Background: The semantic variant of primary progressive aphasia (svPPA) is a form of dementia, mainly featuring language impairment, for which the extent of white matter (WM) damage is less described than its associated grey matter (GM) atrophy. Our study aimed to characterise the extent of this damage using a sensitive and unbiased approach. Methods: We conducted a between-group study comparing 10 patients with a clinical diagnosis of svPPA, recruited between 2011 and 2014 at a tertiary reference centre, with 9 cognitively healthy, age-matched controls. From diffusion tensor imaging (DTI) data, we extracted fractional anisotropy (FA) values using a tract-based spatial statistics approach. We further obtained GM volumetric data using the Freesurfer automated segmentation tool. We compared both groups using non-parametric Wilcoxon rank-sum tests, correcting for multiple comparisons. Results: Demographic data showed that patients and controls were comparable. As expected, clinical data showed lower results in svPPA than controls on cognitive screening tests. Tractography showed impaired diffusion in svPPA patients, with FA mostly decreased in the longitudinal, uncinate, cingulum and external capsule fasciculi. Volumetric data show significant atrophy in svPPA patients, mostly in the left entorhinal, amygdala, inferior temporal, middle temporal, superior temporal and temporal pole cortices, and bilateral fusiform gyri. Conclusions: This syndrome appears to be associated not only with GM but also significant WM degeneration. Thus, DTI could play a role in the differential diagnosis of atypical dementia by specifying WM damage specific to svPPA.

Most endovascular innovations have been introduced into clinical care by showing good outcomes in small enthusiastic case series of selected patients. Randomized clinical trials (RCTs) have rarely been performed, except for acute ischemic stroke, but even then most trial designs were too explanatory to inform clinical decisions. In this article, we review 2 × 2 tables and forest plots that summarize RCT results to examine methodological issues in the design and interpretation of clinical studies. Research results can apply in practice when RCTs are all-inclusive, pragmatic trials. Common problems include the following: (i) using restrictive eligibility criteria in explanatory trials, instead of including the diversity of patients in need of care, which hampers future generalizability of results; (ii) ignoring an entire line of the 2 × 2 table and excluding patients who do not meet the proposed criteria of a diagnostic test in its evaluation (perfusion studies) which renders clinical inferences misleading; (iii) ignoring an entire column of the 2 × 2 table and comparing different patients treated using the same treatment instead of different treatments in the same patients (the “wrong axis” comparisons of prognostic studies and clinical experience) which leads to unjustified treatment decisions and actions; or (iv) combining all aforementioned problems (case series and epidemiological studies). The most efficient and reliable way to improve patient outcomes, after as well as long before research results are available, is to change the way we practice: to use care trials to guide care in the presence of uncertainty.

The Canadian Association of Neuropathologists (CANP) held their 58th annual meeting at the Halifax Harbourfront Marriott from October 3rd to 6th, 2018, under the leadership of Dr Marc Del Bigio, CANP president, and Dr. Sidney Croul handled the local arrangements. The annual banquet was held at Chives restaurant in Halifax.

The academic program of 20 scientific abstracts and 8 unknown cases was compiled by the CANP Secretary-Treasurer Dr Julia Keith into 5 sessions; I. Traumatic and Neurodegenerative Neuropathology, II. Pediatric, Epilepsy and Miscellaneous Neuropathology, III. Tumour Neuropathology, IV. Infectious/Immune Mediated Neuropathology, and V. Quality Assurance in Neuropathology. The Quality Assurance session included a guided interactive forum led by Dr Marc Del Bigio, and the Neurodegenerative session included an invited talk on Butyrylcholinesterase as a Biomarker for Alzheimer’s Disease by Dr Sultan Darvesh (Faculty of Medicine, Dalhousie University). The digital pathology images from the 8 unknown cases are available for viewing online (www.canp.ca) thanks to the CANP webmaster, Dr Jason Karamchandani.

The Presidential Symposium explored the theme of Brain Inflammation. Dr Sean Pittock (Dept of Neurology, Mayo Clinic, Rochester, MN) delivered the Dr Jerzy Olszewski Guest Lecture entitled Neural autoantibody discovery: the new era of autoimmune neurology – out with the old and in with the new! Dr Christian Pagnoux (Vasculitis Clinic, Mount Sinai Hospital, Toronto ON) was an invited speaker who spoke on Vasculitis – effects on the nervous system. Dr Alex Easton (Dept of Pathology, Dalhousie University, Halifax NS) was the Dr Gordon Mathieson invited lecturer speaking about The blood brain barrier and inflammation, and Dr Serge Rivest (Directeur du Centre de Recherche du CHU de Québec, Université Laval, Quebec QC) delivered the Dr David Robertson invited lecture on Microglial roles in human neuropathology. The symposium concluded with a panel discussion and group Question and Answer session with the speakers moderated by Dr Marc Del Bigio.

