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BACKGROUND: Delusions affect approximately a third of Alzheimer’s disease(AD) patients and are associated with poor outcomes. Previous studies investigating the neuroanatomical correlates of delusions have yet to reach a consensus, with findings of reduced volume across all the lobes, particularly in frontal regions. The current study examined the grey matter(GM) differences associated with delusions in AD. METHODS: Using voxel-based morphometry(VBM), we assessed GM for 23 AD patients who developed delusions(AD+D) and 36 comparable AD patients who did not develop delusions(AD-D) at baseline and follow up. ANOVA was used to identify consistent differences between AD+D and AD-D patients across both timepoints(main effect of group), consistent changes from baseline to follow up(main effect of time) and differential changes between AD+D and AD-D over time(interaction of group and time). All data were obtained from the NACC database. RESULTS: The AD+D group had consistently lower frontal GM volume, although both groups showed decreased GM in fronto-temporal brain regions over time. An interaction was observed between delusions and longitudinal change, with AD+D patients having significantly elevated GM in predominantly temporal areas at baseline assessment, which had declined to become significantly lower than the AD-D group at follow-up. CONCLUSION: These findings suggest that although individuals with and without delusion show long-term GM decreases, there are specific volumetric markers that distinguish patients with delusion from those without, before and after the onset of delusions. Specifically, the decline of GM in temporal areas that were elevated prior to the onset of delusion may be involved in the manifestation of delusions.

Medulloblastoma (MB) is a pediatric malignant brain tumor composed of four different subgroups (WNT, SHH, Group 3, Group 4), each of which are a unique biological entity with distinct clinico-pathological, molecular, and prognostic characteristics. Although risk stratification of patients with MB based on molecular features may offer personalized therapies, conventional subgroup identification methods take too long and are unable to deliver subgroup information intraoperatively. This limitation prevents subgroup-specific adjustment of the extent or the aggressiveness of the tumor resection by the neurosurgeon. In this study, we investigated the potential of rapid tumor characterization with Picosecond infrared laser desorption mass spectrometry (PIRL-MS) for MB subgroup classification based on small molecule signatures. One hundred and thirteen ex vivo MB tumors from a local tissue bank were subjected to 10- to 15-second PIRL-MS data collection and principal component analysis with linear discriminant analysis (PCA-LDA). The MB subgroup model was established from 72 independent tumors; the remaining 41 de-identified unknown tumors were subjected to multiple, 10-second PIRL-MS samplings and real-time PCA-LDA analysis using the above model. The resultant 124 PIRL-MS spectra from each sampling event, after the application of a 95% PCA-LDA prediction probability threshold, yielded a 98.9% correct classification rate. Post-ablation histopathologic analysis suggested that intratumoral heterogeneity or sample damage prior to PIRL-MS sampling at the site of laser ablation was able to explain failed classifications. Therefore, upon translation, 10-seconds of PIRL-MS sampling is sufficient to allow personalized, subgroup-specific treatment of MB during surgery. Significance: This study demonstrates that laser-extracted lipids allow immediate grading of medulloblastoma tumors into prognostically important subgroups in 10 seconds, providing medulloblastoma pathology in an actionable manner during surgery.

Objective Spinal meningiomas are one of the frequently seen intradural extramedullary spinal tumors. They are almost always World Health Organization grade I, and a complete removal of the tumor can be curative. However, ventrally located spinal meningioma removal can be challenging due to the position in front of the spinal cord through a narrow corridor provided by routine dorsal approaches. Incomplete excision of the relatively inaccessible dural attachment can consequently lead to recurrence. We describe a safe and reproducible technique used to achieve Simpson grade I removal of ventrally located spinal meningioma. Methods Since the spinal dura can be easily divided into inner and outer layers and the tumor usually spares the outer layer, we developed a simple technique to achieve total resection of the tumor and involved dura while leaving the outer dural layer intact. Results An advantage of this procedure is that it exploits an interdural approach to allow early devascularization of the tumor without cord manipulation and provides access to the ventral dura to achieve Simpson grade I excision. Another advantage is complete dural closure to minimize postoperative cerebrospinal fluid leak or ventral cord herniation without the need for dural substitutes. Conclusion Its novel interdural approach can be used for all ages and all spinal meningiomas.

Objectives:To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study.Design:Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed.Setting:Community-based multi-centered study based in Toronto across 5 academic sites.Participants:Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls.Measurements:We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores.Results:A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD.Conclusions:This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.

Neuropsychiatric symptoms (NPS) are common sequelae of traumatic brain injuries (TBI) among adults. However, little is known about NPS associated with a history of TBI in adults relative to adults without a history of TBI and to what extent NPS may be modulated by sex and other factors. Using the National Alzheimer's Coordinating Center Uniform Data Set, we examined the association between Neuropsychiatric Inventory-Questionnaire (NPI-Q) scores in cognitively normal older adults with and without a history of TBI. A binomial logistic regression model was used to examine NPI-Q domains in adults with a history of TBI (n = 266) versus without a history of TBI (n = 1508). History of TBI, sex, age, and body mass index were used as covariates. Adults with a history of TBI had a greater probability of exhibiting agitation, anxiety, apathy, disinhibition and aberrant motor behavior relative to adults without a history of TBI. In terms of sex differences, males with and without a history of TBI had an increased likelihood of agitation, apathy, disinhibition, and apnea, whereas females had an increased likelihood of anxiety and insomnia relative to males. Our study confirms that history of TBI is associated with an increased prevalence of specific NPS, including agitation, anxiety, apathy, disinhibition, and aberrant motor behavior. Given that the aforementioned NPS are linked through different pathways, damage to any of them may cause an alteration in behavior. As well, NPS appear to be modulated by sex, with symptoms differing between males and females. Our research suggests future studies examining NPS sequelae of TBI should adjust for sex.

