Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies.

OBJECTIVES: We explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE). METHODS: Serum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuronal cell lines. Treatment effects were studied in 86 patients with lupus under belimumab therapy. RESULTS: We found a close correlation between the titre of anti-NR2 antibodies, the severity of fatigue, the clinical disease activity index (Systemic Lupus Erythematosus Disease Activity Index 2000) and anti-double stranded DNA antibodies-independently of the presence of neuropsychiatric lupus manifestations. Pathogenic effects could be demonstrated by (1) detection of anti-NR2 antibodies in the cerebrospinal fluid, (2) in situ binding of anti-NR2 antibodies to NMDAR of the hippocampus area and (3) distinct functional effects in vitro: downregulating the energy metabolism of neuronal cells without enhanced cytotoxicity. Treatment with belimumab for at least 6 months affected both the severity of fatigue and the levels of anti-NR2 antibodies. CONCLUSION: The presence of anti-NR2 antibodies in patients with SLE with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with SLE.

Structural integrity of the corpus callosum predicts long-term transfer of fluid intelligence-related training gains in normal aging.

Although cognitive training usually improves cognitive test performance, the capability to transfer these training gains into respective or functionally related cognitive domains varies significantly. Since most studies demonstrate rather limited transfer effects in older adults, aging might be an important factor in transfer capability differences. This study investigated the transfer capability of logical reasoning training gains to a measure of Fluid Intelligence (Gf) in relation to age, general intelligence, and brain structural integrity as measured by diffusion tensor imaging. In a group of 41 highly educated healthy elderly, 71% demonstrated successful transfer immediately after a 4-week training session (i.e. short-term transfer). In a subgroup of 22% of subjects transfer maintained over a 3-month follow-up period (i.e. long-term transfer). While short-term transfer was not related to structural integrity, long-term transfer was associated with increased structural integrity in corpus and genu of the corpus callosum. Since callosal structural integrity was also related to age (in the present and foregoing studies), previously observed associations between age and transfer might be moderated by the structural integrity. Surprisingly, age was not directly associated with transfer in this study which could be explained by the multi-dependency of the structural integrity (modulating factors beside age, e.g. genetics). In this highly educated sample, general intelligence was not related to transfer suggesting that high intelligence is not sufficient for transfer in normal aging. Further studies are needed to reveal the interaction of transfer, age, and structural integrity and delineate mechanisms of age-dependent transfer capabilities.

Quality of life in dementia: impact of cognition and insight on applicability of the SF-36.

OBJECTIVES: Comparability of measures of quality of life in dementia and in other diagnostic groups, such as mild cognitive impairment, normal aging, or other diseases, is highly desirable. However, the impact of cognitive deficits and impaired insight on applicability and validity of generic instruments is sparsely studied. PARTICIPANTS AND MEASUREMENTS: Sixty patients with dementia [38 women; age: mean (SD) = 78.7 (6.4) years; Mini-Mental State Examination (MMSE): mean (SD) = 20.2 (6.0)] recruited as part of the start-modem study, a multicenter care research study in Germany, completed the generic instrument SF-36 and the specific instrument Quality of Life-Alzheimer's Disease (QOL-AD). RESULTS: QOL-AD self-rating scores [mean (SD) = 32.8 (5.9)] and SF-36 subscales indicated moderate to good quality of life in the total group. Reliability and validity of five subdomains of the SF-36 were poor in subgroups of patients with impaired insight or with MMSE scores less than 17 (Cronbach's α <0.7, no significant correlation to the QOL-AD). In contrast, for patients with both adequate insight and MMSE score greater than 16 (n = 33; 55%) Cronbach's α of the subdomains of the SF-36 ranged between 0.920 and 0.676. Seven of the eight subdomains correlated significantly with the QOL-AD self-rating and composite score in this group of patients (0.355 ≤ r ≤ 0.709). CONCLUSIONS: Despite the impact of insight and cognition on self-rated quality of life, we found reliable and valid data for a broad spectrum of patients with dementia. According to the present data, the SF-36 is suitable for dementia patients with both insight into their deficits and an MMSE score greater than 16.

Automated tractography of the cingulate bundle in Alzheimer's disease: a multicenter DTI study.