Several trainee awards were handed out. The Dr Mary Tom Award for best clinical science paper was awarded to Dr Maryam Abdollahi (supervisor Dr David Munoz) and the Dr Morrison H. Finlayson Award for best basic science/research paper went to Dr Maliha Khara (Drs Zhou, Wong, Renwick).

The following abstracts were presented at the 58th annual meeting of the Canadian Association of Neuropathologists (CANP) in October 2018.

Background: Observational studies have reported an association between childhood obesity and a higher risk of multiple sclerosis (MS). However, the difficulties to fully account for confounding and long recall periods make causal inference from these studies challenging. The objective of this study was to assess the contribution of childhood obesity to the development of MS through Mendelian randomization, which uses genetic associations to minimize the risk of confounding. Methods: We selected 23 independent genetic variants strongly associated with childhood body mass index (BMI) in a genome-wide association study (GWAS) which included 47,541 children. The corresponding effects of these variants on risk of MS were obtained from a GWAS of 14,802 MS cases and 26,703 controls. Standard two-sample Mendelian randomization methods were performed, with additional sensitivity analyses to assess the likelihood of bias from genetic pleiotropy. Results: The inverse-variance weighted MR analysis revealed that one standard deviation increase in childhood BMI increased odds of MS by 26% (odds ratio=1.26, 95% confidence interval 1.10-1.45, p=0.001). There was no significant heterogeneity across the individual estimates. Sensitivity analyses were consistent with the main findings and provided no evidence of pleiotropy. Conclusions: This study provides genetic support of a role for increased childhood BMI in the development of MS.

In Canada, recreational use of cannabis was legalized in October 2018. This policy change along with recent publications evaluating the efficacy of cannabis for the medical treatment of epilepsy and media awareness about its use have increased the public interest about this agent. The Canadian League Against Epilepsy Medical Therapeutics Committee, along with a multidisciplinary group of experts and Canadian Epilepsy Alliance representatives, has developed a position statement about the use of medical cannabis for epilepsy. This article addresses the current Canadian legal framework, recent publications about its efficacy and safety profile, and our understanding of the clinical issues that should be considered when contemplating cannabis use for medical purposes.

There has been a significant transformation in the treatment of intracranial aneurysms (IAs) over the past century, with the most pivotal changes occurring in the past three decades. To characterize this evolution, we assessed the number of articles published on various procedures for the treatment of IA as a measure of their interest and usage over time. We separated our analysis into two main areas: surgical and endovascular approaches. We further subdivided these two main categories into clipping and bypass for surgery, and coiling, flow diversion, and liquid material embolization for endovascular approaches. We found 5956 publications on open surgical approaches in the 70-year period from 1947 to 2017, with papers on clipping (n = 4204), being the most common. We found 8602 endovascular publications beginning in 1964, with most of the activity taking place in the late 1990s and beyond. Coiling had the most publications of the endovascular approaches (n = 5436). In 1999, the number of annual publications on endovascular treatments surpassed those of open surgery, signaling a crossover point in the IA literature. The same trend continues to this date.

Background: Mutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 up-regulation exacerbates TDP-43 cytoplasmic aggregates. Methods: To analyse interaction between UBQLN2 and TDP-43 and to produce a relevant ALS animal model, we have generated a new transgenic mouse expressing UBQLN2P497H under the neurofilament heavy (NFH) gene promoter. The mice were then bred with our previously described TDP-43G348C mice to generate double transgenic mice. Results: With low expression UBQLN2, the double transgenic mice developed TDP-43 cytosolic accumulations in motor neurons starting at 5 months of age. These double transgenic mice exhibited motor neuron loss, muscle atrophy, as well as motor and cognitive deficits during aging. The microglia from double transgenic mice were hyperresponsive to lipopolysaccharide (LPS). In vivo and in vitro analyses suggested that extra UBQLN2 proteins can exacerbate cytoplasmic TDP-43 accumulations by competing with the UPS for binding to ubiquitin. Thus, increasing the pool of ubiquitin promoted the UPS function with ensuing reduction of TDP-43 aggregation. Conclusions: In conclusion, the double transgenic UBQLN2P497H; TDP-43G348C mice provides a unique mouse model of ALS/FTD with enhanced TDP-43 pathology that can be exploited for drug testing.