Patients undergoing standard chemoradiation post-resection had MRIs at radiation planning and fractions 10 and 20 of chemoradiation. MRIs were 1.5T and 3D T2-FLAIR, pre- and post-contrast 3D T1-weighted (T1) and echo planar DWI with three b-values (0, 500, and 1000s/mm2) were acquired. T2-FLAIR was coregistered to T1C images. Non-overlapping T1 contrast-enhancing (T1C) and nonenhancing T2-FLAIR hyperintense regions were segmented, with necrotic/cystic regions, the surgical cavity, and large vessels excluded. The simplified IVIM model was used to calculate voxelwise diffusion coefficient (D) and perfusion fraction (f) maps; ADC was calculated using the natural logarithm of b = 1000 over b = 0 images. T1C and T2-FLAIR segmentations were brought into this space, and medians calculated. MGMT promoter methylation status (MGMTPMS), age at diagnosis, and Eastern Cooperative Oncology Group (ECOG) performance status were extracted from electronic medical records. The data were presented, analyzed, and described in the article, “Intravoxel incoherent motion (IVIM) modeling of diffusion MRI during chemoradiation predicts therapeutic response in IDH wildtype Glioblastoma”, published in Radiotherapy and Oncology [1] .

ObjectiveThe Systemic Synuclein Sampling Study (S4) measured α-synuclein in multiple tissues and biofluids within the same patients with Parkinson disease (PD) vs healthy controls (HCs).MethodsS4 was a 6-site cross-sectional observational study of participants with early, moderate, or advanced PD and HCs. Motor and nonmotor measures and dopamine transporter SPECT were obtained. Biopsies of skin, colon, submandibular gland (SMG), CSF, saliva, and blood were collected. Tissue biopsy sections were stained with 5C12 monoclonal antibody against pathologic α-synuclein; digital images were interpreted by neuropathologists blinded to diagnosis. Biofluid total α-synuclein was quantified using ELISA.ResultsThe final cohort included 59 patients with PD and 21 HCs. CSF α-synuclein was lower in patients with PD vs HCs; sensitivity/specificity of CSF α-synuclein for PD diagnosis was 87.0%/63.2%, respectively. Sensitivity of α-synuclein immunoreactivity for PD diagnosis was 56.1% for SMG and 24.1% for skin; specificity was 92.9% and 100%, respectively. There were no significant relationships between different measures of α-synuclein within participants.ConclusionsS4 confirms lower total α-synuclein levels in CSF in patients with PD compared to HCs, but specificity is low. In contrast, α-synuclein immunoreactivity in skin and SMG is specific for PD but sensitivity is low. Relationships within participants across different tissues and biofluids could not be demonstrated. Measures of pathologic forms of α-synuclein with higher accuracy are critically needed.Classification of evidenceThis study provides Class III evidence that total CSF α-synuclein does not accurately distinguish patients with PD from HCs, and that monoclonal antibody staining for SMG and skin total α-synuclein is specific but not sensitive for PD diagnosis.

ObjectiveIn individuals over the age of 65, concomitant neurodegenerative pathologies contribute to cognitive and/or motor decline and can be aggravated by cerebrovascular disease, but our understanding of how these pathologies synergize to produce the decline represents an important knowledge gap. The Ontario Neurodegenerative Disease Research Initiative (ONDRI), a multi-site, longitudinal, observational cohort study, recruited participants across multiple prevalent neurodegenerative diseases and cerebrovascular disease, collecting a wide array of data and thus allowing for deep investigation into common and unique phenotypes. This paper describes baseline features of the ONDRI cohort, understanding of which is essential when conducting analyses or interpreting results.MethodsFive disease cohorts were recruited: Alzheimer’s disease/amnestic mild cognitive impairment (AD/MCI), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease (PD), and cerebrovascular disease (CVD). Assessment platforms included clinical, neuropsychology, eye tracking, gait and balance, neuroimaging, retinal imaging, genomics, and pathology. We describe recruitment, data collection, and data curation protocols, and provide a summary of ONDRI baseline characteristics.Results520 participants were enrolled. Most participants were in the early stages of disease progression. Participants had a median age of 69 years, a median Montreal Cognitive Assessment score of 25, a median percent of independence of 100 for basic activities of daily living, and a median of 93 for instrumental activities. Variation between disease cohorts existed for age, level of cognition, and geographic location.ConclusionONDRI data will enable exploration into unique and shared pathological mechanisms contributing to cognitive and motor decline across the spectrum of neurodegenerative diseases.

Skilled professional artists are sometimes able to maintain their talents while other cognitive functions deteriorate due to brain diseases. The objective of this study is to asses the preserved artistry of a professional painter in spite of the presence of strokes affecting brain areas implicated in art expression. She had a neurologic evaluation and brain imaging after the stroke; painter-curators analyzed and compared the painter's pictorial artwork created before and after the stroke. In spite of cerebellar, visuospatial, motor, cognitive, and functional deficits likely related to strokes affecting bilateral cerebellar, left occipital, and right temporal-occipital areas, the patient was able to maintain most of their artistic painting skills.. After a short period of functional recovery, our patient showed discrepancy among their impaired cerebellar cerebral functions in day activities and their preserved painting abilities.

Purpose To validate ferumoxytol-based quantitative blood oxygenation level-dependent (BOLD) MRI for mapping oxygenation of human infiltrative astrocytomas by using intraoperative measurement of tissue oxygen tension and histologic staining. Materials and Methods Fifteen patients with infiltrative astrocytomas were recruited into this prospective multicenter study between July 2014 and December 2016. Prior to treatment, participants underwent preoperative quantitative BOLD MRI with ferumoxytol to generate tissue oxygen saturation (StO2) maps. Two intratumoral sites were identified, one with low StO2 and one with high StO2. Neuronavigation was used to locate sites intraoperatively for insertion of oxygen-sensing probes to measure local tissue oxygen tension (PtO2). Biopsies from both sites were taken and stained for markers of hypoxia (hypoxia-inducible factor 1α, carbonic anhydrase IX) and neoangiogenesis (vascular endothelial growth factor, endoglin [CD105]). Spearman correlation and nonparametric sign-rank tests were used to analyze data. Results Ten patients with median age of 58.5 years (interquartile range, 25 years; four men and six women) completed the study. Because there is no linear relationship between StO2 and PtO2, the ratios of low to high StO2 versus low to high PtO2 in each patient were compared and a significant correlation was found (r = 0.73; P = .01). Pathologic analyses revealed differences between carbonic anhydrase IX (P = .03) for sites of low StO2 versus high StO2. CD105 displayed a similar trend but was not significant (P = .09). Conclusion Ferumoxytol-based quantitative blood oxygenation level-dependent MRI can potentially be used as a noninvasive surrogate for oxygenation mapping in infiltrative astrocytomas. This technique can potentially be integrated in treatment planning for aggressive targeting of hypoxic areas in tumors.

