Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

A methodological primer of extracellular vesicles isolation and characterization via different techniques.

We present four different protocols of varying complexity for the isolation of cell culture-derived extracellular vesicles (EVs)/exosome-enriched fractions with the objective of providing researchers with easily conducted methods that can be adapted for many different uses in various laboratory settings and locations. These protocols are primarily based on polymer precipitation, filtration and/or ultracentrifugation, as well as size-exclusion chromatography (SEC) and include: (i) polyethylene glycol and sodium chloride supplementation of the conditioned medium followed by low-speed centrifugation; (ii) ultracentrifugation of conditioned medium; (iii) filtration of conditioned media through a 100-kDa exclusion filter; and (iv) isolation using a standard commercial kit. These techniques can be followed by further purification by ultracentrifugation, sucrose density gradient centrifugation, or SEC if needed and the equipment is available. HEK293 and SH-SY5Y cell cultures were used to generate conditioned medium containing exosomes. This medium was then depleted of cells and debris, filtered through a 0.2-µM filter, and supplemented with protease and RNAse inhibitors prior to exosomal isolation. The purified EVs can be used immediately or stably stored at 4°C (up to a week for imaging or using intact EVS downstream) or at -80°C for extended periods and then used for biochemical study. Our aim is not to compare these methodologies but to present them with descriptors so that researchers can choose the "best method" for their work under their individual conditions.

Co-registration of MALDI-MSI and histology demonstrates gangliosides co-localize with amyloid beta plaques in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological condition characterized by impaired cognitive function and behavioural alterations. While AD research historically centered around mis-folded proteins, advances in mass spectrometry techniques have triggered increased exploration of the AD lipidome with lipid dysregulation emerging as a critical player in AD pathogenesis. Gangliosides are a class of glycosphingolipids enriched within the central nervous system. Previous work has suggested a shift in a-series gangliosides from complex (GM1) to simple (GM2 and GM3) species may be related to the development of neurodegenerative disease. Additionally, complex gangliosides with 20 carbon sphingosine chains have been shown to increase in the aging brain. In this study, we utilized matrix assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) to interrogate the in situ relationship of a-series gangliosides with either 18 or 20 carbon sphingosine chains (d18:1 or d20:1 respectively) in the post-mortem human AD brain. Here, we expanded upon previous literature and demonstrated a significant decrease in the GM1 d20:1:GM1 d18:1 ratio in regions of the dentate gyrus and entorhinal cortex in AD relative to control brain tissue. Then we demonstrated that the MALDI-MSI profile of GM3 co-localizes with histologically confirmed amyloid beta (Aß) plaques and found a significant increase in both GM1 and GM3 in proximity to Aß plaques. Collectively these results support past literature and demonstrate a perturbation of the ganglioside profile in AD. Moreover, this work validates a pipeline for MALDI-MSI and classic histological staining in the same tissue sections. This demonstrates feasibility for integrating untargeted mass spectrometry imaging approaches into a digital pathology framework.

Tandem SERS and MS/MS Profiling of Plasma Extracellular Vesicles for Early Ovarian Cancer Biomarker Discovery.

Extracellular vesicles (EVs) are vectors of biomolecular cargo that play essential roles in intercellular communication across a range of cells. Protein, lipid, and nucleic acid cargo harbored within EVs may serve as biomarkers at all stages of disease; however, the choice of methodology may challenge the specificity and reproducibility of discovery. To address these challenges, the integration of rigorous EV purification methods, cutting-edge spectroscopic technologies, and data analysis are critical to uncover diagnostic signatures of disease. Herein, we demonstrate an EV isolation and analysis pipeline using surface-enhanced Raman spectroscopy (SERS) and mass spectrometry (MS) techniques on plasma samples obtained from umbilical cord blood, healthy donor (HD) plasma, and plasma from women with early stage high-grade serous carcinoma (HGSC). Plasma EVs were purified by size exclusion chromatography and analyzed by surface-enhanced Raman spectroscopy (SERS), mass spectrometry (MS), and atomic force microscopy. After determining the fraction of highest EV purity, SERS and MS were used to characterize EVs from HDs, pooled donors with noncancerous gynecological ailments (n = 6), and donors with early stage [FIGO (I/II)] with HGSC. SERS spectra were subjected to different machine learning algorithms such as PCA, logistic regression, support vector machine, naïve Bayes, random forest, neural network, and k nearest neighbors to differentiate healthy, benign, and HGSC EVs. Collectively, we demonstrate a reproducible workflow with the potential to serve as a diagnostic platform for HGSC.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Pick's disease presenting with corticobasal syndrome: A case report and clinicopathological review.

