Citations

X‐linked adrenoleukodystrophy (X‐ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello‐brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy‐confirmed cases exceedingly rare. We report a 69‐year‐old White man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X‐ALD or Addison's disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of MSA. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS‐positive, CD68‐positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting the optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft‐like trilamellar cytoplasmic inclusions in macrophages typical of X‐ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello‐brainstem dominant form of X‐ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult‐onset cerebello‐brainstem dominant form of X‐ALD. Although rare, X‐ALD should be considered in the differential diagnosis of MSA.

AbstractIntroductionAlzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders.MethodsWe review the contributions of the MRI core from present and past cycles of ADNI (ADNI‐1, ‐Grand Opportunity and ‐2). We also review plans for the future‐ADNI‐3.ResultsContributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials.DiscussionOver the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future.

Objective To examine the validity of a tablet computer–based audiometer for measuring hearing thresholds in a moderately noisy environment. Study Design A prospective single‐cohort repeated measures study. Setting Tertiary care institution providing hearing health care to a diverse population. Subjects and Methods Subjects included 49 participants (44 adults, 5 children) with all degrees of hearing sensitivity. Potential participants were excluded if they were <4 years old or had cognitive deficits or ear drainage. Participants were tested with established audiometric tests and a tablet audiometer. Threshold values were measured for both ears using various stimuli (500, 1000, 2000, and 4000 Hz). Testing with the tablet audiometer was conducted in a non‐sound‐treated room; room properties were characterized by ambient noise level and reverberation testing. Calibration assessment of the tablet audiometer was performed on 3 occasions. Results Within the test thresholds for hearing level, results from the tablet device were within 10 dB of those determined by conventional audiometry for 164 of 172 hearing levels and did not show proportional bias over the testing range. Calibration assessment showed accurate proximity between output and target values, though crosstalk and linearity failed initial assessments. Conclusion The tablet‐based automated audiometer presents a new method for threshold hearing assessment outside conventional sound booths.

Background and purposeLow density lipoprotein receptor related proteins (LRPs) 1 and 6 have been implicated in cerebral ischaemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischaemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischaemic stroke as part of the Ischemic Stroke Genetics Study (ISGS).MethodsA Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls) were included. Fourteen LRP6 variants and three LRP1 variants were genotyped and assessed for association with ischaemic stroke.ResultsIn the Caucasian series, significant associations with ischaemic stroke were observed for LRP6 rs2075241 [odds ratio (OR) 0.42, P = 0.023], rs2302685 (OR 0.44, P = 0.049), rs7975614 (OR 0.07, P = 0.017), rs10492120 (OR 0.62, P = 0.036) and rs10743980 (OR 0.66, P = 0.037). Risk of ischaemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non‐carriers (OR 0.57, P = 0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischaemic stroke subtypes, whilst the effects of rs23022685, rs10492120 and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR 1.89, P = 0.006).ConclusionsThe results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischaemic stroke. Validation in larger studies is warranted.

Differences in the aggregation and release of growth factors including matrix metalloproteinases (MMPs) after loss of ovarian hormones could contribute to an exaggerated response to injury in arteries of ovariectomized animals. Therefore, experiments were designed to compare aggregation, dense granular ATP release, expression of MMPs (MMP-2, MMP-9, and MMP-14) and tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2) in circulating platelets from sexually mature (7 mo old) gonadally intact and ovariectomized (4 wk) female pigs. Numbers of circulating platelets did not change after ovariectomy, but the percentage of reticulated platelets increased significantly. Platelet aggregation and dense granular ATP secretion also increased significantly with ovariectomy. In platelet lysates, active MMP-2 increased, whereas MMP-14 significantly decreased, after ovariectomy; the expression of TIMP-1, TIMP-2, and P-selectin did not change. These results suggest that platelet turnover, aggregation, and ATP secretion increase with ovariectomy. Also, ovarian hormones selectively regulate the expression and activity of MMPs in porcine platelets. Increased platelet aggregation and activity of MMP-2 would alter platelet-platelet and platelet-vessel wall interactions, contributing to an exaggerated response to injury with loss of ovarian hormones.

Experiments were designed to determine how ovariectomy modulates mitogenic factors in platelets and how these factors affect proliferation of coronary arterial smooth muscle. Platelet-derived growth factors (PDGFABand PDGFBB), transforming growth factors (TGF-β1and TGF-β2), and vascular endothelial growth factor (VEGF165) were quantified in platelet lysates and platelet-poor plasma from adult gonadally intact and ovariectomized female pigs by ELISA. Proliferation of cultured coronary arterial smooth muscle cells (SMCs) from both groups of pigs was determined in response to autologous or heterologous platelet lysates. Platelet concentrations of PDGFBB, but not PDGFAB, TGF-β1, and TGF-β2, increased with ovariectomy. VEGF165was not detected in platelets from either group. Proliferation of SMCs from ovariectomized females was significantly greater on exposure to autologous or heterologous platelet lysates than proliferation of SMCs from intact females. These results indicate that ovariectomy increases concentrations of PDGFBBin platelets. Higher levels of PDGFBBin platelets in synergy with other platelet-derived products could contribute to increased proliferative arterial response to injury after ovariectomy.