Consider neuronal intranuclear inclusion disease in a patient with high diffusion-weighted imaging signals along the corticomedullary junction and paravermal high T2 signals on brain MRI. A prompt skin biopsy must be performed to assess for the presence of characteristic intranuclear inclusions.

Introduction The relative contributions of vascular and degenerative pathology to dementia are unknown. We aim to quantify the proportion of dementia explained by potentially preventable vascular lesions. Methods We systematically searched for population-based cohorts before February 2017 reporting clinicopathological data for individuals with and without dementia. We calculated the summary proportion and absolute risk of dementia comparing subjects with and without the pathology. Results We identified 10 studies comprising 2856 subjects. Vascular-type pathology and mixed pathology are respectively two and three times more likely in demented patients. The summary proportion of dementia is 77%–86% in subjects with mixed degenerative and vascular pathology and 45% in subjects with pure Alzheimer-type pathology. Discussion Patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer-type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component.

Congenital cytomegalovirus (CMV) infection in the 2supnd/supand 3suprd/suptrimester results in catastrophic CNS abnormalities. This susceptibility is thought to result from the high proportion of neural stem cells in the developing brain. In immunocompromised adults, CNS infection by CMV preferentially affects ependymal surfaces, from where it expands to involve the parenchyma. Experimental models of murine CMV infection demonstrate viral tropism for the dentate gyrus (DG) and subventricular zone, the areas in which adult neurogenesis occurs. We present two cases of CMV infection of the DG of immunocompromised allogeneic stem cell transplant recipients. Both cases showed CMV-positive neurons in the DG granular cell layer, as well as contiguous layers. The majority of infected cells contained Nissl substance and expressed nestin, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), and neurofilament. These cases demonstrate that CMV infects the DG in humans. Co-expression of nestin and GFAP, indicative of early neurogenesis, is consistent with experimental models showing neural stem cells as the target of CMV, providing further histological evidence of neurogenesis in the human dentate. Finally, the cases suggest that CMV infection produces abnormal migration of newly formed neurons as evidenced by the finding of virally infected neurons in the molecular layer of the dentate. .

Background: Sporadic progressive ataxia and palatal tremor is a rare syndrome characterized by mid- to late-adult-onset symptomatic palatal tremor and slowly progressive cerebellar ataxia. To date, there has been only one autopsy report, which described a novel 4-repeat tauopathy with hypertrophic olivary degeneration and tau-positive inclusions in olivary neurons and dystrophic neuritic processes termed glomeruloid bodies. We report on 2 additional autopsy cases. Methods: Sections from selected paraffin-embedded brain regions were stained with hematoxylin and eosin/Luxol fast blue and processed for phosphorylated tau, 3-repeat tau, 4-repeat tau, neurofilament, glial fibrillary acid protein, phosphorylated α-synuclein, phosphorylated TAR DNA-binding protein 43, beta-amyloid, and p62 immunohistochemistry. Results: Two male patients were aged 74 and 64 years at onset. Both had clinical findings consistent with progressive ataxia and palatal tremor and T2 hyperintensity in the bilateral olives on MRI. Pathological findings included bilateral hypertrophic olivary degeneration accompanied by glomeruloid bodies, 3-repeat and 4-repeat tau-positive neuronal inclusions in the olive, and additional tauopathy in the midbrain, pons, and thalamus. Cerebellar cortical degeneration was extensive, but involvement of the dentate was minimal. P62-positive, but tau- and TAR DNA-binding protein 43–negative, inclusions in the cerebellum of 1 case was also a feature. Conclusions: Whereas our findings are largely in keeping with the previously published case report, we found a more extensive and mixed 3/4-repeat tauopathy and additional cerebellar p62 pathology, highlighting our incomplete understanding of the pathogenesis of this disease. © 2017 International Parkinson and Movement Disorder Society

Introduction The rate of clinical misdiagnosis of Alzheimer's disease (AD) and how psychosis impacts that clinical judgment is unclear. Methods Using data from National Alzheimer's Coordinating Center, we compared the clinical and neuropathologic diagnosis in patients with a diagnosis of AD with autopsy and in neuropathology-confirmed AD cases (n = 961). We determined the rate of true positives, false positives, and false negatives in patients with and without psychosis. Results A total of 76% received a correct AD diagnosis, 11.9% had a false-negative diagnosis, and 12.1% had a false-positive diagnosis of AD. Psychotic patients had a higher rate of false-negative diagnosis and a lower rate of false-positive diagnosis of AD compared with nonpsychotic patients. Discussion Patients with psychosis were five times more likely to be misdiagnosed as dementia with Lewy bodies, whereas patients without psychosis were more likely to be falsely diagnosed with AD when vascular pathology is the underlying neuropathologic cause of dementia., Highlights • Clinical misdiagnosis of Alzheimer's disease (AD) by psychosis subtype is examined • 24% of cases were misdiagnosed; false positive and false negative both being 12% • Lower false positive but high false negative AD diagnosis in psychotic patients • Clinicians more likely to diagnose psychotic AD patients with DLB • In the absence of psychosis clinicians should consider alternative diagnoses to AD