Pick's disease (PiD) is a rare form of frontal temporal lobar degeneration. The pathognomonic feature is atrophy of the frontotemporal lobes and intraneuronal deposits of 3R-τ inclusions, the Pick body. Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome with a heterogeneous spectrum of underlying pathologies. We report a case of clinically diagnosed CBS with a post-mortem diagnosis of PiD and conduct a clinicopathological review of the literature on this unusual presentation.

Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases.

Oculomotor tasks generate a potential wealth of behavioural biomarkers for neurodegenerative diseases. Overlap between oculomotor and disease-impaired circuitry reveals the location and severity of disease processes via saccade parameters measured from eye movement tasks such as prosaccade and antisaccade. Existing studies typically examine few saccade parameters in single diseases, using multiple separate neuropsychological test scores to relate oculomotor behaviour to cognition; however, this approach produces inconsistent, ungeneralizable results and fails to consider the cognitive heterogeneity of these diseases. Comprehensive cognitive assessment and direct inter-disease comparison are crucial to accurately reveal potential saccade biomarkers. We remediate these issues by characterizing 12 behavioural parameters, selected to robustly describe saccade behaviour, derived from an interleaved prosaccade and antisaccade task in a large cross-sectional data set comprising five disease cohorts (Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and cerebrovascular disease; n = 391, age 40-87) and healthy controls (n = 149, age 42-87). These participants additionally completed an extensive neuropsychological test battery. We further subdivided each cohort by diagnostic subgroup (for Alzheimer's disease/mild cognitive impairment and frontotemporal dementia) or degree of cognitive impairment based on neuropsychological testing (all other cohorts). We sought to understand links between oculomotor parameters, their relationships to robust cognitive measures, and their alterations in disease. We performed a factor analysis evaluating interrelationships among the 12 oculomotor parameters and examined correlations of the four resultant factors to five neuropsychology-based cognitive domain scores. We then compared behaviour between the abovementioned disease subgroups and controls at the individual parameter level. We theorized that each underlying factor measured the integrity of a distinct task-relevant brain process. Notably, Factor 3 (voluntary saccade generation) and Factor 1 (task disengagements) significantly correlated with attention/working memory and executive function scores. Factor 3 also correlated with memory and visuospatial function scores. Factor 2 (pre-emptive global inhibition) correlated only with attention/working memory scores, and Factor 4 (saccade metrics) correlated with no cognitive domain scores. Impairment on several mostly antisaccade-related individual parameters scaled with cognitive impairment across disease cohorts, while few subgroups differed from controls on prosaccade parameters. The interleaved prosaccade and antisaccade task detects cognitive impairment, and subsets of parameters likely index disparate underlying processes related to different cognitive domains. This suggests that the task represents a sensitive paradigm that can simultaneously evaluate a variety of clinically relevant cognitive constructs in neurodegenerative and cerebrovascular diseases and could be developed into a screening tool applicable to multiple diagnoses.

The psychophysiology of guilt in healthy adults.

