor protein metabolites in cerebrospinal flui

Altered DNA base excision repair profile in brain tissue and blood in Alzheimer’s disease

Background Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia globally. AD is associated with increased oxidative stress, resulting from imbalance in production and clearance of reactive oxygen species (ROS). ROS can damage DNA and other macromolecules, leading to genome instability and disrupted cellular functions. Base excision repair (BER) plays a major role in repairing oxidative DNA lesions. Here, we compared the expression of BER components APE1, OGG1, PARP1 and Polβ in blood and postmortem brain tissue from patients with AD, mild cognitive impairment (MCI) and healthy controls (HC). Results BER mRNA levels were correlated to clinical signs and cerebrospinal fluid biomarkers for AD. Notably, the expression of BER genes was higher in brain tissue than in blood samples. Polβ mRNA and protein levels were significantly higher in the cerebellum than in the other brain regions, more so in AD patients than in HC. Blood mRNA levels of OGG1 was low and PARP1 high in MCI and AD. Conclusions These findings reflect the oxidative stress-generating energy-consumption in the brain and the importance of BER in repairing these damage events. The data suggest that alteration in BER gene expression is an event preceding AD. The results link DNA repair in brain and blood to the etiology of AD at the molecular level and can potentially serve in establishing novel biomarkers, particularly in the AD prodromal phase