Minocycline for sporadic and hereditary cerebral amyloid angiopathy (BATMAN): study protocol for a placebo-controlled randomized double-blind trial.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients. METHODS: The BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics. DISCUSSION: The results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT05680389. Registered on January 11, 2023.

Cerebellar hemorrhages in patients with Dutch-type hereditary cerebral amyloid angiopathy.

BACKGROUND: Recent studies suggest that superficially located cerebellar intracerebral hemorrhage (ICH) and microbleeds might point towards sporadic cerebral amyloid angiopathy (CAA). AIMS: We investigated the proportion of cerebellar ICH and asymptomatic macro- and microbleeds in Dutch-type hereditary CAA (D-CAA), a severe and essentially pure form of CAA. METHODS: Symptomatic patients with D-CAA (defined as ≥1 symptomatic ICH) and presymptomatic D-CAA mutation-carriers were included. We assessed magnetic resonance imaging scans for symptomatic (cerebellar) ICH and asymptomatic cerebellar macro- and microbleeds according to the STRIVE-criteria. Location was assessed as superficial-cerebellar (cortex, vermis or juxta-cortical) or deep-cerebellar (white matter, pedunculi cerebelli and gray nuclei). RESULTS: We included 63 participants (mean age 58 years, 60% women, 42 symptomatic). In total, the 42 symptomatic patients with D-CAA had 107 symptomatic ICH (range 1-7). None of these ICH were located in the cerebellum. Six of 42 (14%, 95%CI 4-25%) symptomatic patients and none of the 21 (0%, 95%CI 0-0%) presymptomatic carriers had ≥ 1 asymptomatic cerebellar macrobleed(s). All macrobleeds were superficially located. Cerebellar microbleeds were found in 40 of 63 (64%, 95%CI 52-76) participants (median 1.0, range 0-159), 81% in symptomatic patients and 29% in presymptomatic carriers. All microbleeds were strictly or predominantly superficially (ratio superficial versus deep 15:1) located. CONCLUSIONS: Superficially located asymptomatic cerebellar macrobleeds and microbleeds are common in D-CAA. Cerebellar microbleeds are already present in the presymptomatic stage. Despite the high frequency of cerebellar micro and macrobleeds, CAA pathology did not result in symptomatic cerebellar ICH in patients with D-CAA.

Neuroimaging Findings in Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations is caused by TREX1 mutations. High-quality systematic follow-up neuroimaging findings have not been described in presymptomatic and symptomatic mutation carriers. We present MR imaging findings of 29 TREX1 mutation carriers (20-65 years of age) and follow-up of 17 mutation carriers (30-65 years of age). Mutation carriers younger than 40 years of age showed a notable number of punctate white matter lesions, but scan findings were generally unremarkable. From 40 years of age onward, supratentorial lesions developed with long-term contrast enhancement (median, 24 months) and diffusion restriction (median, 8 months). In these lesions, central susceptibility artifacts developed, at least partly corresponding to calcifications on available CT scans. Some lesions (n = 2) additionally showed surrounding edema and mass effect (pseudotumors). Cerebellar punctate enhancing lesions developed mainly in individuals older than 50 years of age. These typical neuroimaging findings should aid neuroradiologic recognition of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, which may enable early treatment of manifestations of the disease.

Striped occipital cortex and intragyral hemorrhage: Novel magnetic resonance imaging markers for cerebral amyloid angiopathy.

