White matter changes and gait decline in cerebral small vessel disease.

The relation between progression of cerebral small vessel disease (SVD) and gait decline is uncertain, and diffusion tensor imaging (DTI) studies on gait decline are lacking. We therefore investigated the longitudinal associations between (micro) structural brain changes and gait decline in SVD using DTI. 275 participants were included from the Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort (RUN DMC), a prospective cohort of participants with cerebral small vessel disease aged 50-85 years. Gait (using GAITRite) and magnetic resonance imaging measures were assessed during baseline (2006-2007) and follow-up (2011 - 2012). Linear regression analysis was used to investigate the association between changes in conventional magnetic resonance and diffusion tensor imaging measures and gait decline. Tract-based spatial statistics analysis was used to investigate region-specific associations between changes in white matter integrity and gait decline. 56.2% were male, mean age was 62.9 years (SD8.2), mean follow-up duration was 5.4 years (SD0.2) and mean gait speed decline was 0.2 m/s (SD0.2). Stride length decline was associated with white matter atrophy (ß = 0.16, p = 0.007), and increase in mean white matter radial diffusivity and mean diffusivity, and decrease in mean fractional anisotropy (respectively, ß = - 0.14, p = 0.009; ß = - 0.12, p = 0.018; ß = 0.10, p = 0.049), independent of age, sex, height, follow-up duration and baseline stride length. Tract-based spatial statistics analysis showed significant associations between stride length decline and fractional anisotropy decrease and mean diffusivity increase (primarily explained by radial diffusivity increase) in multiple white matter tracts, with the strongest associations found in the corpus callosum and corona radiata, independent of traditional small vessel disease markers. White matter atrophy and loss of white matter integrity are associated with gait decline in older adults with small vessel disease after 5 years of follow-up. These findings suggest that progression of SVD might play an important role in gait decline.

Diffusion tensor imaging of the hippocampus predicts the risk of dementia; the RUN DMC study.

INTRODUCTION: Cerebral small vessel disease is one of the most important risk factors for dementia, and has been related to hippocampal atrophy, which is among the first observed changes on conventional MRI in patients with dementia. However, these volumetric changes might be preceded by loss of microstructural integrity of the hippocampus for which conventional MRI is not sensitive enough. Therefore, we investigated the relation between the hippocampal diffusion parameters and the risk of incident dementia, using diffusion tensor imaging, independent of hippocampal volume. METHODS: The RUNDMC study is a prospective study among 503 elderly with small vessel disease, without dementia, with 5 years follow-up in 2012 (99.6% response-rate). Cox regression analysis was performed to calculate hazard ratios for dementia, of fractional anisotropy and mean diffusivity within the hippocampus, adjusted for demographics, hippocampal volume, and white matter. This was repeated in participants without evident hippocampal volume loss, because in these participants the visible damage might not yet have already started, whereas damage might have started on a microstructural level. RESULTS: 43 participants developed dementia (8.6%), resulting in a 5.5-year cumulative risk of 11.1% (95%CI 7.7-14.6). Higher mean diffusivity was associated with an increased 5-year risk of dementia. In the subgroup of participants with the upper half hippocampal volume, higher hippocampal mean diffusivity, more than doubled the 5-year risk of dementia. CONCLUSION: This is the first prospective study showing a relation between a higher baseline hippocampal mean diffusivity and the risk of incident dementia in elderly with small vessel disease at 5-year follow-up, independent of hippocampal volume and white matter volume.

Microstructural integrity of the cingulum is related to verbal memory performance in elderly with cerebral small vessel disease: the RUN DMC study.