Background Molecular signatures are being increasingly incorporated into cancer classification systems. DNA methylation-based central nervous system (CNS) tumor classification is being recognized as having the potential to aid in cases of difficult histopathological diagnoses. Here, we present our institutional clinical experience in integrating a DNA-methylation-based classifier into clinical practice and report its impact on CNS tumor patient diagnosis and treatment. Methods Prospective case review was undertaken at CNS tumor board discussions over a 3-year period and 55 tumors with a diagnosis that was not certain to two senior neuropathologists were recommended for methylation profiling based on diagnostic needs. Tumor classification, calibrated scores, and copy number variant (CNV) plots were obtained for all 55 cases. These results were integrated with histopathological findings to reach a final diagnosis. We retrospectively reviewed each patient's clinical course to determine final neuro-pathology diagnoses and the impact of methylation profiling on their clinical management, with a focus on changes that were made to treatment decisions. Results Following methylation profiling, 46 of the 55 (84%) challenging cases received a clinically relevant diagnostic alteration, with two-thirds having a change in the histopathological diagnosis and the other one-third obtaining clinically important molecular diagnostic or subtyping alterations. WHO grading changed by 27% with two-thirds receiving a higher grade. Patient care was directly changed in 15% of all cases with major changes in clinical decision-making being made for these patients to avoid unnecessary or insufficient treatment. Conclusions The integration of methylation-based CNS tumor classification into diagnostics has a substantial clinical benefit for patients with challenging CNS tumors while also avoiding unnecessary health care costs. The clinical impact shown here may prompt the expanded use of DNA methylation profiling for CNS tumor diagnostics within prominent neuro-oncology centers globally.

The update on the WHO classification of central nervous system (CNS) tumors incorporated molecular signatures for a more accurate diagnosis. Recently, DKFZ has demonstrated the utility of DNA methylation profiling(MP) for molecular classification of CNS tumors. We performed a prospective clinical study over the last three years to evaluate the clinical utility ofDNA MP on FFPE samples of 66 challenging CNS tumor cases using online DKFZ classifier. Eleven samples were excluded due to low tumor DNA content or low calibration(predictive) scores(CS)< 0.3.DNA MP confirmed the original pathology diagnoses in 15(27%)cases. The integrated molecular diagnoses were changed in 38/55(70%) including establishment of a new diagnostic entity, change in molecular signature and subtyping. TheWHO grades were changed in 16(27%) of the tumors; about two-thirds resulted in upgrading. We detected non-canonical IDH mutations in 9 diffuse gliomas and the CNV plots revealed false positive FISH results for 1p/19q co-deletion in two diffuse gliomas. The CNV plots contributed to the final diagnosis in 40(72%) patients. The molecular subtypes of medulloblastoma, ependymoma and glioblastoma subclasses were determined in 36(65%) cases. Seventy-five percent of cases with confirmation of initial diagnosis or change in molecular diagnosis had CS > 0.5, among which 51% had a CS >0.9. The median and range CS of cases with new diagnostic entity and confirmed cases were 0.86(0.37–0.99) and 0.98(0.42–0.99), respectably. Furthermore, we detected higher CS in IDH-mutant gliomas in comparison to glioblastoma IDH-wild type(P=0.04). We also observed lower CS in mesenchymal glioblastoma in comparison to other subclasses. The MGMT promoter methylation was determined in 17/20(85%) glioblastoma cases. While the DKFZ group established CS of 0.9 as a cut-off for matching to methylation classes, our findings suggest lower threshold values in challenging CNS tumor cases. Our experience indicates clinical utility of MP of challenging CNS tumors as a reliable ancillary diagnostic tool in routine neuropathology practice.

INTRODUCTION: Older adults are particularly vulnerable to poor long term outcomes and the rate of TBI in this group is increasing. Studies have shown females experience worse outcome from TBI than males, however this research has been limited. The aim of this study is to examine gender effects on the frequency of sleep disturbances in older adults post TBI. METHODS: An analysis was conducted on data obtained from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set. A total of 405 patients greater than 60 years of age were examined. Sleep disturbances were measured using the Nighttime Behavioural Disturbances domain of theNeuropsychiatric Inventory – Questionnaire (NPI-Q) RESULTS: A significant difference (p=0.025) in reported sleep disturbance was identified in the female TBI population relative to the female non-TBI population. In the male No TBI group, 14.8% (n=12) experienced nighttime disturbances while those with TBI experienced 19.8% (n=17). This difference was not significant (p=0.305). CONCLUSION: These results suggest there is a greater impact from traumatic brain injury on sleep disturbances in older females than males. Further research examining gender differences in older adults related to neuropsychiatric outcomes of TBI should be considered given the implications for treatment.

Background Neuropsychiatric symptoms (NPS) are common, accelerate the conversion to dementia, and are associated with increased caregiver burden in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Objective The aim of this study is to identify potential associations between the core cerebrospinal fluid (CSF) biomarkers (amyloid/tau) and NPS in AD/MCI. Methods For this systematic review, four databases, PubMed (1946-2018), Cochrane (2005-2018), EMBASE (1947-2018), and PsycINFO (1806-2018) were searched for relevant observational studies using an extensive list of keywords. English studies were selected for critical appraisal based on our inclusion/exclusion criteria. Inclusion criteria were defined as 1) at least one AD CSF biomarker has been measured; 2) at least one NPS has been assessed; and 3) analysis has been done to examine the association between core AD CSF biomarker and NPS (main outcome). Animal, postmortem, and review studies were excluded. Results In total, 21 studies qualified for the systematic review. The overall picture regarding the association between NPS and AD CSF biomarkers is conflicting. However, agitation/aggression was significantly and consistently related to core AD CSF biomarkers. Moreover, depression was the only NPS to occasionally be associated with lower core AD CSF pathology. Conclusion Our study has revealed agitation/aggression as the most consistent NPS related to core AD CSF biomarkers. Future studies are required to focus on other neglected NPS domains such as disinhibition. Moreover, why depression was the only NPS inversely associated with core AD CSF pathology remains to be elucidated. Our study also revealed a great degree of heterogeneity, hence calling for a more standardized "objective" approach for the evaluation of NPS.