BACKGROUND AND AIM: To investigate whether a striped occipital cortex and intragyral hemorrhage, two markers recently detected on ultra-high-field 7-tesla-magnetic resonance imaging in hereditary cerebral amyloid angiopathy (CAA), also occur in sporadic CAA (sCAA) or non-sCAA intracerebral hemorrhage (ICH). METHODS: We performed 7-tesla-magnetic resonance imaging in patients with probable sCAA and patients with non-sCAA-ICH. Striped occipital cortex (linear hypointense stripes perpendicular to the cortex) and intragyral hemorrhage (hemorrhage restricted to the juxtacortical white matter of one gyrus) were scored on T2*-weighted magnetic resonance imaging. We assessed the association between the markers, other CAA-magnetic resonance imaging markers and clinical features. RESULTS: We included 33 patients with sCAA (median age 70 years) and 29 patients with non-sCAA-ICH (median age 58 years). Striped occipital cortex was detected in one (3%) patient with severe sCAA. Five intragyral hemorrhages were found in four (12%) sCAA patients. The markers were absent in the non-sCAA-ICH group. Patients with intragyral hemorrhages had more lobar ICHs (median count 6.5 vs. 1.0), lobar microbleeds (median count >50 vs. 15), and lower median cognitive scores (Mini Mental State Exam: 20 vs. 28, Montreal Cognitive Assessment: 18 vs. 24) compared with patients with sCAA without intragyral hemorrhage. In 12 (36%) patients, sCAA diagnosis was changed to mixed-type small vessel disease due to deep bleeds previously unobserved on lower field-magnetic resonance imaging. CONCLUSION: Whereas a striped occipital cortex is rare in sCAA, 12% of patients with sCAA have intragyral hemorrhages. Intragyral hemorrhages seem to be related to advanced disease and their absence in patients with non-sCAA-ICH could suggest specificity for CAA.

Are serum autoantibodies associated with brain changes in systemic lupus erythematosus? MRI data from the Leiden NP-SLE cohort.

OBJECTIVE: The effect of serum autoantibodies on the brain of systemic lupus erythematosus (SLE) patients remains unclear. We investigated whether serum autoantibodies, individually and assessed in groups, are associated with specific brain-MRI abnormalities or whether these structural changes are associated with other SLE-related or traditional cardiovascular disease risk factors. METHODS: All patients underwent brain 3Tesla-MRI. White matter hyperintensities (WMHs), ischemic lesions, inflammatory-like lesions and cerebral atrophy were scored. Serum autoantibodies analyzed included lupus anticoagulant (LAC), anticardiolipine (aCL) IgG and IgM (first 3 also grouped into antiphospholipid autoantibodies (aPL)), anti-dsDNA, anti-SSA, anti-SSB, anti-RNP, and anti-Sm (the latter 5 grouped into SLE-related autoantibodies). Associations were assessed using logistic regression analysis adjusted for potential confounders. Furthermore, a sensitivity analysis including anti-Beta2 glycoprotein-1 antibodies (anti-ß2GP1) in the aPL group was performed and the potential modification role of the neuropsychiatric clinical status in the model was assessed. RESULTS: 325 patients (mean age 42 years (SD 14), 89% female) were included. The following MRI-brain abnormalities were found: WMHs (71%), lacunar infarcts (21%), gliosis (11%), micro-hemorrhages (5%), large hemorrhages (2%), inflammatory-like lesions (6%) and atrophy (14%). No associations were found between individual or total SLE-related autoantibodies and inflammatory-like lesions. A higher number of positive aPL was associated with lacunar infarcts (OR 1.37 (95%CI 1.02-1.99) and gliosis (OR 2.15 (1.37-3.37)). LAC was associated with lacunar infarcts in white matter (OR 3.38 (1.32-8.68)) and atrophy (OR 2.49 (1.01-6.15)), and aCL IgG with gliosis (OR 2.71 (1.05-7.02)). Among other variables, SLE patients with hypertension presented a higher chance for WMHs (OR 5.61 (2.52-12.48)) and lacunar infarcts in WM (OR 2.52 (1.10-5.74)) and basal ganglia (OR 8.34 (2.19-31.70)), while cumulative SLE-damage was correlated with lacunar infarcts in WM (OR 1.43 (1.07-1.90)), basal ganglia (OR 1.72 (1.18-2.51)) and cerebellum (OR 1.79 (1.33-2.41)). These associations were confirmed in the sensitivity analysis. CONCLUSIONS: Brain abnormalities in SLE represent different underlying pathogenic mechanisms. aPL are associated with ischemic brain changes in SLE, while the presence of SLE-related serum autoantibodies is not related to inflammatory-like lesions. Hypertension and cumulative SLE-damage associate with ischemic MRI-brain changes in SLE, suggesting the importance of accelerated atherosclerosis in this process.