BACKGROUND: Cerebral small vessel disease (SVD) is related to verbal memory failures. It is suggested that early white matter damage, is located, among others, in the (posterior) cingulum at an early stage in neurodegeneration. Changes in the microstructural integrity of the cingulum assessed with diffusion tensor imaging (DTI), beyond detection with conventional MRI, may precede macrostructural changes and be related to verbal memory failures. OBJECTIVE: To investigate the relation between cingular microstructural integrity and verbal memory performance in 503 non-demented elderly with cerebral SVD. METHODS: The RUN DMC study is a prospective cohort study in elderly (50-85 years) with cerebral SVD. All participants underwent T1 MPRAGE, FLAIR and DTI scanning and the Rey Auditory Verbal Learning Test. Mean diffusivity (MD) and fractional anisotropy (FA) were assessed in six different cingular regions of interests (ROIs). Linear regression analysis was used to assess the relation between verbal memory performance and cingular DTI parameters, with appropriate adjustments. Furthermore a TBSS analysis of the whole brain was performed to investigate the specificity of our findings. RESULTS: Both our ROI-based and TBSS analysis showed that FA was positively related to immediate memory, delayed recall, delayed recognition and overall verbal memory performance of the cingulum, independent of confounders. A similar distribution was seen for the inverse association with MD and verbal memory performance with TBSS analysis. No significant relations were found with psychomotor speed, visuospatial memory and MMSE. When stratified on hippocampal integrity, the MD and FA values of the cingular ROIs differed significantly between participants with a good and poor hippocampal integrity. CONCLUSION: Microstructural integrity of the cingulum, assessed by DTI, is specifically related to verbal memory performance, in elderly with SVD. Furthermore we found that when the integrity of the hippocampus is disrupted, the cingulum integrity is impaired as well.

Depressive Symptoms and Amygdala Volume in Elderly with Cerebral Small Vessel Disease: The RUN DMC Study.

Introduction. Late onset depressive symptoms (LODSs) frequently occur in elderly with cerebral small vessel disease (SVD). SVD cannot fully explain LODS; a contributing factor could be amygdala volume. We investigated the relation between amygdala volume and LODS, independent of SVD in 503 participants with symptomatic cerebral SVD. Methods. Patients underwent FLAIR and T1 scanning. Depressive symptoms were assessed with structured questionnaires; amygdala and WML were manually segmented. The relation between amygdala volume and LODS/EODS was investigated and adjusted for age, sex, intracranial volume, and SVD. Results. Patients with LODS had a significantly lower left amygdala volume than those without (P = 0.02), independent of SVD. Each decrease of total amygdala volume (by mL) was related to an increased risk of LODS (OR = 1.77; 95% CI 1.02-3.08; P = 0.04). Conclusion. Lower left amygdala volume is associated with LODS, independent of SVD. This may suggest differential mechanisms, in which individuals with a small amygdala might be vulnerable to develop LODS.

Subjective cognitive failures and hippocampal volume in elderly with white matter lesions.

BACKGROUND: Subjective cognitive failures (SCF) and subjective memory failures (SMF) have been reported to be an early predictor of Alzheimer disease (AD) and have been attributed to white matter lesions (WML). Since AD is characterized by hippocampal degeneration, it is surprising that its relation with hippocampal atrophy has been investigated only sparsely. Previous studies on this are rare, limited in sample size, and did not adjust for WML. OBJECTIVE: To determine the relation between SCF and hippocampal volume in strata of objective cognitive performance among elderly without dementia with incidental WML. METHODS: The Radboud University Nijmegen Diffusion tensor and MRI Cohort study is a prospective cohort study among 503 subjects with WML aged between 50 and 85 years. All subjects underwent FLAIR and T1 MRI scanning. The amount of SCF and SMF was rated by the Cognitive Failure Questionnaire. Cognitive function was assessed by a cognitive screening battery. Volumetric measures of hippocampus and WML were manually performed. We assessed the relation between hippocampal volume and SCF and SMF adjusted for age, sex, education, depression, intracranial volume, and WML volume. RESULTS: Subjects with SCF and SMF had lower hippocampal volumes than those without (p = 0.01 and p = 0.02). This was most noteworthy in subjects with good objective cognitive performance (p(trend) = 0.007 and p(trend) = 0.03), and not in those with poor objective cognitive performance. CONCLUSION: Subjective cognitive failures (SCF) are associated with lower hippocampal volume, even in subjects without objective cognitive impairment and independent of white matter lesions. SCF has a radiologic detectable pathologic-anatomic substrate.

Diagnostic accuracy of the clapping test in Parkinsonian disorders.

BACKGROUND: To determine the diagnostic value of the clapping test, which has been proposed as a reliable measure to differentiate between progressive supranuclear palsy (where performance is impaired) and Parkinson's disease (where performance should be normal). METHODS: Our study group included a large cohort of consecutive outpatients including 44 patients with Parkinson's disease, 48 patients with various forms of atypical parkinsonism and 149 control subjects. All subjects performed the clapping test according to a standardized protocol. RESULTS: Clapping test performance was normal in all control subjects, and impaired in 63% of the patients with atypical parkinsonism. Unexpectedly, we also found an impaired clapping test in 29% of the patients with Parkinson's disease. CONCLUSION: Although the proportion with an abnormal clapping test was significantly higher in atypical parkinsonism, the clapping test did not discriminate well between Parkinson's disease and atypical parkinsonism.

