Comorbid amyloid-ß pathology affects clinical and imaging features in VCD.

INTRODUCTION: To date, the clinical relevance of comorbid amyloid-ß (Aß) pathology in patients with vascular cognitive disorders (VCD) is largely unknown. METHODS: We included 218 VCD patients with available cerebrospinal fluid Aß42 levels. Patients were divided into Aß+ mild-VCD (n = 84), Aß- mild-VCD (n = 68), Aß+ major-VCD (n = 31), and Aß- major-VCD (n = 35). We measured depression with the Geriatric Depression Scale, cognition with a neuropsychological test battery and derived white matter hyperintensities (WMH) and gray matter atrophy from MRI. RESULTS: Aß- patients showed more depressive symptoms than Aß+. In the major-VCD group, Aß- patients performed worse on attention (P = .02) and executive functioning (P = .008) than Aß+. We found no cognitive differences in patients with mild VCD. In the mild-VCD group, Aß- patients had more WMH than Aß+ patients, whereas conversely, in the major-VCD group, Aß+ patients had more WMH. Atrophy patterns did not differ between Aß+ and Aß- VCD group. DISCUSSION: Comorbid Aß pathology affects the manifestation of VCD, but effects differ by severity of VCD.

Methylphenidate and galantamine in patients with vascular cognitive impairment-the proof-of-principle study STREAM-VCI.

BACKGROUND: To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI), we investigated whether a single dose of a monoaminergic drug (methylphenidate) improves executive functioning and whether a single dose of a cholinergic drug (galantamine) improves memory in VCI patients. METHODS: STREAM-VCI is a single-center, double-blind, three-way crossover trial. We included 30 VCI patients (Mini-Mental State Examination (MMSE) ≥ 16 and Clinical Dementia Rating score 0.5-1.0) with cerebrovascular pathology on MRI. All patients received single doses of methylphenidate (10 mg), galantamine (16 mg), and placebo in random order on three separate study visits. We used the NeuroCart®, a computerized test battery, to assess drug-sensitive cognitive effects. Predefined main outcomes, measured directly after a single dose of a study drug, were (i) change in performance on the adaptive tracker for executive functioning and (ii) performance on the Visual Verbal Learning Test-15 (VVLT-15) for memory, compared to placebo. We performed mixed model analysis of variance. RESULTS: The study population had a mean age of 67 ± 8 years and MMSE 26 ± 3, and 9 (30%) were female. Methylphenidate improved performance on the adaptive tracker more than placebo (mean difference 1.40%; 95% confidence interval [CI] 0.56-2.25; p = 0.002). In addition, methylphenidate led to better memory performance on the VVLT-15 compared to placebo (mean difference in recalled words 0.59; 95% CI 0.03-1.15; p = 0.04). Galantamine did not improve performance on the adaptive tracker and led to worse performance on delayed recall of the VVLT-15 (mean difference - 0.84; 95% CI - 1.65, - 0.03; p = 0.04). Methylphenidate was well tolerated while galantamine produced gastrointestinal side effects in a considerable number of patients. CONCLUSIONS: In this proof-of-principle study, methylphenidate is well tolerated and improves executive functioning and immediate recall in patients with VCI. Galantamine did not improve memory or executive dysfunction. Results might be influenced by the considerable amount of side effects seen. TRIAL REGISTRATION: http://www.clinicaltrials.gov. Registration number: NCT02098824. Registration date: March 28, 2014.

Lower cerebral blood flow in subjects with Alzheimer's dementia, mild cognitive impairment, and subjective cognitive decline using two-dimensional phase-contrast magnetic resonance imaging.