PURPOSE: To evaluate the feasibility of multicenter tractography of the cingulate bundle (CB) in Alzheimer's disease (AD). MATERIALS AND METHODS: Automated deterministic tractography of the CB was applied to scans of 45 patients with probable AD and 58 healthy controls (HC) acquired with Siemens Sonata (1.5T; 60 gradients), Trio (3T; 61 gradients), and Avanto (1.5T; 30 gradients). Diagnosis and center effects on the tracking indices fractional anisotropy (FA), mean diffusivity (MD), track density, and volume were estimated with analysis of variance. RESULTS: The multicenter coefficients of variance (CVs) in HC and AD patients were 7% and 7% for FA, 10% and 8% for MD, 18% and 20% for density, and 21% and 21% for volume. Multicenter and single-center CVs were within a similar range. Significant center effects declined in the order MD > FA > density > volume. After adjustment for center and age, the AD group showed significantly higher MD (P < 0.001) and lower FA (P < 0.05) as compared with the HC group. CONCLUSION: Despite strong center effects, we detected significantly altered microstructural integrity of the CB in AD patients. Diffusion-tensor imaging indices of the CB as obtained by automated tractography might qualify as a biologically sustained surrogate marker for diagnostic and monitoring purposes in multicenter AD trials.

State dependent posterior hippocampal volume increases in patients with major depressive disorder.

BACKGROUND: The hippocampal formation has been implicated in etiology and therapy response in major depressive disorder (MDD). However, prospective longitudinal studies investigating volumes in hippocampal subregions and their association with clinical findings are still lacking. METHODS: Global and regional hippocampal volumes and neuropsychological performance were assessed longitudinally in 15 young patients with unipolar early onset MDD who responded to therapy and 13 matched healthy control subjects. RESULTS: Although volumes at baseline did not differ between groups, patients with MDD showed significant posterior hippocampal volume increases during the treatment course (mean observation period 161.4 ± 58.6 days). Posterior hippocampal volume increases were seen in every single patient. The detected posterior hippocampal volume increases were significantly correlated with the number of solved problems in a planning task at baseline. LIMITATIONS: The study is limited by the small sample size. Moreover, future studies should include patients who do not respond to antidepressant treatment. CONCLUSION: Patients with MDD showed selective increases in posterior hippocampal volumes which were not correlated to the degree of functional restitution. However, posterior hippocampal volume increases might constitute a surrogate parameter of neuroplasticity taking place during antidepressant therapy which might be predicted by executive functioning at baseline.

Functional implications of hippocampal degeneration in early Alzheimer's disease: a combined DTI and PET study.

PURPOSE: Hypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer's disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippocampal formation. Here, we explored the association between microstructural alterations within the hippocampus and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment. METHODS: Twenty patients with early AD (Mini-Mental State Examination 25.7 ± 1.7) were studied with [(18)F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippocampus, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test for unique contributions of diffusivity and metabolic indices in the prediction of memory function. RESULTS: Diffusivity in the left anterior hippocampus negatively correlated with FDG uptake primarily in the left anterior hippocampus, parahippocampal gyrus and the PCC (p < 0.005). The same correlation pattern was found for right hippocampal diffusivity (p < 0.05). In linear regression analysis, left anterior hippocampal diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippocampal diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD. CONCLUSION: These findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippocampal output pathways as a significant contributor to the genesis of episodic memory impairment.

Relationships between hippocampal microstructure, metabolism, and function in early Alzheimer's disease.

Abnormal microstructural integrity and glucose metabolism of the hippocampus are common in subjects with Alzheimer's disease (AD) that typically manifest as episodic memory impairment. The above-tissue alterations can be captured in vivo using diffusion tensor imaging (DTI) and positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET). Here, we explored relationships between the above neuroimaging and cognitive markers of early AD-specific hippocampal damage. Twenty patients with early AD (MMSE 25.7 ± 1.7) were studied using DTI and FDG-PET. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). In the between-modality correlation analysis, FDG uptake was strongly associated with diffusivity in the left anterior hippocampus only (r = -0.81, p < 0.05 Bonferroni's corrected for multiple tests). Performance on DVR significantly correlated with left anterior (r = -0.80, p < 0.05) and left mean (r = -0.72, p < 0.05) hippocampal diffusivity, while the correlation with left anterior FDG uptake did not reach statistical significance (r = 0.52, n.s.). DTI-derived diffusivity of the anterior hippocampus might be a sensitive early marker of hippocampal dysfunction as reflected at the synaptic and cognitive levels. This neurobiological distinction of the anterior hippocampus might be related to the disruption of the perforant pathway that is known to occur early in the course of AD.