Guilt is a negative emotion, elicited by realizing one has caused actual or perceived harm to another person. Anecdotally, guilt often is described as a visceral and physical experience. However, while the way that the body responds to and contributes to emotions is well known in basic emotions, little is known about the characteristics of guilt as generated by the autonomic nervous system. This study investigated the physiologic signature associated with guilt in adults with no history of psychological or autonomic disorder. Healthy adults completed a novel task, including an initial questionnaire about their habits and attitudes, followed by videos designed to elicit guilt, as well as the comparison emotions of amusement, disgust, sadness, pride, and neutral. During the video task, participants' swallowing rate, electrodermal activity, heart rate, respiration rate, and gastric activity rate were continuously recorded. Guilt was associated with alterations in gastric rhythms, electrodermal activity, and swallowing rate relative to some or all the comparison emotions. These findings suggest that there is a mixed pattern of sympathetic and parasympathetic activation during the experience of guilt. These results highlight potential therapeutic targets for modulation of guilt in neurologic and psychiatric disorders with deficient or elevated levels of guilt, such as frontotemporal dementia, posttraumatic stress disorder, and Obsessive-compulsive disorder.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Targeted copy number variant identification across the neurodegenerative disease spectrum.

BACKGROUND: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. METHODS: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). RESULTS: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1-5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7-11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. CONCLUSION: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.

Disentangling Reversal-learning Impairments in Frontotemporal Dementia and Alzheimer Disease.

BACKGROUND: Individuals with frontotemporal dementia (FTD) often present with poor decision-making, which can affect both their financial and social situations. Delineation of the specific cognitive impairments giving rise to impaired decision-making in individuals with FTD may inform treatment strategies, as different neurotransmitter systems have been associated with distinct patterns of altered decision-making. OBJECTIVE: To use a reversal-learning paradigm to identify the specific cognitive components of reversal learning that are most impaired in individuals with FTD and those with Alzheimer disease (AD) in order to inform future approaches to treatment for symptoms related to poor decision-making and behavioral inflexibility. METHOD: We gave 30 individuals with either the behavioral variant of FTD or AD and 18 healthy controls a stimulus-discrimination reversal-learning task to complete. We then compared performance in each phase between the groups. RESULTS: The FTD group demonstrated impairments in initial stimulus-association learning, though to a lesser degree than the AD group. The FTD group also performed poorly in classic reversal learning, with the greatest impairments being observed in individuals with frontal-predominant atrophy during trials requiring inhibition of a previously advantageous response. CONCLUSION: Taken together, these results and the reversal-learning paradigm used in this study may inform the development and screening of behavioral, neurostimulatory, or pharmacologic interventions aiming to address behavioral symptoms related to stimulus-reinforcement learning and response inhibition impairments in individuals with FTD.

Microvessel stenosis, enlarged perivascular spaces, and fibrinogen deposition are associated with ischemic periventricular white matter hyperintensities.

Periventricular white matter hyperintensities (pvWMH) are neuroimaging abnormalities surrounding the lateral ventricles that are apparent on magnetic resonance imaging (MRI). They are associated with age, neurodegenerative disease, and cerebrovascular risk factors. While pvWMH ultimately represent a loss of white matter structural integrity, the pathological causes are heterogeneous in nature, and currently, cannot be distinguished using neuroimaging alone. pvWMH could occur because of a combination of small vessel disease (SVD), ependymal loss, blood-brain barrier dysfunction, and microgliosis. In this study we aimed to characterize microvascular stenosis, fibrinogen extravasation, and microgliosis within pvWMH with and without imaging evidence of periventricular infarction. Using postmortem neuroimaging of human brains (n = 20), we identified pvWMH with and without periventricular infarcts (PVI). We performed histological analysis of microvessel stenosis, perivascular spaces, microgliosis, and immunohistochemistry against fibrinogen as a measure of serum protein extravasation. Herein, we report distinctions between pvWMH with and without periventricular infarcts based on associations with microvessel stenosis, enlarged perivascular spaces, and fibrinogen IHC. Microvessel stenosis was significantly associated with PVI and with cellular deposition of fibrinogen in the white matter. The presence of fibrinogen was associated with PVI and increased number of microglia. These findings suggest that neuroimaging-based detection of infarction within pvWMH may help distinguish more severe lesions, associated with underlying microvascular disease and BBB dysfunction, from milder pvWMH that are a highly frequent finding on MRI.

Characterization of ovarian cancer-derived extracellular vesicles by surface-enhanced Raman spectroscopy.