Introduction: White matter hyperintensities (WMHs) were commonly seen in brain magnetic resonance imaging (MRI) of the elderly. Many studies found that WMHs were associated with cognitive decline and dementia. However, the association between WMHs in different brain regions and cognitive decline remains debated. Methods: We explored the association of the severity of WMHs and cognitive decline in 115 non-demented elderly (≥50 years old) sampled from the Wuliqiao Community located in urban area of Shanghai. MRI scans were done during 2009–2011 at the beginning of the study. Severity of WMHs in different brain regions was scored by Improved Scheltens Scale and Cholinergic Pathways Hyperintensities Scale (CHIPS). Cognitive function was evaluated by Mini-Mental State Examination (MMSE) every 2 to 4 years during 2009–2018. Results: After adjusting for confounding factors including age, gender, education level, smoking status, alcohol consumption, depression, hypertension, diabetes, hyperlipidemia, brain infarcts, brain atrophy, apoE4 status, and baseline MMSE score, periventricular and subcortical WMH lesions as well as WMHs in cholinergic pathways were significantly associated with annual MMSE decline ( p < 0.05), in which the severity of periventricular WMHs predicted a faster MMSE decline (–0.187 points/year, 95% confidence interval: –0.349, –0.026, p = 0.024). Conclusions: The severity of WMHs at baseline was associated with cognitive decline in the non-demented elderly over time. Interventions on WMH lesions may offer some benefits for cognitive deterioration.

This literature review provides an overview of the research using magnetic resonance imaging (MRI) in pediatric migraine and compares findings with the adult migraine literature. A literature search using PubMed was conducted using all relevant sources up to February 2019. Using MRI methods to categorize and explain pediatric migraine in comparison with adult migraine is important, in order to recognize and appreciate the differences between the two entities, both clinically and physiologically. We aim to demonstrate the differences and similarities between pediatric and adult migraine using data from white matter and gray matter structural studies, cerebral perfusion, metabolites, and functional MRI (fMRI) studies, including task-based and resting-state blood oxygen level-dependent studies. By doing this we identify areas that need further research, as well as possible areas where intervention could alter outcomes.

Mild traumatic brain injury (mTBI) or concussion is a very common occurrence in contact sports, and can cause brain damage with long-term symptoms, including depression, aggression, memory loss, and an increased risk of neurodegeneration later in life. Recently, there has been increased attention towards concussion in sport both in research and media, however the nature and pathophysiology of mTBI-induced neurodegeneration remain unknown. The objective of this study is to identify early pathophysiological markers of TBI. This study used a collection of donated postmortem brains with a history of repetitive mTBI in contact sports and non-TBI control brains. Nanostring ncounter’s immune panel was used to evaluate gene expression, and results showed that brains with a history of TBI tended to group with significantly older brains with no history of TBI in regards to their immune profile. Further analysis of this expression panel revealed that genes associated with senescence and secretory phenotype were upregulated in brains with a history of mTBI. Additionally, immunohistochemistry for γ-H2AX (a marker for double stranded DNA breaks) showed that brains with a history of repetitive TBI accumulated a spectrum of DNA damages not present in controls. This damage was widespread and involved mainly glial cells including oligodendrocytes, and astrocytes. The latter showed morphological changes reminiscent of senescence, including soma swelling and beading of processes. Further, these changes were accompanied by translocation of structural nuclear proteins. These changes preceded the appearance of abnormal protein deposition in the brain. Overall, these results suggest that DNA damage and cellular senescence are upstream events in the manifestation of post-mTBI symptoms and pathology, and represent promising opportunities for discovery of biomarkers for early TBI detection and follow-up of progression.