Increased hippocampal head diffusivity predicts impaired episodic memory performance in early Alzheimer's disease.

Recent neuroanatomical and functional neuroimaging studies indicate that the anterior part of the hippocampus, rather than the whole structure, may be specifically involved in episodic memory. In the present work, we examined whether anterior structural measurements are superior to other regional or global measurements in mapping functionally relevant degenerative alterations of the hippocampus in Alzheimer's disease (AD). Twenty patients with early AD (MMSE 25.7+/-1.7) and 18 healthy controls were studied using magnetic resonance and diffusion-tensor imaging. Using a regions-of-interest analysis, we obtained volumetric and diffusivity measures of the hippocampal head and body-tail-section as well as of the whole hippocampus. Detailed cognitive evaluation was based on the CERAD battery. All volumetric measures as well as diffusivity of the hippocampus head were significantly (p<0.01) altered in patients as compared to controls. In patients, increased left head diffusivity significantly (p<0.01) correlated with performance on free delayed verbal recall test (DVR) (r=-0.74, p=0.0002) and with the CERAD global score. Reduced volume of the left body-tail was also associated with performance on DVR (r=0.62, p=0.004). Stepwise regression analyses revealed that increased left head diffusivity was the only predictor for performance on DVR (R(2)=52%, p<0.0005). These findings suggest that anterior hippocampus diffusivity is more closely related to verbal episodic memory impairment than other regional or global structural measures. Our data support the hypothesis of functional differentiation in general and the specific role of the anterior hippocampus in episodic memory in particular. Diffusivity measurements might be highly sensitive to functionally relevant degenerative alterations of the hippocampus.

Functional relevant loss of long association fibre tracts integrity in early Alzheimer's disease.

The aim of our study was to quantify the structural integrity of the long association fibre tracts in early Alzheimer's disease (AD) and to correlate the findings with the cognitive performance of the patients. We conducted region-of-interest-based analyses of color-coded diffusion-tensor imaging in 12 patients with early AD (age 69.8+/-8.0 years; MMSE 25.3+/-1.8) and 16 age- and education-matched healthy controls. Early AD patients showed significantly decreased fractional anisotropy (FA) of the cingulate bundles and the inferior fronto-occipital fascicles bilaterally, whereas FA values of the superior longitudinal fascicles (second division) did not differ significantly between patients and controls. Neuropsychological performance of patients in the verbal episodic memory test domain correlated significantly with disturbances of left cingulate fibre tract integrity. Reduced left cingulate bundle integrity was most strongly correlated with impaired performance in a verbal recognition task (Spearman's rho=0.81, P=0.001). Moreover, Boston naming test performance also correlated with the left cingulate bundle integrity (Spearman's rho=0.71, P=0.009). These findings suggest substantial disturbances of the structural connectivity within long association fibre tracts, especially the cingulate bundles and the inferior fronto-occipital fascicles, in early AD and highlight the important role of the cingulate bundles in verbal recognition.

Quantification of brain tissue alterations in Fabry disease using diffusion-tensor imaging.

UNLABELLED: Central nervous system involvement is a major burden in Fabry disease. Conventional cranial magnetic resonance imaging (MRI) shows micro- and macroangiopathic changes such as severe and progressive white matter lesions (WMLs) at an early age on T2- and fluid-attenuated inversion recovery-weighted images, increased signal intensity in the pulvinar on T1-weighted MRI, as well as tortuosity and dilatation of the larger vessels (dolicho-ectasia). Using diffusion tensor imaging (DTI), a new structural MRI-technique that measures water diffusion characteristics, we showed marked brain tissue alterations in Fabry disease predominantly in the periventricular white matter. Even patients with few WMLs had significantly elevated brain tissue diffusivity. CONCLUSION: DTI is more sensitive in detecting brain tissue changes in Fabry disease than conventional MRI. DTI measurements could provide appropriate surrogate parameters with which to monitor the natural history of structural brain involvement and potential effects of therapy (such as enzyme replacement) in Fabry disease.