This systematic review and meta-analysis assessed the bidirectional association between AD pathology and dementia in community-dwelling elderly populations. We searched PubMed/MEDLINE, Embase, Scopus, Web of Science, and references of the pertinent articles for community/population-based longitudinal cohorts with regular assessment of cognitive status of participants followed by postmortem neuropathology data, with no language and date restrictions, until 20 September 2019. Finally, we retrieved 18 articles with data from 17 cohorts comprising 4677 persons. Dementia was twice as likely in participants with definitive neuropathological indicator for AD compared to those without it: moderate/high Braak and Braak (BB) stages III-VI of neurofibrillary tangles (54 % vs. 26 % in participants with BB stages 0-II), the Consortium to Establish a Registry for AD (CERAD) moderate/frequent neuritic plaques scores (64 % vs. 33 % in participants with CERAD none/infrequent), and National Institute on Aging and the Reagan Institute of the Alzheimer's Association criteria intermediate/high AD probability (52 % vs. 28 % in participants with no/low AD probability). Accordingly, a substantial proportion of community-dwelling elderly people with definitive AD pathology may not develop dementia. Brain reserve or contribution of other factors and pathologies, such as vascular and degenerative pathology to dementia might explain this apparent discrepancy. These findings also suggest caution in equating Alzheimer pathology biomarkers with dementia.

Chronic subdural hematomata (CSDH) are treated by evacuation. Recurrence occurs in 3-20% of cases, but the factors determining its occurrence have not been determined. Having observed that eosinophil cell infiltrates are often present in the outer membrane of CSDH, our aim was to determine whether such infiltrates are associated with risk of recurrence. Histological sections of the resections from 72 patients with primary CSDH (Mean age 73.4) and 16 with recurrent CSDH (Mean age 72.1) stained with H&E were graded by blinded observers for eosinophilic cell infiltrates using a semiquantitative 0 to 3 scale. The risk of recurrence requiring reoperation (RrR) in primary CSDH was 11.1%, and 12.5% in recurrent CSDH (meaning third surgery was required). A dense (grades 2 or 3) eosinophilic infiltrate was present in 22.2% of primary CSDH; the RrR was 0% in these cases, as compared with 14.8% in cases with sparse (grades 0-1) eosinophilic infiltrate. Among recurrent CSDH cases, 12.5% (2/15) showed a dense eosinophilic infiltrate; the RrR was also 0%, contrasting with 14.3% in those with sparse eosinophilic infiltrate. We conclude that eosinophils either play a role or are a marker of a process leading to stabilizing CSDH, making them less prone to rebleeding. Abstract not previously publishedLearning ObjectivesDescribe the risk of recurrence following surgical evacuation of chronic subdural hematomataRecognize the variable presence of eosinophils in chronic subdural hematomataCite the presence of eosinophils is predictive of absence of recurrence

We examined recurrence after gross total resection (GTR) or subtotal resection (STR) at St. Michael’s Hospital, Toronto, of 181 cases of atypical meningioma (WHO grade II). In the entire group, Kaplan-Meier survival curves showed that combined necrosis and brain invasion was the feature associated with the worst outcome, followed in order by necrosis, histological variants (clear cell, rhabdoid, and chordoid), high mitotic count, and brain invasion. The highly significant difference between necrosis and brain invasion and necrosis was seen only in patients receiving GTR, and lost in those treated with STR. Adjuvant radiotherapy was associated with worse outcome, more so in patients receiving GTR. In the presence of high mitotic count (defined as >4/10HPF) radiation did not affect recurrence, but necrosis and specially combined necrosis and brain invasion magnified the apparent deleterious effect of adjuvant radiotherapy. In the presence of brain invasion, radiotherapy’s small effect did not reach significance. Since patients were not randomized to adjuvant radiotherapy, these results should not be construed as indicating that this treatment is injurious. It can be stated that in the presence of necrosis and particularly necrosis and brain invasion, but not brain invasion alone, or high mitotic count, atypical meningiomas are more resistant to any possible beneficial effect of radiation in delaying recurrence.LEARNING OBJECTIVESThis presentation will enable the learner to: 1.Describe histological and treatment factors determining recurrence in atypical meningioma.2.List histological factors associated with radioresistance in atypical meningioma.

Introduction Cardiovascular risk factors (CVRFs) such as hypertension (HTN) and hypercholesterolemia (HCL) have been associated with an increased risk of cognitive impairment as measured by the Mini Mental State Exam (MMSE) and Montreal Cognitive Assessment (MOCA) (Ettorre et al., 2012). Previous studies have not addressed the extent to which age and CVRFs may interact to specifically drive diminished cognitive scores in more comprehensive cognitive test batteries such as the Behavioural Neurology Assessment-Short Form (BNA-SF) (Darvesh et al., 2005). Objective To further understanding of the relationship between the CVRFs of HTN and HCL and their potential effect on patients' BNA-SF scores across a diverse age range. The effect of CVRFs in relation to all the BNA testing domains (including; orientation, immediate memory recall, delayed memory recall, delayed recognition, visuospatial, working memory, and language) was analyzed and compared across age groups. Methods Mann-Whitney U tests and Kruskal-Wallis one-way ANOVAs were conducted on two primary cohorts of participants, above age 65 (n=130) and under 65 (n=98) from the St. Michael's Hospital Memory Clinic database. These groups were examined for histories of HTN and HCL and further subdivided into four testing cohorts consisting of: Below 65 controls (n=56), above 65 controls (n=39), below 65 with either or both HTN and HCL (n=42), and above 65 with either or both HTN and HCL (n=91). Mann-Whitney U tests were used to compare test scores of control patients and patients with either CVRFs within one age group. Kruskal-Wallis one-way ANOVAs were conducted to compare test scores between the four testing cohorts to further analyze the effect of age. Results When compared within one age group, there was no significant difference for BNA scores of patients with either HCL or HTN and the age specific controls. Comparative analyses between cohorts below 65 and above 65 revealed significantly higher scores in the subcategory of memory immediate recall in control patients below 65 vs patients above 65 with one or both CRVFs (p Conclusions Our findings suggest that CVRFs have an effect on scores of specific BNA categories when patients from different age ranges are cross analyzed. The BNA subcategories of immediate memory recall, delayed memory recall, and delayed memory recognition are particularly sensitive to the combined influence of CVRFs and age related cognitive decline. This illustrates the importance of a higher CVRF burden in relation to increased age, and its potential impact on cognitive performance. Funding St Michael's Hospital Foundation, Eric and Heather Donnelly Endowment Fund