Ovarian cancer is the most lethal gynecological malignancy, owing to the fact that most cases are diagnosed at a late stage. To improve prognosis and reduce mortality, we must develop methods for the early diagnosis of ovarian cancer. A step towards early and non-invasive cancer diagnosis is through the utilization of extracellular vesicles (EVs), which are nanoscale, membrane-bound vesicles that contain proteins and genetic material reflective of their parent cell. Thus, EVs secreted by cancer cells can be thought of as cancer biomarkers. In this paper, we present gold nanohole arrays for the capture of ovarian cancer (OvCa)-derived EVs and their characterization by surface-enhanced Raman spectroscopy (SERS). For the first time, we have characterized EVs isolated from two established OvCa cell lines (OV-90, OVCAR3), two primary OvCa cell lines (EOC6, EOC18), and one human immortalized ovarian surface epithelial cell line (hIOSE) by SERS. We subsequently determined their main compositional differences by principal component analysis and were able to discriminate the groups by a logistic regression-based machine learning method with ∼99% accuracy, sensitivity, and specificity. The results presented here are a great step towards quick, facile, and non-invasive cancer diagnosis.

Contribution of rare variant associations to neurodegenerative disease presentation.

Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson's disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.

Neuropathology of Perry Syndrome: Evidence of Medullary and Hypothalamic Involvement.

BACKGROUND: Perry syndrome is a rare genetic parkinsonian disorder with TAR DNA binding protein 43 (TDP-43) pathology clinically presenting with parkinsonism, neuropsychiatric features, weight loss, and central hypoventilation. As respiratory complications are often the cause of death, studies likely show the early stage of the neurodegenerative process. Because of the rarity of this condition, few studies exist, and each case provides insight into pathological findings in this neurodegenerative condition. OBJECTIVE: To study the clinical and pathological correlations of an autopsy case of Perry syndrome. METHODS: The patient was a woman in her 50s with Perry syndrome and a DCTN1 gene mutation. Between October 2016 and July 2019, she underwent postmortem and pathological examination at University Hospital in London, Ontario, Canada. Data were obtained through clinical pathological examination. RESULTS: Microscopy showed significant neuronal loss with pigmentary incontinence and gliosis in the substantia nigra. There was no atrophy elsewhere, including the frontal and cingulate cortex. Intraneuronal cytoplasmic TDP-43 inclusions and neurites were noticed in a moderate number in the substantia nigra and midbrain and were sparsely noticed in the basal ganglia, thalamus, thoracic motor neuron, posterior nucleus of the hypothalamus, and rostral ventral medulla. ß-Amyloid, Lewy body, and tau pathologies were absent. Rare axonal swelling was identified at the rostral ventrolateral medulla. CONCLUSIONS AND RELEVANCE: This study confirms that Perry syndrome is characterized by TDP-43 pathology with absent Lewy bodies or tau pathology. These findings support the hypothesis of dysfunctional neurons in the medulla and hypothalamus, which may respectively correlate to the clinical symptoms of hypoventilation and weight loss in Perry syndrome.

Regional Lipid Expression Abnormalities Identified Using MALDI IMS Correspond to MRI-Defined White Matter Hyperintensities within Post-mortem Human Brain Tissues.

Periventricular white matter hyperintensities (pvWMHs) are a neurological feature detected with magnetic resonance imaging that are clinically associated with an increased risk of stroke and dementia. pvWMHs represent white matter lesions characterized by regions of myelin and axon rarefaction and as such likely involve changes in lipid composition; however, these alterations remain unknown. Lipids are critical in determining cell function and survival. Perturbations in lipid expression have previously been associated with neurological disorders. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is an emerging technique for untargeted, high-throughput investigation of lipid expression and spatial distribution in situ; however, the use of MALDI IMS has been previously been limited by the need for non-embedded, non-fixed, fresh-frozen samples. In the current study, we demonstrate the novel use of MALDI IMS to distinguish regional lipid abnormalities that correlate with magnetic resonance imaging (MRI) defined pvWMHs within ammonium formate washed, formalin-fixed human archival samples. MALDI IMS scans were conducted in positive or negative ion detection mode on tissues sublimated with 2,5-dihydroxybenzoic acid or 1,5-diaminonaphthalene matrices, respectively. Using a broad, untargeted approach to lipid analysis, we consistently detected 116 lipid ion species in 21 tissue blocks from 11 different post-mortem formalin-fixed human brains. Comparing the monoisotopic mass peaks of these lipid ions elucidated significant differences in lipid expression between pvWMHs and NAWM for 31 lipid ion species. Expanding our understanding of alterations in lipid composition will provide greater knowledge of molecular mechanisms underpinning ischemic white matter lesions and provides the potential for novel therapeutic interventions targeting lipid composition abnormalities.