After five positive randomized controlled trials showed benefit of mechanical thrombectomy in the management of acute ischemic stroke with emergent large-vessel occlusion, a multi-society meeting was organized during the 17th Congress of the World Federation of Interventional and Therapeutic Neuroradiology in October 2017 in Budapest, Hungary. This multi-society meeting was dedicated to establish standards of practice in acute ischemic stroke intervention aiming for a consensus on the minimum requirements for centers providing such treatment. In an ideal situation, all patients would be treated at a center offering a full spectrum of neuroendovascular care (a level 1 center). However, for geographical reasons, some patients are unable to reach such a center in a reasonable period of time. With this in mind, the group paid special attention to define recommendations on the prerequisites of organizing stroke centers providing medical thrombectomy for acute ischemic stroke, but not for other neurovascular diseases (level 2 centers). Finally, some centers will have a stroke unit and offer intravenous thrombolysis, but not any endovascular stroke therapy (level 3 centers). Together, these level 1, 2, and 3 centers form a complete stroke system of care. The multi-society group provides recommendations and a framework for the development of medical thrombectomy services worldwide.

Different treatment options for carotid in-stent restenosis (ISR) have been reported with good outcome, including carotid endarterectomy (CEA), repeated carotid angioplasty stenting (CAS) and percutaneous transluminal angioplasty (PTA) with drug-coated balloons (DCBs). However, the optimal treatment option for ISR has not yet been determined. A systematic literature search was performed in the databases of Medline, Embase, Cochrane library, and unpublished data from clinicaltrials.gov from 1990 to March 1, 2019. Studies were enrolled if they reported treatment strategies for carotid ISR treatment and met the inclusion criteria. After study inclusions, data were extracted and summarized. Totally 25 cross-sectional studies were included, containing 5 comparative studies, 16 studies using repeated PTA, and 4 studies adopting CEA treatment. Our study summarized the current available data, showing that all the studies could effectively relieve the carotid ISR by significantly improving the angiographic stenosis and decreasing the peak systolic velocity values. Meanwhile, CEA treatment had the best long-term effects in relieving restenosis, while re-PTA with stenting/balloon angioplasty had a certain rate of restenosis, ranging from 33% to 83%. Furthermore, re-PTA/stenting and balloon angioplasty treatment had less complications compared with CEA. Also, we analyzed the risk factors that might affect the long-term prognosis of carotid ISR patients. The therapeutic measures for carotid ISR had their own features, with CEA had the highest efficacy while re-PTA/stenting and balloon angioplasty were with less complications. More large-scale comparative clinical studies are needed to further ascertain the best strategies.

Among healthy volunteers in psychiatric brain functional magnetic resonance imaging (fMRI) research studies, the prevalence of incidentalomas can be as high as 34%, of which 10% show clinical significance. An incidentaloma is a lesion found by coincidence without clinical symptoms or suspicion. Like lesions and other types of accidental findings, it is found in healthy individuals recruited to take part in psychiatric studies. The prevalence of these accidental findings among specific psychiatric populations remains unknown. However, a precise understanding of cerebral neuroanatomy, neuroradiological expertise, and an appropriate choice of fMRI exploration sequences will increase the sensitivity of identifying these accidental findings and enable researchers to address their clinical relevance and nature. We present recommendations on how to appropriately inform patients or participants of the accidental findings. Additionally, we propose specific suggestions pertaining to the clinical research setting aimed for investigators and psychiatrists. Unlike current articles pertaining to incidentaloma, the current report provides a distinct focus on psychiatric issues and specific recommendations for studies involving psychiatric patients.

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease that targets motor neurons. Upper motor neurons degeneration is pathologically characterized by brain iron accumulation. Signal attenuation in the shape of a ribbon at the posterior border of the precentral gyrus can be observed on conventional magnetic resonance imaging (MRI) sequences including T2-weighted sequence. Methods: With the aim to know the qualities of this potential marker of ALS, we conducted a prospective study. Patients with definite ALS in the age range of 40–70 years and healthy controls underwent 3T brain MRI using a standardized sequence. A second MRI was performed 18 months later under the same conditions in the patients with ALS. Results: Most of the patients with ALS (91.66%) exhibited a “black ribbon” (BR) with an average area of 79.98 mm3. Signal attenuation discriminated ALS with a mean value of 63.97 arbitrary units (AU) on the left BR (95% CI: 60.67–67.27), a mean value of 59.15 AU (95% CI: 54.78–63.53) on the right BR, and a significant difference with control subjects presenting a mean value of 107.85 AU (p < 0.001). The optimal cut-off point for differentiating patients with ALS from controls (sensitivity, 0.92; specificity, 0.93) was 83 AU. Forced vital capacity and muscle strength in the contralateral upper extremity were significantly correlated with the ribbon intensity in ALS. Patients who underwent a second study exhibited significant changes in the BR related to the rapid evolution of the disease. Conclusions: This marker represents a valuable tool for the selection of candidates and their follow-up in clinical trials.