Introduction Apolipoprotein (APOE) e4 is one of the strongest genetic biomarkers for Alzheimer's disease (AD) however, the relationship between APOE and Neuropsychiatric Symptoms (NPS) remains unclear. Our recent analyses suggested that female sex modulated the association of APOE e4 on specific NPS domains such as psychosis 1 and nighttime behaviours 2 in an autosomal recessive manner. The goal of this new analysis was to investigate the associations between APOE and sex on overall NPS burden in a cohort of participants with a condition putting them at risk for AD: Mild cognitive impairment (MCI) and/or a history of Major Depressive Disorder (MDD). Methods Baseline Neuropsychiatric Inventory Questionnaire (NPI-Q), APOE and demographic data were obtained in 181 participants from an ongoing clinical trial, “Preventing Alzheimer's dementia with cognitive remediation plus transcranial direct current stimulation in mild cognitive impairment and depression (PACt-MD)”. NPS burden was measured with the NPI-Q Total score and NPI-Severity Total. One extreme outlier was omitted from analysis (>7 inter quartile ranges (IQR) from the median NPI-Severity and >2 IQR from the next nearest data point). We tested whether APOE status, sex, or an interaction of the two were associated with our two outcomes using Ordinal Least Square (OLS) regression. Subsequent models were fit adjusting for the effects of age, education and diagnosis group (i.e., MCI or MDD (with/without MCI)). APOE e3/e3, the most common isoform, was used as the baseline category in regression analysis. All findings reported are compared to this baseliine category. Results When analysing the effects of APOE and sex alone, we only found a significant inverse association between NPI-Q Total and APOE e3/e4 carriers compared to APOE e3/e3 carriers (n = 38, b = -1.04, t(170) = -2.28, p = 0.024). When analysing our interaction terms APOE e4/e4 females (n = 6) were significantly associated with higher NPI-Q total scores (b = 1.95, t(171) = 2.14, p = 0.034). We also found that APOE e2/e3 females (n = 10) were associated with higher NPI-Q total scores (b = 1.55, t(171) = 2.04, p = 0.044). Results were consistent after adjusting for covariates. Sex or APOE status alone were not associated with NPI-Q Total severity scores. When analysing the interaction terms, APOE e2/e3 females showed higher NPI-Q Total severity scores than APOE e3/e3 carriers (b = 3.57, t(171) = 2.45, p = 0.015). After adjusting for covariates, being APOE e2/e3 females (b = 3.3, t(162) = 1.49, p = 0.027) or APOE e4/e4 females (b = 3.8, t(162) = 1.78 p = 0.033) was associated with greater NPI-Severity. Conclusions In older adults at risk for progression to AD, sex may play a modulatory role in the association between APOE and NPS burden. Consistent with recent findings 1 , 2 , females who are homozygous for APOE e4 may be susceptible to the highest NPS burden. Further investigation of the interactive effects of sex and APOE e4 on NPS burden with larger samples are needed. Funding This Project has been made possible by Brain Canada through the Canada Brain Research Fund, with the financial support of Health Canada and the Chagnon Family.

We report two different cases of IgG4-related hypophysitis. In the first case, a pituitary lesion was accompanied by lymphocytic meningitis possibly mimicking tuberculous meningitis. The second case was unassociated with involvement of other organs. No histologic differences were noted between the two cases indicating that the morphologic features of the hypophysial lesion do not depend on the presence of other lesions. The pathogenesis of IgG4 hypophysitis is not known, and further study is necessary to explore the cause, progression, and influencing factors of this disease.

BACKGROUND Neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD. OBJECTIVE To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(-)] of agitation/aggression (A) in autopsy-confirmed AD. METHODS Data was collected from the UDS data as of 2015 on the NACC database. Patients were stratified as intermediate (IAD) or high (HAD) pathological load of AD. Clinical diagnoses were not considered; additional pathological diagnoses were treated as variables. Analysis of data did not include a control group or corrections for multiple comparisons. RESULTS 1,716 patients met the eligibility criteria; 31.2% of the IAD and 47.8% of the HAD patients were A(+), indicating an association with severity of pathology (p = 0.001). Risk factors for A(+) included: age at initial visit, age at death, years of education, smoking (in females), recent cardiac events (in males), and clinical history of traumatic brain injury (TBI) (in males). A history of hypertension was not related to A(+). In terms of comorbidity, clinical diagnosis of Lewy body dementia syndrome was associated with A(+) but the association was not confirmed when pathological diagnosis based on demonstration of Lewy bodies was used as the criterion. The additional presence of phosphorylated TDP-43, but not tau pathologies, was associated with A(+)HAD. Vascular lesions, including lacunes, large arterial infarcts, and severity of atherosclerosis were negatively associated with A(+). Associated symptoms included delusions, hallucinations, and depression, but not irritability, aberrant motor behavior, sleep and night time behavioral changes, or changes in appetite and eating habits. CONCLUSIONS Smoking, TBI, and phosphorylated TDP-43 are associated with A(+)AD in specific groups, respectively. A(+) is directly associated with AD pathology load and inversely with vascular lesions.

Background: The pathophysiology behind psychosis in patients with Alzheimer’s disease (AD) remains unknown. Recently, vascular risk factors have been recognized as important modifiers of the clinical presentation of AD. Objective: The purpose of our study is to investigate the mechanism through which vascular risk factors mediate psychosis and whether or not it involves cerebrovascular lesions. Methods: Data was provided by the National Alzheimer’s Coordinating Centre. The Uniform Data Set was used to collect information on subject-reported history of vascular risk factors, clinician-reported state of cognitive performance, and presence of psychosis based on the Neuropsychiatric Inventory Questionnaire (NPI-Q). The Neuropathology Data Set was used to evaluate the presence of vascular lesions and the severity of AD pathology. Subjects with high probability of AD based on the NIA/AA Reagan criteria were included in the analysis. Results: We identified 1,459 patients with high probability of AD and corresponding NPI-Q scores. We confirmed the association between hypertension and diabetes on psychosis, specifically in delusions and the co-occurrence of delusions and hallucinations. Furthermore, the presence of white matter rarefaction based on pathological evaluation was associated with hallucinations. A history of vascular risk factors was positively associated with vascular lesions. However, vascular lesions in the presence of vascular risk factors did not increase the likelihood of psychosis. Furthermore, vascular lesions were not associated with greater cognitive or functional impairments in this group with severe AD pathology. Conclusion: Vascular risk factors and vascular lesions are independently associated with psychosis in patients with severe AD. However, vascular lesions are not the mechanism through which vascular risk factors mediate psychosis.