Dose evaluation for long-term magnesium treatment in aneurysmal subarachnoid haemorrhage.

BACKGROUND: Magnesium is a neuroprotective agent that might prevent or reverse delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage (SAH). We are presently running a randomized, placebo-controlled, double blind trial with magnesium sulphate (64 mmol/day intravenously). We studied whether this treatment regime resulted in our target serum magnesium levels of 1.0-2.0 mmol/L. METHODS: Magnesium sulphate was administered intravenously as soon as possible after admission and continued until 14 days after occlusion of the aneurysm. Serum magnesium measurements were done at baseline and at least every 2 days during administration of trial medication. For comparison we used the serum magnesium levels of the placebo-treated patients. RESULTS: Magnesium therapy was begun in 94 patients. The mean magnesium level in the treatment period was 1.47 +/- 0.32 mmol/L. In 81 patients serum magnesium stayed within target levels during the entire treatment period. One patient had a serum magnesium level below 1.0 mmol/L (0.91 mmol/L) in a single measurement and 10 patients had serum magnesium levels above 2.0 mmol/L at one or more measurements. In six patients magnesium therapy was discontinued: in three because of nausea, headache, or both in combination with serum magnesium levels above 2.0 mmol/L and in the other three because of hypotension, phlebitis and renal failure. CONCLUSIONS: With an intravenous dosage schedule of 64 mmol magnesium sulphate a day, serum magnesium levels of 1.0-2.0 mmol/L can easily be maintained without severe side effects for an extended period in a vast majority of patients with SAH.

[Alzheimer's disease and treatment of vascular risk factors]. / De ziekte van Alzheimer en behandeling van vasculaire risicofactoren.

There is increasing evidence that vascular risk factors including hypertension, high cholesterol, hyperhomocysteinaemia and diabetes mellitus are connected to the risk of Alzheimer's disease (AD). The risk of AD may be reduced by the treatment of hypertension prior to onset of cognitive impairment. One small randomised clinical trial has provided some evidence of beneficial effects on cognition of cholesterol-lowering drugs such as the statins in patients with AD. Treatment of hypertension, hyperhomocysteinaemia and diabetes mellitus with the aim of halting the progression of cognitive decline in AD is still under study and results are awaited. For the time being findings from the trials carried out thus far should be interpreted with care due to methodological shortcomings, both in study design and execution. In order to investigate the role of vascular risk factors both in the aetiology and treatment of AD, large prospective randomised trials with long-term follow-up of AD patients who have been diagnosed using revised uniform diagnostic criteria that take the heterogeneity of the disease into account, are necessary.

Urinary retinol binding protein in Indo-Asian patients with idiopathic interstitial nephritis.

BACKGROUND: Idiopathic interstitial nephritis (IIN) is common in the UK Indo-Asian population. Lack of systemic involvement and unremarkable urinalysis on stick testing suggest that it may underlie some cases of end-stage renal failure of undetermined cause. If IIN is diagnosed early, prompt initiation of treatment can improve long-term outcome. AIMS: To investigate whether urinary retinol binding protein (RBP) is elevated more commonly than urinary albumin in IIN, and might be useful in the early detection of renal disease in Indo-Asian patients. DESIGN: Preliminary observational study METHODS: We measured urinary RBP and urinary albumin in 19 Indo-Asian patients in whom a renal biopsy had shown IIN, 10 of whom had already been treated with corticosteroids at the time of specimen collection. A further 28 Indo-Asian patients with glomerular disease, and six with normal light-microscopic renal biopsy, were assessed in parallel. RESULTS: Urinary RBP/creatinine ratio (RCR) was elevated in all 19 cases of IIN, compared to 12/19 in whom the albumin/creatinine ratio (ACR) was elevated. Elevated urinary RBP was thus significantly more common than albuminuria in this group (p<0.01). Twelve of the 19 cases also satisfied the criteria for tubular proteinuria. RCR was elevated to >30 times the upper limit of normal in 7/9 who had not previously received corticosteroids, of whom four had normal ACR; none had ACR >5 times the upper limit of normal. DISCUSSION: These data suggest that measurement of urinary RBP should be explored as an adjunct to albuminuria, if screening for renal disease in the Indo-Asian population is contemplated.