Vidar Stenset

Multimodal imaging in mild cognitive impairment: Metabolism, morphometry and diffusion of the temporal-parietal memory network.

This study compared sensitivity of FDG-PET, MR morphometry, and diffusion tensor imaging (DTI) derived fractional anisotropy (FA) measures to diagnosis and memory function in mild cognitive impairment (MCI). Patients (n=44) and normal controls (NC, n=22) underwent FDG-PET and MRI scanning yielding measures of metabolism, morphometry and FA in nine temporal and parietal areas affected by Alzheimers disease and involved in the episodic memory network. Patients also underwent memory testing (RAVLT). Logistic regression analysis yielded 100% diagnostic accuracy when all methods and ROIs were combined, but none of the variables then served as unique predictors. Within separate ROIs, diagnostic accuracy for the methods combined ranged from 65.6% (parahippocampal gyrus) to 73.4 (inferior parietal cortex). Morphometry predicted diagnostic group for most ROIs. PET and FA did not uniquely predict group, but a trend was seen for the precuneus metabolism. For the MCI group, stepwise regression analyses predicting memory scores were performed with the same methods and ROIs. Hippocampal volume and FA of the retrosplenial WM predicted learning, and hippocampal metabolism and parahippocampal cortical thickness predicted 5 minute recall. No variable predicted 30 minute recall independently of learning. In conclusion, higher diagnostic accuracy was achieved when multiple methods and ROIs were combined, but morphometry showed superior diagnostic sensitivity. Metabolism, morphometry and FA all uniquely explained memory performance, making a multi-modal approach superior. Memory variation in MCI is likely related to conversion risk, and the results indicate potential for improved predictive power by the use of multimodal imaging.

Diffusion Tensor Imaging Surpasses Cerebrospinal Fluid as Predictor of Cognitive Decline and Medial Temporal Lobe Atrophy in Subjective Cognitive Impairment and Mild Cognitive Impairment

Neuropathological correlates of Alzheimers disease (AD) emerge years before dementia. Biomarkers preceding cognitive decline and reflecting the causative processes can potentially aid early intervention and diagnosis. Diffusion tensor imaging (DTI) indirectly reflects tissue microstructure. To answer whether DTI is an early biomarker for AD and to explore the relationship between DTI and the established biomarkers of medial temporal lobe atrophy and cerebrospinal fluid (CSF) Aβ(42), T-tau, and P-tau, we longitudinally studied normal controls and patients with subjective (SCI) or mild (MCI) cognitive impairment. 21 controls and 64 SCI or MCI cases recruited from a university-hospital based memory clinic were re-examined after two to three years. FreeSurfer was used for longitudinal processing of morphometric data, and DTI derived fractional anisotropy, radial diffusivity, and mean diffusivity were analyzed in Tract-Based Spatial Statistics. Using regression models, we explored and compared the predictive powers of DTI and CSF biomarkers in regard to cognitive change and atrophy of the medial temporal lobe. Both DTI and CSF biomarkers significantly predicted cognitive decline and atrophy in the medial temporal lobe. In this population, however, DTI was a better predictor of dementia and AD-specific medial temporal lobe atrophy than the CSF biomarkers. The case for DTI as an early biomarker for AD is strengthened, but further studies are needed to confirm these results.

Morphometric Changes in the Episodic Memory Network and Tau Pathologic Features Correlate with Memory Performance in Patients with Mild Cognitive Impairment

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) may affect several cognitive domains, including attention and reasoning, but is often first characterized by memory deficits. The purpose of this study was to ask these 2 questions: 1) Can levels of CSF tau proteins and amyloid beta 42 peptide explain thinning of the cerebral cortex in patients with MCI? 2) How are brain morphometry, CSF biomarkers, and apolipoprotein E (APOE) allelic variation related to episodic memory function in MCI? MATERIALS AND METHODS: Hippocampal volume and cortical thickness were estimated by MR imaging and compared for patients with MCI (n = 18) and healthy controls (n = 18). In addition, regions of interest (ROIs) were selected in areas where the MCI group had atrophy and which overlapped with the episodic memory network (temporal, entorhinal, inferior parietal, precuneus/posterior cingulate, and frontal). Relationships among morphometry, CSF biomarkers, APOE, and memory were tested. The analyses were repeated with an independent sample of patients with MCI (n = 19). RESULTS: Patients with MCI and pathologic CSF values had hippocampal atrophy. However, both patients with pathologic and patients with nonpathologic CSF had a thinner cortex outside the hippocampal area. CSF pathology was related to hippocampal volume, whereas relationships with cortical thickness were found mainly in one of the samples. Morphometry correlated robustly with memory performance across MCI samples, whereas less stable results were found for tau protein. CONCLUSION: The differences in hippocampal volume between the MCI and the healthy control groups were only found in patients with pathologic CSF biomarkers, whereas differences in cortical thickness were also found for patients without such pathologic features. Morphometry in areas in the episodic memory network was robustly correlated with memory performance. It is speculated that atrophy in these areas may be associated with the memory problems seen in MCI.