Background Parasellar dural invasion can be associated with treatment failure after excision of functioning pituitary adenomas. Because the medial wall of the cavernous sinus is a common site of microscopic disease, we hypothesize that its resection may lead to improvement in biochemical remission and recurrence rates. We aim to describe our technique in the resection of the medial wall of the cavernous sinus using binasal endoscopic transsphenoidal surgery (BETS); and compare tumor control and biochemical remission rates against a matched cohort. Methods Patients with functioning pituitary adenomas who underwent resection of the medial cavernous wall in addition to tumor excision via BETS were compared to a cohort matched for tumor type, size, and Knosp grade. Biochemical remission rates, tumor control at follow-up, and complication rates were assessed. Results Sixteen patients underwent resection of the medial wall of the cavernous sinus. Of 14 cases with wall specimens deemed adequate for histopathologic analysis, 43 % had microscopic evidence of tumor. Two of three patients with Knosp grade 0 scores had microscopic tumor invasion of the medial wall. The mean blood loss in the cohort was 175 mL (comparable to control, p = 0.895), with no operative complications noted. Gross total excision was achieved in 81 % of cases in the treatment cohort. At a median follow-up of 11 months, no statistical difference was noted in the biochemical remission and oncologic control rates between groups. Conclusion Resection of the medial wall of the cavernous sinus is safe and technically feasible using BETS when performed by experienced surgeons. The Knosp classification may not be reliable for microscopic tumor invasion. The effect of this technique on clinical outcomes remains to be determined by larger cohorts with matched controls and long-term follow-up.

BACKGROUND Meningiomas are the most common tumors in the central nervous system, with variable recurrence rates depending on WHO grading. Atypical (WHO grade II) meningioma has a higher recurrence rate than benign meningioma (WHO grade I). The efficacy of adjuvant radiotherapy (RT) to improve tumor control has been questioned. METHODS This cohort study retrospectively reviewed all patients at St. Michaels Hospital Tumor Patient Database with a diagnosis of atypical meningioma (AM) who underwent surgical resection between 1995 and 2015. Patient and tumor characteristics such as location, neuropathological diagnosis, resection extent, RT and time to reoccurrence or progression were recorded. Resection extent was defined by Simpson Grading Scale as either Gross Total (GTR) or Subtotal (STR) resection. Cox univariate regression and Kaplan-Meier survival analysis were employed to identify risk factors for recurrence and radio-resistance. RESULTS In our cohort of 181 patients, the combination of necrosis and brain invasion was associated with an increased reoccurrence risk (HR= 4.560, P=0.001) and the lowest progression-free survival relative to other histopathological predictors. This trend was maintained after GTR (P=0.001), whereas necrosis alone and combined necrosis and brain invasion were both associated with low progression-free survival in STR (P=0.001). Radiotherapy was associated with decreased progression-free survival (P=0.001), especially in patients who received GTR (P=0.001). This trend was maintained in patients with necrosis alone (P=0.002) but especially in patients with combined necrosis and brain invasion (P=0.001). CONCLUSION Combined necrosis and brain invasion is a strong predictor of tumor recurrence and radio-resistance in AM, regardless of extent of resection or RT.

Ganglioglioma (GG) is a mixed glio-neuronal tumour, comprised of a neoplastic glial component and dysplastic ganglion cells. GG is a tumour of unclear histogenesis; previous studies examining BRAF mutations and chromosome imprinting has provided evidence that both the neuronal and glial components likely arise from a common precursor. Both p.V600E mutation and KIAA1549-BRAF fusion have been described in pilocytic astrocytoma (PA) and GG, but they differ with regards to the rates of different BRAF alterations, and careful histological examination is an important component of patho-molecular correlations. More recently, cases of PA with gangliocytic differentiation (PA-GD) have been described, and these cases are thus far restricted to those with the KIAA1549-BRAF fusion. Here, we describe three cases of GGs in patients with history of previously diagnosed PAs. The cases differ with respect to the chronologic intervals between the PA and the GG diagnoses. In two of the cases, where the PA-GG diagnostic intervals are less than ten years, pathological review revealed the older specimens to have been misdiagnosed as PAs. In the third case, where the interval spanned multiple decades, the GG was found to be positive for both BRAF p.V600E immunohistochemistry (IHC) and for the KIAA1549-BRAF fusion. Molecular study for the BRAF p.V600E mutation was negative, proving the IHC result to be a false-positive. Our case demonstrates that cases of GG can harbour the KIAA1549-BRAF fusion, even with positive BRAF p.V600E IHC results, and the case highlights a diagnostic challenge that may be encountered.

Scleroderma is a rare disease of unknown etiology, which is characterized by thickening and hardening of skin due to an increased collagen production. A 44-year-old female patient with a scleroderma on the scalp known by our department, also presented an ipsilateral brain lesion since 2015, which was showing growth without any clinical symptomatology and the patient wanted the lesion to be removed. This atypical lesion underneath the scleroderma shows that diagnosis can be missed without brain imaging and biopsy.