INTRODUCTION: In this cross-sectional study, we aimed to detect differences in cerebral blood flow (CBF) between subjects with Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD), using two-dimensional phase-contrast magnetic resonance imaging. METHODS: We included 74 AD patients (67 years, 51% female), 36 MCI patients (66 years, 33% female), and 62 patients with SCD (60 years, 32% female) from the Amsterdam Dementia Cohort. Patients with SCD are those who visited the memory clinic with subjective cognitive complaints without objective cognitive impairment. Whole-brain CBF (mL/100 g/min) was calculated using total volume flow measured with two-dimensional phase-contrast magnetic resonance imaging and normalized for brain volume. RESULTS: Mean CBF values (SD) were lower in AD compared to SCD (age and sex adjusted 70 ± 26 vs. 82 ± 24 mL/100 g/min, P < .05). Mean CBF values of MCI were comparable to AD. Across clinical groups, lower CBF was associated with lower scores on the Mini-Mental State Examination (age and sex adjusted stß = 0.19 per mL/100 g/min; P = .02). DISCUSSION: Lower whole-brain CBF is seen in AD patients compared to SCD patients and is associated with worse cognitive function.

Effect of magnesium treatment and glucose levels on delayed cerebral ischemia in patients with subarachnoid hemorrhage: a substudy of the Magnesium in Aneurysmal Subarachnoid Haemorrhage trial (MASH-II).

BACKGROUND: Magnesium treatment did not improve outcome in patients with aneurysmal subarachnoid haemorrhage in the Magnesium in Aneurysmal Subarachnoid Haemorrhage II trial. We hypothesized that high glucose levels may have offset a potential beneficial effect to prevent delayed cerebral ischemia. We investigated if magnesium treatment led to less delayed cerebral ischemia and if glucose levels interacted with magnesium treatment in the Magnesium in Aneurysmal Subarachnoid Haemorrhage II trial. AIM: To investigate the effect of magnesium treatment on occurrence of delayed cerebral ischemia and the interaction between glucose levels and magnesium treatment in subarachnoid hemorrhage patients. METHODS: The Magnesium in Aneurysmal Subarachnoid Haemorrhage was a phase III randomized placebo-controlled trial assessing the effect of magnesium sulphate on clinical outcome in aneurysmal subarachnoid hemorrhage patients. For the current study, we included only the patients admitted to the University Medical Centre-Utrecht. We calculated hazard ratios for occurrence of delayed cerebral ischemia in patients treated with magnesium vs. placebo for the entire study population, and separately in the subgroups of patients with high and low mean fasting and mean daily glucose levels until onset of delayed cerebral ischemia. We used the cross-product of magnesium and glucose in the regression analysis to evaluate whether an interaction between magnesium and glucose existed. RESULTS: We included 616 patients: 307 received magnesium and 309 placebo; 156 patients had delayed cerebral ischemia. Hazard ratio for magnesium on occurrence of delayed cerebral ischemia was 1·0 (95% confidence interval: 0·7-1·4). Results were similar in patients with low or high fasting or daily glucose levels. We found no interactions between magnesium treatment and high fasting (P = 0·54) and daily glucose (P = 0·60). CONCLUSIONS: Magnesium treatment did not reduce the risk of delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage, nor was there an interaction with glucose levels. It is therefore unlikely that glucose levels explain the failure of magnesium to prevent delayed cerebral ischemia and poor outcome after aneurysmal subarachnoid hemorrhage.

Nemaline myopathy caused byTNNT1 mutations in a Dutch pedigree.

Nemaline myopathy (NM) is genetically heterogeneous disorder characterized by early onset muscular weakness and sarcoplasmatic or intranuclear inclusions of rod-shaped Z-disk material in muscle fibers. Thus far, mutations in seven genes have been identified as cause of NM. Only one singleTNNT1 nonsense mutation has been previously described that causes autosomal recessive NM in the old order Amish with a very specific clinical phenotype including rapidly progressive contractures. Here, we report a patient who is compound heterozygous for a c.309+1G>A mutation and an exon 14 deletion in theTNNT1 gene. This report confirms the specific clinical phenotype ofTNNT1 NM and documents two newTNNT1 mutations outside the old order Amish.