Qiang Gang

Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum

Sporadic cerebral amyloid angiopathy (CAA) is a common age related cerebral small vessel disease, characterised by progressive deposition of amyloid-β (Aβ) in the wall of small to medium sized arteries, arterioles and capillaries of the cerebral cortex and overlying leptomeninges. Previously considered to be a rare neurological curiosity, CAA is now recognised as an important cause of spontaneous intracerebral haemorrhage and cognitive impairment in the elderly, two fundamental challenges in the field of cerebrovascular disease. Our understanding of the pathophysiology and clinical manifestations of CAA continues to evolve rapidly, with the use of transgenic mouse models and advanced structural and/or molecular neuroimaging techniques. Yet, despite remarkable recent interest, CAA remains under-recognised by neurologists and stroke physicians. In this review, a fresh look at key developments in understanding the complex pathophysiology, important clinical and radiological features, diagnostic approaches and prospects for rational therapies for this enigmatic small vessel disorder is provided.

Cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk Updated meta-analysis

Objective: We performed a systematic review and meta-analysis to assess whether the presence of cerebral microbleeds (CMBs) on pretreatment MRI scans of patients with acute ischemic stroke treated with thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (ICH). Methods: We searched PubMed for relevant studies and calculated pooled odds ratios (ORs) for symptomatic ICH, using the Mantel–Haenszel fixed-effects method, among individuals with vs without CMBs on pretreatment MRI scans. To minimize potential bias, sensitivity analysis was performed including studies providing data on patients treated only with IV thrombolysis. Results: Ten eligible studies including 2,028 patients were pooled in meta-analysis. The overall prevalence of CMBs was 23.3%. Among patients with CMBs, 40 of 472 (8.5%; 95% confidence interval [CI]: 6.1%–11.4%) experienced a symptomatic ICH after thrombolysis compared with 61 of 1,556 patients (3.9%; 95% CI: 3%–5%) without CMBs. The pooled OR of ICH across all studies was 2.26 (95% CI: 1.46–3.49; p p Conclusions: Our meta-analysis of the available published data demonstrates an increased risk of symptomatic ICH after thrombolysis for acute ischemic stroke in patients with CMBs. However, we cannot fully exclude bias or confounding, so our results should be considered hypothesis-generating. Detecting CMBs should not prevent thrombolytic treatment based on present evidence. Further analyses, taking into account CMB number and location, as well as measures of functional outcome, are needed.Objective: We performed a systematic review and meta-analysis to assess whether the presence of cerebral microbleeds (CMBs) on pretreatment MRI scans of patients with acute ischemic stroke treated with thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (ICH). Methods: We searched PubMed for relevant studies and calculated pooled odds ratios (ORs) for symptomatic ICH, using the Mantel–Haenszel fixed-effects method, among individuals with vs without CMBs on pretreatment MRI scans. To minimize potential bias, sensitivity analysis was performed including studies providing data on patients treated only with IV thrombolysis. Results: Ten eligible studies including 2,028 patients were pooled in meta-analysis. The overall prevalence of CMBs was 23.3%. Among patients with CMBs, 40 of 472 (8.5%; 95% confidence interval [CI]: 6.1%–11.4%) experienced a symptomatic ICH after thrombolysis compared with 61 of 1,556 patients (3.9%; 95% CI: 3%–5%) without CMBs. The pooled OR of ICH across all studies was 2.26 (95% CI: 1.46–3.49; p < 0.0001). Eight studies, including 1,704 patients (n = 401 with CMBs), provided data on patients treated with IV thrombolysis only; OR for the presence of CMBs and the development of symptomatic ICH was 2.87 (95% CI: 1.76–4.69; p < 0.0001). Conclusions: Our meta-analysis of the available published data demonstrates an increased risk of symptomatic ICH after thrombolysis for acute ischemic stroke in patients with CMBs. However, we cannot fully exclude bias or confounding, so our results should be considered hypothesis-generating. Detecting CMBs should not prevent thrombolytic treatment based on present evidence. Further analyses, taking into account CMB number and location, as well as measures of functional outcome, are needed.

Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis

Genetic factors have been suggested to be involved in the pathogenesis of sporadic inclusion body myositis (sIBM). Sequestosome 1 (SQSTM1) and valosin-containing protein (VCP) are 2 key genes associated with several neurodegenerative disorders but have yet to be thoroughly investigated in sIBM. A candidate gene analysis was conducted using whole-exome sequencing data from 181 sIBM patients, and whole-transcriptome expression analysis was performed in patients with genetic variants of interest. We identified 6 rare missense variants in the SQSTM1 and VCP in 7 sIBM patients (4.0%). Two variants, the SQSTM1 p.G194R and the VCP p.R159C, were significantly overrepresented in this sIBM cohort compared with controls. Five of these variants had been previously reported in patients with degenerative diseases. The messenger RNA levels of major histocompatibility complex genes were upregulated, this elevation being more pronounced in SQSTM1 patient group. We report for the first time potentially pathogenic SQSTM1 variants and expand the spectrum of VCP variants in sIBM. These data suggest that defects in neurodegenerative pathways may confer genetic susceptibility to sIBM and reinforce the mechanistic overlap in these neurodegenerative disorders.