Outcomes of neuropsychiatric events in systemic lupus erythematosus based on clinical phenotypes; prospective data from the Leiden NP SLE cohort.

Objective The objective of this study was to assess whether clinical and patient's reported outcomes are associated with a different pathophysiological origin of neuropsychiatric events presenting in systemic lupus erythematosus. Methods A total of 232 neuropsychiatric events presenting in 131 systemic lupus erythematosus patients were included. Neuropsychiatric systemic lupus erythematosus diagnosis was established per event by multidisciplinary evaluation. All neuropsychiatric events were divided according to a suspected underlying pathophysiological process into one of the following: non-neuropsychiatric systemic lupus erythematosus related, inflammatory and ischaemic neuropsychiatric systemic lupus erythematosus. The clinical outcome of all neuropsychiatric events was determined by a physician-completed four-point Likert scale. Health-related quality of life was measured with the subscales of the patient-generated Short Form 36 (SF-36) health survey questionnaire. The change between scores at paired visits of all domain scores, mental component summary (SF-36 MCS) and physical component summary (SF-36 PCS) scores were retrospectively calculated and used as patient-reported outcome. The association among these outcomes and the different origin of neuropsychiatric events was obtained using multiple logistic regression analysis. Results The clinical status of 26.8% non-neuropsychiatric systemic lupus erythematosus events, 15.8% ischaemic neuropsychiatric systemic lupus erythematosus and 51.6% inflammatory neuropsychiatric systemic lupus erythematosus improved after re-assessment. Almost all SF-36 domains had a positive change at re-assessment in all groups independently of the origin of neuropsychiatric events. Neuropsychiatric systemic lupus erythematosus ( B = 0.502; p < 0.001) and especially inflammatory neuropsychiatric systemic lupus erythematosus ( B = 0.827; p < 0.001) had better clinical outcome, with change in disease activity being the only important predictor. The change in SF-36 MCS was also independently associated with neuropsychiatric systemic lupus erythematosus ( B = 5.783; p < 0.05) and inflammatory neuropsychiatric systemic lupus erythematosus ( B = 11.133; p < 0.001). Disease duration and change in disease activity were the only predictors in both cases. The change in SF-36 PCS was only negatively associated with age. Conclusion Inflammatory neuropsychiatric systemic lupus erythematosus events have better clinical outcome and meaningful improvement in SF-36 MCS than ischaemic neuropsychiatric systemic lupus erythematosus or non-neuropsychiatric systemic lupus erythematosus.

Percutaneous laser disc decompression versus conventional microdiscectomy for patients with sciatica: Two-year results of a randomised controlled trial.

Background Percutaneous laser disc decompression is a minimally invasive treatment, for lumbar disc herniation and might serve as an alternative to surgical management of sciatica. In a randomised trial with two-year follow-up we assessed the clinical effectiveness of percutaneous laser disc decompression compared to conventional surgery. Materials and methods This multicentre randomised prospective trial with a non-inferiority design, was carried out according to an intent-to-treat protocol with full institutional review board approval. One hundred and fifteen eligible surgical candidates, with sciatica from a disc herniation smaller than one-third of the spinal canal, were randomly allocated to percutaneous laser disc decompression ( n = 55) or conventional surgery ( n = 57). The main outcome measures for this trial were the Roland-Morris Disability Questionnaire for sciatica, visual analogue scores for back and leg pain and the patient's report of perceived recovery. Results The primary outcome measures showed no significant difference or clinically relevant difference between the two groups at two-year follow-up. The re-operation rate was 21% in the surgery group, which is relatively high, and with an even higher 52% in the percutaneous laser disc decompression group. Conclusion At two-year follow-up, a strategy of percutaneous laser disc decompression, followed by surgery if needed, resulted in non-inferior outcomes compared to a strategy of microdiscectomy. Although the rate of reoperation in the percutaneous laser disc decompression group was higher than expected, surgery could be avoided in 48% of those patients that were originally candidates for surgery. Percutaneous laser disc decompression, as a non-surgical method, could have a place in the treatment arsenal of sciatica caused by contained herniated discs.