Cingulum fiber diffusivity and CSF T-tau in patients with subjective and mild cognitive impairment

Diffusion tensor imaging (DTI) and CSF biomarkers are useful diagnostic tools to differentiate patients with mild cognitive impairment (MCI) from normal controls, and may help predict conversion to dementia. Total Tau protein (T-tau) and DTI parameters are both markers for axonal damage, thus it is of interest to determine if DTI parameters are associated with elevated CSF T-tau levels in patients with cognitive impairment. For this purpose, patients with subjective cognitive impairment (SCI) and MCI were recruited from a university based memory clinic. Regions of interest were used to determine fractional anisotropy (FA), radial diffusivity (DR) and axial diffusivity (DA) in known white matter tracts in patients with MCI (n=39) and SCI (n=8) and 26 cognitively healthy controls. Significant lower FA and higher DR values were observed in patients with pathological vs. patients with normal CSF T-tau levels and vs. controls in left posterior cingulum fibers. T-tau values were negatively correlated with FA and positively correlated with DR values in the posterior cingulum fibers. Cingulum fiber diffusivity was related to T-tau pathology in SCI/MCI patients and altered DR may suggest that loss of myelin contributes to early white matter changes in patients at risk of developing Alzheimers disease (AD).

White matter imaging changes in subjective and mild cognitive impairment

To determine whether white matter (WM) memory network changes accompany early cognitive impairment and whether these changes represent early, pathologically independent axonal affection, we combined WM diffusion tensor imaging and cortical morphometric measurements of normal control subjects, patients with only subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).

Cerebrospinal fluid markers in Creutzfeldt-Jakob disease

BackgroundThe 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).MethodsCSF 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: Alzheimers/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.ResultsThe 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%.ConclusionThe 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.

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

BackgroundAlzheimers 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.MethodsSixty-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.ResultsCSF 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.ConclusionsLower 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.

White Matter Lesion Subtypes and Cognitive Deficits in Patients with Memory Impairment

Aim: To analyze the relationship between periventricular (PV) and subcortical (SC) white matter lesions (WML) and cognitive function in patients with memory impairment. Methods: In total, 253 patients with Global Deterioration Scale scores ≧3 who had been referred to a university-based memory unit due to memory complaints were included (mean age 69.7 years, 124 females). Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and the Neurobehavioral Cognitive Status Examination (Cognistat), and full test results were available for 217 patients. PV and SC WML loads (semi-quantitative rating on axial T2-weighted MRI scans) were used in linear regression as predictors of cognition. Results: MMSE was significantly correlated with SC WML (p = 0.005), but not with PV WML (p = 0.19). Cognistat tests for orientation, comprehension, visuoconstruction, calculation, similarities, and judgment were negatively correlated with SC WML (p < 0.01), as was verbal memory with parieto-occipital SC WML (p < 0.05). Visuoconstruction and calculation were negatively correlated with PV WML (p < 0.05). Parieto-occipital WML were more strongly related to cognition than fronto-temporal WML. Only SC WML were significantly correlated with cognition when PV and SC WML were entered simultaneously in the regression model. Conclusion: In patients with cognitive impairment, SC WML, in particular in parieto-occipital regions, were associated with reduced cognitive function.

Mild Cognitive Impairment: Cerebrospinal Fluid Tau Biomarker Pathologic Levels and Longitudinal Changes in White Matter Integrity

PURPOSE To evaluate the relationship between (a) pathologic levels of cerebrospinal fluid (CSF) total tau as an index of the intensity of ongoing neuronal degeneration and (b) longitudinal changes in white matter (WM) integrity in patients with mild cognitive impairment (MCI). MATERIALS AND METHODS Participants gave written informed consent, and the Norwegian committee for medical research ethics approved the study. Thirty patients with MCI and nonpathologic CSF total tau levels, nine patients with MCI and pathologic CSF total tau levels, and 16 age-matched healthy control subjects underwent diffusion-tensor imaging at baseline and after a mean follow-up of 2.6 years ± 0.54 (standard deviation), with range of 1.58-3.98 years. The effect of diagnosis (MCI vs no MCI) at baseline and CSF tau levels at fractional anisotropy (FA), mean diffusivity, radial diffusivity (D(R)), and axial diffusivity were tested with tract-based spatial statistics. Differences in WM integrity at baseline and follow-up and change over time were compared among patients with pathologic CSF total tau levels (MCI high tau), patients with normal CSF total tau levels (MCI low tau), and healthy control subjects. Linear mixed-model between-group within-subject analyses were conducted to examine differences in rate of change over time in FA and D(R). RESULTS Longitudinal analysis of regional WM change revealed significant decrease in FA (P = .038) and increase in D(R) (P = .018) in the MCI high-tau group relative to control subjects. For D(R), the changes were regionally specific to the right cingulum and the right superior and inferior longitudinal fasciculi. CONCLUSION Reduction in WM integrity was greater in patients with MCI who had the most intense neuronal degeneration as indexed by using CSF total tau, suggesting that these patients might represent a subgroup of MCI with more intense WM degeneration who are possibly at greater risk of developing Alzheimer disease.

Diaschisis after thalamic stroke: a comparison of metabolic and structural changes in a patient with amnesic syndrome.

Introduction–  We present a patient with a left anteromedial thalamic lesion with an amnesic syndrome. The patient underwent neuropsychological testing, cerebrospinal fluid (CSF) analyses, magnetic resonance imaging (MRI) [T2, flair, and diffusion tensor imaging (DTI)] and [18F]‐2‐fluoro‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) to assess indirect effects of thalamic lesions on cortical function.