Ultrafiltration and Injection of Islet Regenerative Stimuli Secreted by Pancreatic Mesenchymal Stromal Cells.

The secretome of mesenchymal stromal cells (MSCs) is enriched for biotherapeutic effectors contained within and independent of extracellular vesicles (EVs) that may support tissue regeneration as an injectable agent. We have demonstrated that the intrapancreatic injection of concentrated conditioned media (CM) produced by bone marrow MSC supports islet regeneration and restored glycemic control in hyperglycemic mice, ultimately providing a platform to elucidate components of the MSC secretome. Herein, we extend these findings using human pancreas-derived MSC (Panc-MSC) as "biofactories" to enrich for tissue regenerative stimuli housed within distinct compartments of the secretome. Specifically, we utilized 100 kDa ultrafiltration as a simple method to debulk protein mass and to enrich for EVs while concentrating the MSC secretome into an injectable volume for preclinical assessments in murine models of blood vessel and islet regeneration. EV enrichment (EV+) was validated using nanoscale flow cytometry and atomic force microscopy, in addition to the detection of classical EV markers CD9, CD81, and CD63 using label-free mass spectrometry. EV+ CM was predominately enriched with mediators of wound healing and epithelial-to-mesenchymal transition that supported functional regeneration in mesenchymal and nonmesenchymal tissues. For example, EV+ CM supported human microvascular endothelial cell tubule formation in vitro and enhanced the recovery of blood perfusion following intramuscular injection in nonobese diabetic/severe combined immunodeficiency mice with unilateral hind limb ischemia. Furthermore, EV+ CM increased islet number and ß cell mass, elevated circulating insulin, and improved glycemic control following intrapancreatic injection in streptozotocin-treated mice. Collectively, this study provides foundational evidence that Panc-MSC, readily propagated from the subculture of human islets, may be utilized for regenerative medicine applications.

Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-ß deposition in a mouse model of Alzheimer's disease.

Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer's Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-ß toxicity in vitro and reduced STI1 levels worsen Aß toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aß(3-42) against Aß-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aß-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aß accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

Post-mortem 7 Tesla MRI detection of white matter hyperintensities: A multidisciplinary voxel-wise comparison of imaging and histological correlates.

White matter hyperintensities (WMH) occur in normal aging and across diagnostic categories of neurodegeneration. Ultra-high field imaging (UHF) MRI machines offer the potential to improve our understanding of WMH. Post-mortem imaging using UHF magnetic resonance imaging (MRI) is a useful way of assessing WMH, however, the responsiveness of UHF-MRI to pathological changes within the white matter has not been characterized. In this study we report post-mortem MRI sequences of white matter hyperintensities in normal aging, Alzheimer's disease, and cerebrovascular disease. Seven Tesla post-mortem MRI reliably detected periventricular WMH using both FLAIR and T2 sequences and reflects underlying pathology of myelin and axon density despite prolonged fixation time. Co-registration of histological images to MRI allowed for direct voxel- wise comparison of imaging findings and pathological changes. Myelin content and cerebrovascular pathology were the most significant predictors of MRI white matter intensity as revealed by linear mixed models. Future work investigating the utility of UHF- MRI in studying cell-specific changes within WMH is required to better understand radio-pathologic correlations.

Structural Brain Magnetic Resonance Imaging to Rule Out Comorbid Pathology in the Assessment of Alzheimer's Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials Over the Past 10 Years.

BACKGROUND/OBJECTIVE: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. METHODS: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. RESULTS: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. DISCUSSION: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.