Middle cerebral artery diameter changes during rhythmic handgrip exercise in humans.

Transcranial Doppler (TCD) sonography is a frequently employed technique for quantifying cerebral blood flow by assuming a constant arterial diameter. Given that exercise increases arterial pressure by sympathetic activation, we hypothesized that exercise might induce a change in the diameter of large cerebral arteries. Middle cerebral artery (MCA) cross-sectional area was assessed in response to handgrip exercise by direct magnetic resonance imaging (MRI) observations. Twenty healthy subjects (11 female) performed three 5 min bouts of rhythmic handgrip exercise at 60% maximum voluntary contraction, alternated with 5 min of rest. High-resolution 7 T MRI scans were acquired perpendicular to the MCA. Two blinded observers manually determined the MCA cross-sectional area. Sufficient image quality was obtained in 101 MCA-scans of 19 subjects (age-range 20-59 years). Mixed effects modelling showed that the MCA cross-sectional area decreased by 2.1 ± 0.8% (p = 0.01) during handgrip, while the heart rate increased by 11 ± 2% (p < 0.001) at constant end-tidal CO2 (p = 0.10). In conclusion, the present study showed a 2% decrease in MCA cross-sectional area during rhythmic handgrip exercise. This further strengthens the current concept of sympathetic control of large cerebral arteries, showing in vivo vasoconstriction during exercise-induced sympathetic activation. Moreover, care must be taken when interpreting TCD exercise studies as diameter constancy cannot be assumed.

White matter microstructure of patients with neurofibromatosis type 1 and its relation to inhibitory control.

Neurofibromatosis Type 1 (NF1) is commonly associated with deficits in executive functions such as working memory and inhibitory control. A valid biomarker to describe the pathological basis of these deficits in NF1 is not available. The aim of this study was to investigate whether any abnormalities in white matter integrity of the executive function related anterior thalamic radiation (ATR), cingulate bundle (CB), and superior longitudinal fasciculus (SLF) may be regarded as a pathological basis for inhibitory control deficits in adolescents with NF1. Sixteen NF1 patients and 32 healthy controls underwent 3 T DTI MRI scanning. Whole brain-, ATR-, CB-, and SLF-white matter integrity were studied using fractional anisotropy, mean (MD), radial, and axial (DA) diffusivity. Correlation analyses between white matter metrics and inhibitory control (as measured with a computerized task) were performed. Also, verbal and performance abilities (IQ-estimates) were assessed and correlated with white matter metrics. Patients showed significant whole brain- and local microstructural pathology when compared to healthy controls in all measures. In NF1-patients, whole-brain (MD: r = .646 and DA: r = .673) and ATR- (r-range: -.405-.771), but not the CB- (r-range: -.307-.472) and SLF- (r-range: -.187-.406) white matter integrity, were correlated with inhibitory control. Verbal and performance abilities were not associated with white matter pathology. In NF1, white matter abnormalities are observed throughout the brain, but damage to the ATR seems specifically, or at least most strongly related to inhibitory control. Future studies should examine whether reduced white matter integrity in other brain regions or tracts is (more strongly) associated with different aspects of the cognitive-behavioral phenotype associated with NF1.

Detection superiority of 7 T MRI protocol in patients with epilepsy and suspected focal cortical dysplasia.

In 11 adult patients with suspicion of Focal cortical dysplasia (FCD) on 1.5 T (n = 1) or 3 T (n = 10) magnetic resonance imaging (MRI), 7 T MRI was performed. Visibility, extent, morphological features and delineation were independently rated and subsequently discussed by three observers. Additionally, head-to-head comparisons with corresponding 3 T images were made in the eight patients with a previous 3 T MRI and sustained suspicion of FCD. Comparison with histopathology was done in the five patients that underwent surgery. All lesions, seen at 1.5 and 3 T, were also recognized on 7 T. At 7 T FLAIR highlighted the FCD-like lesions best, whereas T2 and T2* were deemed better suited to review structure and extent of the lesion. Image quality with the used 7 T MRI setup was higher than the quality with the used 3 T MRI setup. In 2 out of 11 patients diagnosis changed, in one after re-evaluation of the images, and in the other based on histopathology. With the used 7 T MRI setup, FCD-like lesions can be detected with more confidence and detail as compared to lower field strength. However, concordance between radiologic diagnosis and final diagnosis seems to be lower than expected.