The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis

A previous study showed that, in carriers of the apolipoprotein E (APOE) genotype ε3/ε3 or ε3/ε4, the presence of a very long (VL) polyT repeat allele in “translocase of outer mitochondrial membrane 40” (TOMM40) was less frequent in patients with sporadic inclusion body myositis (sIBM) compared with controls and associated with a later age of sIBM symptom onset, suggesting a protective effect of this haplotype. To further investigate the influence of these genetic factors in sIBM, we analyzed a large sIBM cohort of 158 cases as part of an International sIBM Genetics Study. No significant association was found between APOE or TOMM40 genotypes and the risk of developing sIBM. We found that the presence of at least 1 VL polyT repeat allele in TOMM40 was significantly associated with about 4 years later onset of sIBM symptoms. The age of onset was delayed by 5 years when the patients were also carriers of the APOE genotype ε3/ε3. In addition, males were likely to have a later age of onset than females. Therefore, the TOMM40 VL polyT repeat, although not influencing disease susceptibility, has a disease-modifying effect on sIBM, which can be enhanced by the APOE genotype ε3/ε3.

Genetic advances in sporadic inclusion body myositis.

Purpose of reviewTo describe recent developments in the genetics of sporadic inclusion body myositis (sIBM). Recent findingsGenes located within major histocompatibility complex regions remain the strongest genetic association with sIBM. The rs10527454 polymorphism in the TOMM40 gene seems to have a disease modifying effect on sIBM by delaying the onset of symptoms, and this effect may be enhanced by the APOE &egr;3/&egr;3 genotype. Rare variants in the VCP and SQSTM1 genes have been identified in sIBM patients in two studies using targeted next-generation sequencing and whole-exome sequencing. Two studies have confirmed the correlation between the amount of cytochrome c oxidase -deficient fibres and the proportion of mitochondrial DNA (mtDNA) deletions in sIBM. Some rare variants in mtDNA-related nuclear genes have also been reported. SummaryThere have been advances in the genetics of sIBM over the past 2 years facilitated by the use of next-generation sequencing. Genes that cause hereditary IBM, which has clinical or pathological features resembling sIBM, have provided clues to the genetic basis of sIBM. To date, genes located in major histocompatibility complex regions and genes involved in protein homeostasis or mtDNA maintenance have been implicated in sIBM. Whole-exome sequencing-association studies, RNA sequencing, and whole-genome sequencing in large sIBM cohorts will be key tools to unravel the genetics of sIBM and its contribution to disease aetiopathogenesis.

Ongoing Developments in Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. Ongoing developments include: genetic studies that may provide insights regarding the pathogenesis of IBM, improved histopathological markers, the description of a new IBM autoantibody, scrutiny of the diagnostic utility of clinical features and biomarkers, the refinement of diagnostic criteria, the emerging use of MRI as a diagnostic and monitoring tool, and new pathogenic insights that have led to novel therapeutic approaches being trialled for IBM, including treatments with the objective of restoring protein homeostasis and myostatin blockers. The effect of exercise in IBM continues to be investigated. However, despite these ongoing developments, the aetiopathogenesis of IBM remains uncertain. A translational and multidisciplinary collaborative approach is critical to improve the diagnosis, treatment, and care of patients with IBM.

Tubular Aggregates and Cylindrical Spirals Have Distinct Immunohistochemical Signatures.

Tubular aggregates and cylindrical spirals are 2 distinct ultrastructural abnormalities observed in muscle biopsies that have similar histochemical staining characteristics on light microscopy. Both are found in a wide range of disorders. Recently, a number of genetic mutations have been reported in conditions with tubular aggregates in skeletal muscle. It is widely accepted that tubular aggregates arise from the sarcoplasmic reticulum, but the origin of cylindrical spirals has been less clearly defined. We describe the histopathological features of myopathies with tubular aggregates, including a detailed immunohistochemical analysis of congenital myasthenic syndromes with tubular aggregates due to mutations in GFPT1 and DPAGT1, and myopathies with cylindrical spirals. Our findings support the notion that cylindrical spirals, like tubular aggregates, derive primarily from the sarcoplasmic reticulum; however, immunohistochemistry indicates that different molecular components of the sarcoplasmic reticulum may be involved and can be used to distinguish between these different inclusions. The immunohistochemical differences may also help to guide genetic testing.