BACKGROUND Aberrant motor behavior (AMB) is a neuropsychiatric symptom (NPS) prevalent in Alzheimer's disease (AD), known to cause great distress to both patients and caregivers. Apolipoprotein E4 (APOE4) is the most important genetic predictor of AD, and it has been associated with high NPS prevalence. OBJECTIVE To investigate the neuropathological substrates and risk factors associated with AMB in AD patients. METHODS Cases with Braak stage I-II and CERAD 0-1 were classified as Low AD (LAD), while Braak stage III-IV and CERAD 2 were grouped as Intermediate AD (IAD). Cases with Braak stage V-VI and CERAD 3 were classified as High AD (HAD) in accordance with NIA-Reagan criteria. All cases were stratified by APOE genotype, yielding No ɛ4 & ɛ4 and ɛ4/ɛ4 groups depending on ɛ4 copy number within APOE. Presence of AMB was assessed using NPI-Q. RESULTS AND CONCLUSION AMB increased in parallel with CERAD and Braak & Braak scores. Hypercholesterolemia, but no other cardiovascular risk factors, was associated with AMB in HAD. AMB prevalence in HAD was significantly increased in the presence of two APOEɛ4 alleles as compared to No ɛ4 & ɛ4. The relationship between homozygous APOE4 and AMB was strongly associated with the presence of both Lewy bodies and cerebral amyloid angiopathy pathologies in both sexes.

Introduction Traumatic Brain injuries (TBIs) cause damage that manifest as a variety of neuropsychiatric sequelae. While it is understood that TBI may be associated with onset of neuropsychiatric symptoms (NPS), whether or not these symptoms differ by sex is not yet clear. Knowing this information is critical as it may lead to differential approaches to treatment and provide important insights into the role of sex in modulating TBI outcomes. The aim of this study was to determine the prevalence of NPS by examining the association between sex and NPI-Q scores in a TBI and without TBI older adult cohort. Methods Using data from the National Alzheimer's Coordinating Center (NACC) database, we identified a cognitively normal sample filtered for co-morbidities (N=1774). We included patients aged 50?years and above. The mean age was 68.7 in the TBI cohort, and 69.8 in the without-TBI cohort. We examined NPI-Q subdomain outcomes in a TBI (n=266) vs. without-TBI (n=1508) cohort using generalized linear models (GLM) that were estimated by generalized estimating equations (GEE). These models were run with age, sex and BMI as covariates. Results Subjects with TBI were more likely to exhibit agitation, anxiety, apathy, disinhibition and aberrant motor behaviour relative to those who did not have a TBI. Anxiety was more common among females while males were more likely to experience agitation, apathy and disinhibition. Sex did not play a role in aberrant motor behaviour. Conclusions TBIs affect the presentation of NPS because the areas of the brain that control these symptoms are closely intertwined. Our findings suggest that TBI is associated with predominantly frontal based NPS, consistent with mechanism of injury. Moreover, sex may modulate the expression of NPS. Thus, treatments should target frontal lobe behaviours and be individualized based on sex. This research was funded by: n/a

Purpose of review This review presents the latest developments covered in the literature regarding psychosis in neurodegenerative disorders and discusses possible future research directions. Recent findings Recent findings in the field of psychosis and neurodegenerative disorders revolve around four main themes. The first theme is the impact of sex on the expression of psychosis in neurodegenerative disorders. The second theme focuses on the relationship between psychosis and neurodegenerative disease biomarkers. The third concerns how psychotic symptoms in neurodegenerative disorders may share common mechanisms with other primary psychotic disorders such as schizophrenia. Finally, there have been some promising developments in the area of therapeutics to treat dementia-related psychosis involving both established and novel treatments. Summary New findings in the field of neurodegeneration and psychosis parallel new directions in the field of neurodegeneration in general. More specifically, we have seen a shift in focus to issues highlighting the role of sex, biomarkers, translation to other disorders, and therapeutics.

Dyskeratosis congenita (DKC) is a rare, inherited disorder classically known by the triad of nail dystrophy, mucosal leukoplakia, and lacy reticulated skin hyperpigmentation. Bone marrow failure is a prominent feature and accounts for most deaths in these patients. Genetic mutations resulting in shortened telomeres have been shown to cause DKC, which is the basis for categorizing it as a "premature aging syndrome". Different modes of inheritance have been identified with X-linked recessive as the most common. There have been reports of intracranial calcifications on neuroradiology in a few cases of DKC, but no histopathologic illustration has been provided. We report a 20-year-old female patient with autosomal dominant DKC established by TINF2 gene mutation. Neostriatal calcifications with a distinctive pattern observed on neuroimaging were confirmed by postmortem microscopic examination. In contrast to the usual pattern of basal ganglia calcification, which starts in the globus pallidus, in this case the deposits were located in the caudate and putamen, sparing the globus pallidus. Iron deposits were also detected with similar distribution. Interestingly, staining for markers of brain aging (τ, amyloid, and p62) yielded negative results. These findings could not be attributed to any other condition (i.e., hypoparathyroidism, infections, etc.). Thus, we conclude that basal ganglia calcification can be a rare feature of DKC. .

Background: The Apolipoprotein (APOE) ε4 allele is a well-known risk factor for Alzheimer’s Disease (AD), and sleep disturbances are commonly associated with AD. However, few studies have investigated the relationship between APOE ε4 and abnormal sleep patterns (N+) in AD. Objective: To examine the relationship between APOE genotype, Lewy body pathology, and abnormal sleep patterns in a large group of subjects with known AD load evaluated upon autopsy. Method: Data from 2,368 cases obtained from the National Alzheimer’s Coordinating Centre database were categorized as follows: Braak Stage V/VI and CERAD frequent neuritic plaques as high load AD, Braak Stage III/IV and moderate CERAD as intermediate load AD, and Braak Stage 0/I/II and infrequent CERAD as no to low load AD. Cases discrepant between the two measures were discarded. Results: Disrupted sleep was more frequent in males (42.4%) compared to females (35.1%), and in carriers (42.3%) as opposed to non-carriers (36.5%) of ε4. Amongst female subjects with high AD load and Lewy body pathology, homozygous (ε4/ε4) carriers experienced disrupted sleep more often compared with heterozygous (ε4/x) or non-carriers of ε4. Such recessive, gender-specific, and Lewy body association is reminiscent of the ε4 effect on psychosis in AD. However, such association was lost after adjusting for covariates. In subjects with no to low AD pathology, female ε4 carriers had significantly more nighttime disturbances than non-carriers; this effect is independent of the presence of Lewy body pathology. Conclusion: The influence of APOE ε4 on sleep disturbances is dependent on gender and severity of AD load.