Is the brain of complex regional pain syndrome patients truly different?

BACKGROUND: In recent years, changes in brain structure and function have been studied extensively in patients with complex regional pain syndrome (CRPS) following clinical observations of altered central processing of sensory stimuli and motor control. However, concerning MRI data, the evidence is complex to interpret due to heterogeneity in statistical methods and results. METHOD: The aim of this study was to determine if CRPS patients exhibit specific, clinically relevant changes in brain structure and function in rest. We do this by presenting MRI data on brain structure and function in 19 chronic, female CRPS patients and age- and sex-matched healthy controls (HCs). In addition, we analyse and report the data in multiple ways to make comparison with previous studies possible and to demonstrate the effect of different statistical methods, in particular, concerning the correction for multiple testing. RESULTS: Using family-wise error (FWE) correction for multiple testing, in our group of CRPS patients, we find no specific difference in brain structure or function in rest in comparison to HCs. In addition, we argue that previously found MRI results in the literature are inconsistent in terms of localization, quantity and directionality of the reported changes in brain structure and function. CONCLUSION: Previously published MRI-based evidence for altered brain structure and function in rest in CRPS patients is not consistent and our data suggests that no such phenomenon exists. WHAT DOES THIS STUDY ADD?: This article does not replicate the previous found results. The reported evidence in MRI literature of aberrant neuroplasticity in CRPS patients is inconsistent in terms of localization, quantity and directionality of changes in brain structure and function.

Susac syndrome: a report of four cases and a review of the literature.

In Susac syndrome, occlusions of pre-capillary arterioles of the brain, retina, and cochlea lead to the classical clinical triad of subacute encephalopathy, visual disturbances due to branch retinal artery occlusions and sensorineural hearing impairment. Its pathogenesis is still obscure, but it is presumed to be mediated by an autoimmune response to an as yet unknown antigen. The syndrome is considered a rare but important differential diagnosis in various neurological, psychiatric, ophthalmological, and ear-nose-throat disorders. Brain magnetic resonance imaging, retinal fluorescein angiography, and audiometry findings enable diagnosis. Early therapy may reduce relapses and improve recovery. The features of four cases of this syndrome are presented, illustrating that cooperation among different medical specialists is essential, and that treatment may be best guided by an immunologist or rheumatologist as a case manager.

Obesity is marked by distinct functional connectivity in brain networks involved in food reward and salience.

We hypothesized that brain circuits involved in reward and salience respond differently to fasting in obese versus lean individuals. We compared functional connectivity networks related to food reward and saliency after an overnight fast (baseline) and after a prolonged fast of 48 h in lean versus obese subjects. We included 13 obese (2 males, 11 females, BMI 35.4 ± 1.2 kg/m(2), age 31 ± 3 years) and 11 lean subjects (2 males, 9 females, BMI 23.2 ± 0.5 kg/m(2), age 28 ± 3 years). Resting-state functional magnetic resonance imaging scans were made after an overnight fast (baseline) and after a prolonged 48 h fast. Functional connectivity of the amygdala, hypothalamus and posterior cingulate cortex (default-mode) networks was assessed using seed-based correlations. At baseline, we found a stronger connectivity between hypothalamus and left insula in the obese subjects. This effect diminished upon the prolonged fast. After prolonged fasting, connectivity of the hypothalamus with the dorsal anterior cingulate cortex (dACC) increased in lean subjects and decreased in obese subjects. Amygdala connectivity with the ventromedial prefrontal cortex was stronger in lean subjects at baseline, which did not change upon the prolonged fast. No differences in posterior cingulate cortex connectivity were observed. In conclusion, obesity is marked by alterations in functional connectivity networks involved in food reward and salience. Prolonged fasting differentially affected hypothalamic connections with the dACC and the insula between obese and lean subjects. Our data support the idea that food reward and nutrient deprivation are differently perceived and/or processed in obesity.

Percutaneous laser disc decompression versus conventional microdiscectomy in sciatica: a randomized controlled trial.

BACKGROUND CONTEXT: Percutaneous laser disc decompression (PLDD) is a minimally invasive treatment for lumbar disc herniation, with Food and Drug Administration approval since 1991. However, no randomized trial comparing PLDD to conventional treatment has been performed. PURPOSE: In this trial, we assessed the effectiveness of a strategy of PLDD as compared with conventional surgery. STUDY DESIGN/SETTING: This randomized prospective trial with a noninferiority design was carried out in two academic and six teaching hospitals in the Netherlands according to an intent-to-treat protocol with full institutional review board approval. PATIENT SAMPLE: One hundred fifteen eligible surgical candidates, with sciatica from a disc herniation smaller than one-third of the spinal canal, were included. OUTCOME MEASURES: The main outcome measures for this trial were the Roland-Morris Disability Questionnaire for sciatica, visual analog scores for back and leg pain, and the patient's report of perceived recovery. METHODS: Patients were randomly allocated to PLDD (n=57) or conventional surgery (n=58). Blinding was impossible because of the nature of the interventions. This study was funded by the Healthcare Insurance Board of the Netherlands. RESULTS: The primary outcome, Roland-Morris Disability Questionnaire, showed noninferiority of PLDD at 8 (-0.1; [95% confidence interval (CI), -2.3 to 2.1]) and 52 weeks (-1.1; 95% CI, -3.4 to 1.1) compared with conventional surgery. There was, however, a higher speed of recovery in favor of conventional surgery (hazard ratio, 0.64 [95% CI, 0.42-0.97]). The number of reoperations was significantly less in the conventional surgery group (38% vs. 16%). Overall, a strategy of PLDD, with delayed surgery if needed, resulted in noninferior outcomes at 1 year. CONCLUSIONS: At 1 year, a strategy of PLDD, followed by surgery if needed, resulted in noninferior outcomes compared with surgery.

Temporalis muscle hypertrophy and reduced skull eccentricity in Duchenne muscular dystrophy.

Muscle hypertrophy and muscle weakness are well known in Duchenne muscular dystrophy. Decreased muscle force can have secondary effects on skeletal growth and development such as facial and dental morphology changes. In this study, we quantified temporal muscle thickness, circumference, and eccentricity of the skull and the head on T1-weighted magnetic resonance imaging (MRI) scans of the head of 15 Duchenne muscular dystrophy patients and 15 controls. Average temporal muscle thickness was significantly increased in patients (12.9 ± 5.2 mm) compared to controls (6.8 ± 1.4 mm) (P < .0001), whereas the shape of the skull was significantly rounder compared to controls. Temporal muscle thickness and skull eccentricity were significantly negatively correlated in patients, and positively in controls. Hypertrophy of the temporal muscles and changes in skull eccentricity appear to occur early in the course of Duchenne muscular dystrophy. Further studies in younger patients are needed to confirm a causal relationship.

Biochemical changes in the brain of hemiplegic migraine patients measured with 7 tesla 1H-MRS.

AIM: The aim of this study was to assess biochemical changes in the brain of patients with hemiplegic migraine in between attacks. METHODS: Eighteen patients with hemiplegic migraine (M:F, 7:11; age 38 ± 14 years) of whom eight had a known familial hemiplegic migraine (FHM) mutation (five in the CACNA1A gene (FHM1), three in the ATP1A2 gene (FHM2)) and 19 age- and sex-matched healthy controls (M:F, 7:12; mean age 38 ± 12 years) were studied. We used single-voxel 7 tesla (1)H-MRS (STEAM, TR/TM/TE = 2000/19/21 ms) to investigate four brain regions in between attacks: cerebellum, hypothalamus, occipital lobe, and pons. RESULTS: Patients with hemiplegic migraine showed a significantly lower total N-acetylaspartate/total creatine ratio (tNAA/tCre) in the cerebellum (median 0.73, range 0.59-1.03) than healthy controls (median 0.79, range (0.67-0.95); p = 0.02). In FHM1 patients with a CACNA1A mutation, the tNAA/tCre was lowest. DISCUSSION: We found a decreased cerebellar tNAA/tCre ratio that might serve as an early biomarker for neuronal dysfunction and/or loss. This is the first high-spectral resolution 7 tesla (1)H-MRS study of interictal biochemical brain changes in hemiplegic migraine patients.

Mortality in neuropsychiatric systemic lupus erythematosus (NPSLE).

The standardized mortality ratio (SMR) for systemic lupus erythematosus (SLE) is three; SMR increases to six in case of renal involvement. Up to now data on survival in case of neuropsychiatric involvement in SLE (NPSLE) have been scarce, therefore we calculated an SMR for NPSLE. Furthermore, we identified characteristics that influenced survival by Cox regression analyses. All patients suspected of NPSLE in our center since 1989 were evaluated and included in this study when a diagnosis of primary NPSLE could be established. Patient's life/death status was tracked using the civic registries. Thirty-two (19%) of the 169 included NPSLE patients died within a median follow-up period of six years (range 0.5-24 years). This resulted in a significantly increased mortality rate compared to the general population: SMR 9.5 (95% CI 6.7-13.5). Hazard ratios (HRs) were highest in patients with acute confusional state (HR 3.4) and older age at diagnosis of NPSLE (HR 1.1). A decreased mortality risk was seen with the prescription of antiplatelet therapy (HR 0.22). The time period in which NPSLE was diagnosed did not significantly influence survival. Most frequent causes of death were infection and NPSLE itself.

Magnetization transfer imaging in premanifest and manifest huntington disease: a 2-year follow-up.

BACKGROUND AND PURPOSE: MTI is a quantitative MR imaging technique that has recently demonstrated structural integrity differences between controls and patients with HD. Potentially, MTI can be used as a biomarker for monitoring disease progression. To establish the value of MTI as a biomarker, we aimed to examine the change in these measures during the course of HD. MATERIALS AND METHODS: From the Leiden TRACK-HD study, 25 controls, 21 premanifest gene carriers, and 21 patients with manifest HD participated at baseline and during a 2-year follow-up visit. Brain segmentation of the cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed by using the automated tools FAST and FIRST in FSL. Individual MTR values were calculated from these regions, and MTR histograms were constructed. RESULTS: In the premanifest HD group stage "far from disease onset," a significant increase in MTR peak height of the putamen was observed with time. During the manifest HD stage, neither the mean MTR nor the MTR peak height showed a significant change during a 2-year follow-up. CONCLUSIONS: MTI-derived measures are not suitable for monitoring in Huntington disease during a 2-year period because there was no decrease in structural integrity detected in any of the manifest HD groups longitudinally. The finding of increased putaminal MTR peak height in the premanifest far from disease onset group could relate to a predegenerative process, compensatory mechanisms, or aberrant development but should be interpreted with caution until future studies confirm this finding.

The heart-brain connection: mechanistic insights and models.

While both cardiac dysfunction and progressive loss of cognitive function are prominent features of an ageing population, surprisingly few studies have addressed the link between the function of the heart and brain. Recent literature indicates that autoregulation of cerebral flow is not able to protect the brain from hypoperfusion when cardiac output is reduced or atherosclerosis is prominent. This suggests a close link between cardiac function and large vessel atherosclerosis on the one hand and brain perfusion and cognitive functioning on the other. Mechanistically, the presence of vascular pathology leads to chronic cerebral hypoperfusion, blood brain barrier breakdown and inflammation that most likely precede neuronal death and neurodegeneration. Animal models to study the effects of chronic cerebral hypoperfusion are available, but they have not yet been combined with cardiovascular models.

Piccolo genotype modulates neural correlates of emotion processing but not executive functioning.

Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene--involved in monoaminergic neurotransmission--as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD.