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Introduction Inhibition capabilities have been shown to be a strong predictor of social and educational life outcomes (Mischel & Ebbesen, 1970; Shoda et al., 1990). Inhibition capabilities have an enormous impact on attention and impulsivity (Bari & Robbins, 2013). These two executive functions are associated with numerous psychiatric disorders but are not well understood in terms of white matter (WM) connectivity (Puiu et al., 2018). Novel techniques and statistical approaches in neuroimaging bring us closer to a biologically sustained model. Objectives This research aims to: 1) identify WM connections associated with attention/impulsivity performance and 2) characterize the differences in WM microstructure associated with the variation of the performance. Methods 157 children (GESTE cohort, 8-12 years, 27 Dx ADHD, 2 Dx ASD) with b=1500mm2/s, 2mm isotropic dMRI acquisitions were included. Tractography was performed with TractoFlow pipeline (Theaud et al., 2020). Dimensionality reduction of diffusion metrics yielded two components : microstructural complexity (DTI Metrics, AFD & NuFo) and axonal density (AFD_fixel) (Chamberland et al., 2019). Attention/impulsivity were evaluated with the CPT3. Multivariate linear regression was performed in python. Results Lower microstructural complexity was associated with poorer attentional performance on regions of the parietal lobe to the occipital gyrus (P-O, p=0.044, R2=0.14, Figure 1.) and the Broadman’s area 8 to area 6 (SF8-SF6, p=0.002, R2=0.12, Figure 1.). Lower axonal density was associated with a less impulsive pattern on SF8-SF6 (p=0.001, R2=0.13, Figure 1.). Results remained significant when removing children with an ADHD or ASD diagnosis. Conclusions We identified underlying difference in WM microstructure that may be associated with the variation in attention/impulsivity performance in school-aged children. Disclosure No significant relationships.

Alzheimer's disease (AD) research has been dominated by the single-factor amyloid hypothesis in the last decades. Several other hypotheses have been proposed and increasingly attract attention considering the limited success of amyloid-based therapeutic strategies. Surprisingly, most published alternative etiological hypotheses for AD are similarly single-factor hypotheses, such as vascular, metabolic, mitochondrial, infectious, and inflammatory hypotheses, but the existence of so many different hypotheses suggests that AD is most likely a complex, multifactorial disorder. This inventory of different etiological hypotheses will hopefully help the field to move forward with explanatory models that consider the multifaceted aspects of this devastating disorder.

Background and Objectives: Rates of cerebrovascular disease increase after menopause, which is often attributed to the absence of hormones. It remains unknown whether the cumulative exposure to hormones across a female person's premenopausal life extends the window of cerebrovascular protection to the postmenopausal period. To investigate this, we examined the relationship between lifetime hormone exposure (LHE) and cerebral small vessel disease in more than 9,000 postmenopausal women in the UK-Biobank., Methods: The cohort consisted of women (aged 40-69 years) who attended one of 22 research centers across the United Kingdom between 2006 and 2010. Women were excluded if they were premenopausal when scanned, had missing reproductive history data, self-reported neurologic disorders, brain cancer, cerebral vascular incidents, head or neurologic injury, and nervous system infection. Endogenous LHE (LHE Endo ) was estimated by summing the number of years pregnant (LHE Parity ) with the duration of the reproductive period (LHE Cycle = age menopause - age menarche). Exogenous LHE (LHE Exo ) was estimated by summing the number of years on oral contraceptives and hormone replacement therapy. Cerebral small vessel disease was determined by estimating white matter hyperintensity volume (WMHV) from T2-fluid-attenuated inversion recovery brain MRI (acquired between 2014 and 2021), normalized to intracranial volume and log-transformed. Multiple linear regressions were used to assess the relationship between LHE Endo on WMHV adjusted for age, cardiovascular risk factors, sociodemographics, and LHE Exo ., Results: A total of 9,163 postmenopausal women (age 64.21 ± 6.81 years) were retained for analysis. Average LHE Endo was 39.77 ± 3.59 years. Women with higher LHE Endo showed smaller WMHV (adj- R 2 = 0.307, LHE Endo β = -0.007 [-0.012 to -0.002], p < 0.01). LHE Parity and LHE Cycle were independent contributors to WMHV (adj- R 2 = 0.308, p << 0.001; LHE Parity β = -0.022 [-0.042 to -0.002], p < 0.05; LHE Cycle β = -0.006 [-0.011 to -0.001], p < 0.05). LHE Exo was not significantly related to WMHV (LHE Exo β = 0.001 [-0.001 to 0.002], p > 0.05)., Discussion: Women with more prolonged exposure to endogenous hormones show relatively smaller burden of cerebral small vessel disease independent of the history of oral contraceptive use or hormone replacement therapy. Our results highlight the critical role endogenous hormones play in female brain health and provide real-world evidence of the protective effects premenopausal endogenous hormone exposure plays on postmenopausal cerebrovascular health., (© 2023 American Academy of Neurology.)

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aβ) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aβ deposition ( 18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aβ and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aβ status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: There is a high prevalence of low back pain and neck pain in Canada, and a large proportion can be treated without spine magnetic resonance imaging (MRI). We hypothesized that there is overuse of lumbar and cervical spine MRI. The primary objective was to describe the proportion of appropriate, possibly appropriate, and inappropriate MRI requests for low back pain and neck pain., Methods: We conducted a retrospective observational study in the electromyography (EMG) clinic in Centre Hospitalier Universitaire de Sherbrooke. All ambulatory cases of low back pain or neck pain who had an EMG evaluation and a request of lumbar and/or cervical spine MRI between March 1, 2018, and May 31, 2018, were analyzed. One hundred and twenty MRI orders were classified as appropriate, possibly appropriate, and inappropriate according to the interactive decision support guide of Institut National d'Excellence en Santé et Services Sociaux for optimal use of MRI., Results: Sixty-three requests (53%) were classified as inappropriate, with a higher proportion in the cervical group (34 (64%)) than the lumbar group (28 (43%)). Appropriate and possibly appropriate requests were 19 (16%) and 38 (31%), respectively. The subgroup with an MRI ordered within 90 days of symptom onset had a similar proportion of inappropriate use., Interpretation: Our study demonstrates that despite recommendations against ordering spine MRI in low back pain or neck pain without red flags, there is an overuse of this imaging modality in our region, contributing to the delay in MRI access for appropriate indications.

Structural and functional magnetic resonance imaging (MRI) studies have suggested a neuroanatomical basis that may underly attention-deficit-hyperactivity disorder (ADHD), but the anatomical ground truth remains unknown. In addition, the role of the white matter (WM) microstructure related to attention and impulsivity in a general pediatric population is still not well understood. Using a state-of-the-art structural connectivity pipeline based on the Brainnetome atlas extracting WM connections and its subsections, we applied dimensionality reduction techniques to obtain biologically interpretable WM measures. We selected the top 10 connections-of-interests (located in frontal, parietal, occipital, and basal ganglia regions) with robust anatomical and statistical criteria. We correlated WM measures with psychometric test metrics (Conner's Continuous Performance Test 3) in 171 children (27 Dx ADHD, 3Dx ASD, 9-13 years old) from the population-based GESTation and Environment cohort. We found that children with lower microstructural complexity and lower axonal density show a higher impulsive behavior on these connections. When segmenting each connection in subsections, we report WM alterations localized in one or both endpoints reflecting a specific localization of WM alterations along each connection. These results provide new insight in understanding the neurophysiology of attention and impulsivity in a general population., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The apparent increase in the prevalence of the attention deficit hyperactivity disorder (ADHD) diagnosis raises many questions regarding the variability of the subjective diagnostic method. This comprehensive review reports findings in studies assessing white matter (WM) bundles in diffusion MRI and symptom severity in children with ADHD. These studies suggested the involvement of the connections between the frontal, parietal, and basal ganglia regions. This review discusses the limitations surrounding diffusion tensor imaging (DTI) and suggests novel imaging techniques allowing for a more reliable representation of the underlying biology. We propose a more inclusive approach to studying ADHD that includes known endophenotypes within the ADHD diagnosis. Aligned with the Research Domain Criteria Initiative, we also propose to investigate attentional capabilities and impulsive behaviours outside of the borders of the diagnosis. We support the existing hypothesis that ADHD originates from a developmental error and propose that it could lead to an accumulation in time of abnormalities in WM microstructure and pathways. Finally, state-of-the-art diffusion processing and novel artificial intelligence approaches would be beneficial to fully understand the pathophysiology of ADHD., Competing Interests: Conflict of Interest M. Descoteaux is CSO and co-founder at Imeka Solutions Inc. (www.imeka.ca) C. Bocti holds an investment in Imeka Solutions Inc., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The accurate segmentation, labeling and quantification of cerebral blood vessels on MR imaging is important for basic and clinical research, yet results are not generalizable, and often require user intervention. New methods are needed to automate this process., Purpose: To automatically segment, label and quantify Circle of Willis (CW) arteries on Magnetic Resonance Angiography images using deep convolutional neural networks., Materials and Methods: MRA images were pooled from three public and private databases. A total of 116 subjects (mean age 56 years ± 21 [standard deviation]; 72 women) were used to make up the training set (N=101) and the testing set (N=15). In each image, fourteen arterial segments making up or surrounding the CW were manually annotated and validated by a clinical expert. Convolutional neural network (CNN) models were trained on a training set to be finally combined in an ensemble to develop eICAB. Model performances were evaluated using (1) quantitative analysis (dice score on test set) and (2) qualitative analysis (external datasets, N=121). The reliability was assessed using multiple MRAs of healthy participants (ICC of vessel diameters and volumes on test-retest)., Results: Qualitative analysis showed that eICAB correctly predicted the large, medium and small arteries in 99±0.4%, 97±1% and 88±7% of all images, respectively. For quantitative assessment, the average dice score coefficients for the large (ICAs, BA), medium (ACAs, MCAs, PCAs-P2), and small (AComm, PComm, PCAs-P1) vessels were 0.76±0.07, 0.76±0.08 and 0.41±0.27, respectively. These results were similar and, in some cases, statistically better (p<0.05) than inter-expert annotation variability and robust to image SNR. Finally, test-retest analysis showed that the model yielded high diameter and volume reliability (ICC=0.99)., Conclusion: We have developed a quick and reliable open-source CNN-based method capable of accurately segmenting and labeling the CW in MRA images. This method is largely independent of image quality. In the future, we foresee this approach as a critical step towards fully automated analysis of MRA databases in basic and clinical research., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier Inc.)

Ketones, the brain's alternative fuel to glucose, bypass the brain glucose deficit and improve cognition in mild cognitive impairment (MCI). Our goal was to assess the impact of a 6-month ketogenic intervention on the functional connectivity within eight major brain resting-state networks, and its possible relationship to improved cognitive outcomes in the BENEFIC trial. MCI participants were randomized to a placebo (n = 15) or ketogenic medium chain triglyceride (kMCT; n = 17) intervention. kMCT was associated with increased functional connectivity within the dorsal attention network (DAN), which correlated to improvement in cognitive tests targeting attention. Ketone uptake ( 11 C-acetoacetate PET) specifically in DAN cortical regions was highly increased in the kMCT group and was directly associated with the improved DAN functional connectivity. Analysis of the structural connectome revealed increased fiber density within the DAN following kMCT. Our findings suggest that ketones in MCI may prove beneficial for cognition at least in part because they improve brain network energy status, functional connectivity and axonal integrity., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Accumulating evidence suggests that there is a sexual dimorphism in brain health, with women exhibiting greater disability following strokes of comparable size and having a higher prevalence of cognitive impairment later in life. Despite the critical implication of the cerebrovascular architecture in brain perfusion and brain health, it remains unclear whether structural differences in vessel density exist across the sexes., Methods: In this study, we used high-density MRI imaging to characterize the intracerebral arterial and venous density of 28 (14 women) sex-matched healthy young volunteers in vivo. Using an in-house vessel segmentation algorithm, we quantified and compared these vascular features across the cortical and subcortical deep gray matter, white matter, and periventricular white matter., Results: We found that, on average, women have reduced intracerebral arterial density in comparison to men (F 2.34 ± 0.48%, M 2.67 ± 0.39%; p<.05). This difference was most pronounced in the subcortical deep gray matter (F 1.78 ± 0.53%, M 2.38 ± 0.82%; p<.05) and periventricular white matter (F 0.68 ± 0.15%, M 1.14 ± 0.33%; p<.0005), indicating a potential sex-specific vulnerability to hypoperfusion in areas critical to core cerebral functions. In contrast, venous density did not exhibit a significant difference between sexes., Conclusions: While this research remains exploratory, it raises important pathophysiological considerations for brain health, adverse cerebrovascular events, and dementia across the sexes. Our findings also highlight the need to take into account sex differences when investigating cerebral characteristics in humans., (© 2021 American Society of Neuroimaging.)

Alzheimer's disease is a major cause of morbidity and mortality. Currently, there are no disease-modifying pharmacotherapies for this condition. Aducanumab, an amyloid beta-directed monoclonal antibody that targets aggregated forms of amyloid-beta in the brains of people with Alzheimer's disease, has raised hopes that such a therapy has been discovered, but its approval by the US Food and Drug Administration has engendered a good deal of controversy. A similar application for approval has been submitted to Health Canada. In response to this, a group of Canadian clinical dementia experts representing a number of organizations, including the Canadian Geriatrics Society, was convened by the Canadian Consortium on Neurodegeneration in Aging (CCNA) to discuss the evidence currently available on this agent and seek consensus on what advice they would offer Health Canada on the application. There was wide-spread agreement that it would be premature for aducanumab to receive approval for the treatment of Alzheimer's disease. It was also noted that the Canadian health-care system is poorly prepared at this time to deal with a disease-modifying therapeutic with targeting, administration, and monitoring characteristics like aducanumab. In this paper, the consensus reached is presented along with its underlying rationale., Competing Interests: CONFLICT OF INTEREST DISCLOSURES Dr. Chertkow has participated as an unpaid advisor in 2020 for establishment of an international database by Biogen. Rockwood is Co-founder of Ardea Outcomes, which (as DGI Clinical) in the last three years has contracts with pharma and device manufacturers (Biogen, Hollister, Novartis, Nutricia, Roche, Takeda) on individualized outcome measurement. In 2019 he accepted an honorarium from Biogen for taking part in an interview. Dr. Black discloses that in the last 5 years (2016–2021) she has received personal fees for ad hoc consulting from Hoffman LaRoche, Biogen, Pfizer, Eli Lilly, Novartis and Merck. She has also received personal fees for speaking from Biogen, Eli Lilly and Novartis. Dr. Black discloses support to her institution for contract research from Eli Lilly, GE Healthcare, Eisai Biogen, Genentech, Optina, Hoffman LaRoche, NovoNordisk, and UCB. Dr. Borrie is principal investigator for Biogen and a sub-investigator for Eisai for two clinical trials and does not personally receive any compensation from Biogen. Dr. Hsiung has received research support as a clinical trials site investigator from Anavax, Biogen, Eli Lilly and Roche. Dr. Kirk has participated in and been recompensed by advisory boards for Biogen, Genzyme and Roche. He has also received compensation for speaking engagements with Biogen. Dr. Masellis reports consulting fees from Biogen Canada relevant to the submitted work. Dr. Nygaard is a paid, independent consultant to Biogen Canada National Advisory Board. Dr. Verret has received funds from Biogen (for the ENGAGE TRIAL). He is a member and has received funds for the advisory boards of Biogen, Roche, Abbvie; and has received funds from Biogen for continuous medical education. David Hogan, Natalie Phillips, Manuel Montero-Odasso, Shabbir Amanullah, Christian Bocti, Howard Feldman, Morris Freedman, and Tarek Rajji report no conflicts of interest relating to this consensus statement., (© 2021 Author(s). Published by the Canadian Geriatrics Society.)

Introduction: White matter (WM) energy supply is crucial for axonal function and myelin maintenance. An exogenous source of ketones, the brain's alternative fuel to glucose, bypasses the brain's glucose-specific energy deficit and improves cognitive outcomes in mild cognitive impairment (MCI). How an additional supply of ketones affects glucose or ketone uptake in specific WM fascicles in MCI has not previously been reported., Methods: This 6-month interventional study included MCI participants randomized to a placebo ( n  = 16) or ketogenic medium chain triglyceride (kMCT; n  = 17) drink. A neurocognitive battery and brain imaging were performed pre- and post-intervention. WM fascicle uptake of ketone and glucose and structural properties were assessed using positron emission tomography and diffusion imaging, respectively., Results: Ketone uptake was increased in the kMCT group by 2.5- to 3.2-fold in all nine WM fascicles of interest ( P  < .001), an effect seen both in deep WM and in fascicle cortical endpoints. Improvement in processing speed was positively associated with WM ketone uptake globally and in individual fascicles, most importantly the fornix ( r  = +0.61; P  = .014)., Discussion: A 6-month kMCT supplement improved WM energy supply in MCI by increasing ketone uptake in WM fascicles. The significant positive association with processing speed suggests that ketones may have a role in myelin integrity in MCI., Competing Interests: SCC has consulted for or received travel honoraria or test products from Nestlé Health Science, German Nutrition Society, Bulletproof, Cerecin, Abbott, Servier, Pro‐Diet and Abitec. SCC is the founder and director of Senotec Ltd. MD is CSO and shareholder of Imeka Solutions Inc and MR is consultant for Imeka Solutions Inc. MD and MR were part of advisory boards for INmune Bio Inc and MD received consulting fees from INmune Bio Inc. All other authors have nothing to disclose., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Mild cognitive impairment (MCI) is often accompanied by metabolic abnormalities and inflammation that might play a role in the development of cognitive impairment. The use of ketogenic medium-chain triglycerides (kMCT) to improve cognition in this population has shown promising results but remains controversial because of the potentially detrimental effect of elevated intake of saturated fatty acids on cardiovascular (CV) health and perhaps inflammatory processes. The primary aim of this secondary data analysis report is to describe changes in cardiometabolic markers and peripheral inflammation during a 6-month kMCT intervention in MCI., Methods: Thirty-nine participants with MCI completed the intervention of 30 g/day of either a kMCT drink or calorie-matched placebo (high-oleic acid) for 6 months. Plasma concentrations of cardiometabolic and inflammatory markers were collected before (fasting state) and after the intervention (2 h following the last drink)., Results: A mixed model ANOVA analysis revealed a time by group interaction for ketones (P < 0.001), plasma 8:0 and 10:0 acids (both P < 0.001) and IL-8 (P = 0.002) with follow up comparison revealing a significant increase in the kMCT group (+48%, P = 0.005), (+3,800 and +4,900%, both P < 0.001) and (+147%, P < 0.001) respectively. A main effect of time was observed for insulin (P = 0.004), triglycerides (P = 0.011) and non-esterified fatty acids (P = 0.036)., Conclusion: Under these study conditions, 30 g/d of kMCT taken for six months and up to 2-hour before post-intervention testing had minimal effect on an extensive profile of circulating cardiometabolic and inflammatory markers as compared to a placebo calorie-matched drink. Our results support the safety kMCT supplementation in individuals with MCI. The clinical significance of the observed increase in circulating IL-8 levels is presently unknown and awaits future studies., (Copyright © 2020. Published by Elsevier Ltd.)

Alzheimer's disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment., Competing Interests: Prof. Dr Tamas Fulop reports grants from CIHR, during the conduct of the study; personal fees from Pfizer and Sanofi, outside the submitted work. Dr Ton Bunt is a share holder of Izumi Biosciences INC, outside the submitted work. In addition, Dr Ton Bunt is a co-inventor for patent US-2014235631-A1 pending and an inventor for a patent WO/2019/183403. Professor Annelise E Barron reports grant (# 5DP1AG072438) from NIH/NIA, during the conduct of the study. In addition, Professor Annelise E Barron has a patent US20190015361A1 pending to Stanford University not related to this study. The authors report no other conflicts of interest in this work., (© 2021 Fulop et al.)

Background: The term progressive apraxia of speech (PAOS) is used to describe speakers presenting with isolated or dominant apraxia of speech in the context of a neurodegenerative syndrome, including primary progressive apraxia of speech (PPAOS) and dominant progressive apraxia of speech (DAOS), respectively. Its motor speech profile has been increasingly explored in the last decade, but description remains vague and very English oriented, although the effect of speakers' language on motor speech phenotypes is increasingly recognized. Although some studies suggest that speakers presenting with isolated PAOS (PPAOS) versus dominant PAOS with concomitant aphasia (DAOS) should be differentiated, distinct characteristics of the two presentations are unclear. Furthermore, a careful description of their clinical presentation in languages other than English is required., Aims: To describe the motor speech characteristics of Quebec French-speaking participants with prominent PAOS and to explore the communication profile of those presenting more specifically with isolated PAOS (PPAOS), and with dominant PAOS and concomitant aphasia (DAOS)., Methods & Procedures: A thorough effort to recruit all speakers presenting with PAOS in the larger population areas of the province of Quebec was conducted over a 3-year span. A total of nine participants with PAOS (pwPAOS; PPAOS = 5, DAOS = 4) underwent a comprehensive language and motor speech assessment, and a cognitive screening. Their performance was compared with 30 matched healthy controls., Outcomes & Results: As a group, pwPAOS differed from healthy speakers on all acoustic and perceptual measures. The PPAOS and PAOS subgroups were similar on several measures, but participants from the PPAOS subgroup tended to perform better on articulatory measures and maximum speech rate tasks., Conclusions & Implications: This study provides an in-depth analysis of motor speech characteristics of PAOS in Quebec French speakers and adds further evidence for the differentiation of PPAOS and DAOS. Combining simple perceptual and acoustic analyses represent a promising approach to distinguish the two variants and identify treatment targets. What this paper adds What is already known on this subject Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome characterized by progressive and initially isolated or dominant apraxia of speech (primary progressive apraxia of speech [PPAOS] and dominant progressive apraxia of speech [DAOS], respectively). Studies mostly report articulatory and prosodic deficits in PAOS, but concomitant deficits such as dysarthria and executive dysfunction are also reported. The description of motor speech skills in PAOS remains vague and English-oriented. Studies suggest that speakers presenting with isolated PAOS vs dominant PAOS with concomitant aphasia should be differentiated, but distinct characteristics of the two presentations are unclear. What this study adds to existing knowledge To the best of the authors' knowledge, this study is the first to report transversal data of Quebec-French participants with PPAOS and DAOS. Moreover, this study is a first step towards identifying potential characteristics that could facilitate the diagnosis of PPAOS and DAOS in Quebec French. It makes a significant contribution to our understanding of progressive apraxia of speech in different cultural languages. What are the potential or actual clinical implications of this work? This study also initiates the search for sensitive tasks for the diagnosis of those speakers (which is an important process), in addition to identifying the core characteristics of PAOS, DAOS, and PPAOS in the development of an assessment battery for this population., (© 2021 Royal College of Speech and Language Therapists.)

Introduction: Counteracting impaired brain glucose metabolism with ketones may improve cognition in mild cognitive impairment (MCI)., Methods: Cognition, plasma ketone response, and metabolic profile were assessed before and 6 months after supplementation with a ketogenic drink containing medium chain triglyceride (ketogenic medium chain triglyceride [kMCT]; 15 g twice/day; n = 39) or placebo (n = 44)., Results: Free and cued recall (Trial 1; P = .047), verbal fluency (categories; P = .024), Boston Naming Test (total correct answers; P = .033), and the Trail-Making Test (total errors; P = .017) improved significantly in the kMCT group compared to placebo (analysis of covariance; pre-intervention score, sex, age, education, and apolipoprotein E4 as covariates). Some cognitive outcomes also correlated positively with plasma ketones. Plasma metabolic profile and ketone response were unchanged., Conclusions: This kMCT drink improved cognitive outcomes in MCI, at least in part by increasing blood ketone level. These data support further assessment of MCI progression to Alzheimer's disease., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The current study explored whether education, a proxy of cognitive reserve, modifies the association between episodic memory (EM) performance and βeta-amyloid load (Aβ), a biomarker of Alzheimer's disease, in a cohort of cognitively normal older adults. One hundred and four participants (mean age 73.3 years) evenly spread out in three bands of education were recruited. Participants underwent neuropsychological assessment, structural MRI as well as PET imaging to quantify Aβ load. Moderation analyses and the Johnson-Neyman technique were carried out to examine the interaction of education with Aβ load to predict EM performance. Linear regressions were then performed within each group of education to better illustrate the interaction effect (all analyses were controlled for age and sex). The interaction between education and Aβ load was significant (p < .05) for years of education, reaching a cutoff point of 13.5 years, above which the relationship between Aβ load and EM was no longer significant. Similarly, significant associations were found between Aβ and EM among participants with secondary (p < .01) and pre-university education (p < .01), but not with a university degree (p = .253). EM performance is associated with Aβ load in cognitively normal older individuals, and this relationship is moderated by educational attainment., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Transient neurological symptoms (TNS) are frequent in patients with subdural hematomas (SDH) and many will receive a diagnosis of epilepsy despite a negative workup., Objective: To explore if patients with TNS and a negative epilepsy workup (cases) evolved differently than those with a positive EEG (controls), which would suggest the existence of alternative etiologies for TNS., Methods: We performed a single-center, retrospective, case-control study of patients with TNS post-SDH. The demographics and clinical and semiological features of cases and controls were compared. The outcome and response to antiepileptic drugs were also assessed and a scoring system developed to predict negative EEG., Results: Fifty-nine patients with SDH-associated TNS were included (39 cases and 20 controls). Demographic characteristics were comparable in both groups. Dysphasia and prolonged episodes were associated with a negative EEG. Clonic movements, impaired awareness, positive symptomatology, complete response to antiepileptic drugs, and mortality were associated with a positive EEG. Using semiological variables, we created a scoring system with a 96.6% sensitivity and 100% specificity in predicting case group patients. The differences observed between both groups support the existence of an alternative etiology to seizures in our case group. We propose the term NESIS (NonEpileptic, Stereotypical, and Intermittent Symptoms) to refer to this subgroup and hypothesize that TNS in these patients might result from cortical spreading depolarization., Conclusion: We describe NESIS as a syndrome experienced by SDH patients with specific prognostic and therapeutic implications. Independent validation of this new entity is now required., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Purpose: The aim of this study was to evaluate random forests (RFs) to identify ROIs on F-florbetapir and F-FDG PET associated with Montreal Cognitive Assessment (MoCA) score., Materials and Methods: Fifty-seven subjects with significant white matter disease presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial, had MoCA and F-florbetapir PET; 55 had F-FDG PET. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter (F-florbetapir PET), or pons (F-FDG PET). SUV ratio data and MoCA score were used for supervised training of RFs programmed in MATLAB., Results: F-Florbetapir PETs were randomly divided into 40 training and 17 testing scans; 100 RFs of 1000 trees, constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: right posterior cingulate gyrus, right anterior cingulate gyrus, left precuneus, left posterior cingulate gyrus, and right precuneus. Amyloid increased with decreasing MoCA score. F-FDG PETs were randomly divided into 40 training and 15 testing scans; 100 RFs of 1000 trees, each tree constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: left fusiform gyrus, left precuneus, left posterior cingulate gyrus, right precuneus, and left middle orbitofrontal gyrus. F-FDG decreased with decreasing MoCA score., Conclusions: Random forests help pinpoint clinically relevant ROIs associated with MoCA score; amyloid increased and F-FDG decreased with decreasing MoCA score, most significantly in the posterior cingulate gyrus.

Introduction: White matter changes (WMC) in the cholinergic tracts contribute to executive dysfunction in the context of cognitive aging. WMC in the external capsule have been associated with executive dysfunction. The objectives of this study were to: 1) Characterize the lateral cholinergic tracts (LCT) and the superior longitudinal fasciculus (SLF). 2) Evaluate the association between diffusion measures within those tracts and cognitive performance., Methods: Neuropsychological testing and high angular resolution diffusion imaging (HARDI) of 34 healthy elderly participants was done, followed by anatomically constrained probabilistic tractography reconstruction robust to crossing fibers. The external capsule was manually segmented on a mean T1 image then merged with an atlas, allowing extraction of the LCT. Diffusion tensor imaging (DTI) and HARDI-based measures were obtained., Results: Correlations between diffusion measures in the LCT and the time of completion of Stroop (left LCT radial and medial diffusivity), the Symbol Search score (right LCT apparent fiber density) and the motor part of Trail-B (left LCT axial and radial diffusivity) were observed. Correlations were also found with diffusion measures in the SLF. WMC burden was low, and no correlation was found with diffusion measures or cognitive performance., Discussion: DTI and HARDI, with isolation of strategic white matter tracts for cognitive functions, represent complimentary tools to better understand the complex process of brain aging., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study examined the additive versus synergistic contribution of beta-amyloid (Aβ) and white matter hyperintensities (WMHs) across 7 cognitive domains in 104 cognitively normal older adults. It also measured the extent to which age-related differences in cognition are driven by measurable brain pathology. All participants underwent neuropsychological assessment along with magnetic resonance imaging and Pittsburg compound B-positron emission tomography imaging for Aβ quantification. WMH severity was quantified using the age-related white matter changes scale. Stepwise regressions, moderation, and mediation modeling were performed. Our findings show that Aβ deposition single-handedly predicts poorer episodic memory performance and that Aβ and WMHs contribute additively to poorer performance in working memory and language while carrying synergistic associations with executive functions and attention. Through mediation modeling, we demonstrated that the influence of age over episodic memory, working memory, executive functions, and language is fully mediated by brain pathology. This study permits to conclude that, in healthy older adults, (1) Aβ burden and WMHs have synergistic associations with some cognitive domains and (2) age-related differences in most cognitive domains are driven by brain pathology associated with dementia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: White matter energy supply to oligodendrocytes and the axonal compartment is crucial for normal axonal function. Although gray matter glucose hypometabolism is extensively reported in Alzheimer's disease (AD), glucose and ketones, the brain's two main fuels, are rarely quantified in white matter in AD., Objective: Using a dual-tracer PET method combined with a fascicle-specific diffusion MRI approach, robust to white matter hyper intensities and crossing fibers, we aimed to quantify both glucose and ketone metabolism in specific white matter fascicles associated with mild cognitive impairment (MCI; n = 51) and AD (n = 13) compared to cognitively healthy age-matched controls (Controls; n = 14)., Methods: Eight white matter fascicles of the limbic lobe and corpus callosum were extracted and analyzed into fascicle profiles of five sections. Glucose (18F-fluorodeoxyglucose) and ketone (11C-acetoacetate) uptake rates, corrected for partial volume effect, were calculated along each fascicle., Results: The only fascicle with significantly lower glucose uptake in AD compared to Controls was the left posterior cingulate segment of the cingulum (-22%; p = 0.016). Non-significantly lower glucose uptake in this fascicle was also observed in MCI. In contrast to glucose, ketone uptake was either unchanged or higher in sections of the fornix and parahippocampal segment of the cingulum in AD., Conclusion: To our knowledge, this is the first report of brain fuel uptake calculated along white matter fascicles in humans. Energetic deterioration in white matter in AD appears to be specific to glucose and occurs first in the posterior cingulum.

Purpose: Amyloid (Aβ) brain deposition can occur in cognitively normal individuals and is associated with cortical volume abnormalities. Aβ-related volume changes are inconsistent across studies. Since volume is composed of surface area and thickness, the relative contribution of Aβ deposition on each of these metrics remains to be understood in cognitively normal individuals., Methods: A group of 104 cognitively normal individuals underwent neuropsychological assessment, PiB-PET scan, and MRI acquisition. Surface-based cortical analyses were performed to investigate the effects of cortical and subcortical Aβ burden on cortical volume, thickness, and surface area. Mediation analyses were used to study the effect of thickness and surface area on Aβ-associated volume changes. We also investigated the relationships between structural metrics in clusters with abnormal morphology and regions underlying resting-state functional networks and cognitive performance., Results: Cortical Aβ was not associated with cortical morphology. Subcortical Aβ burden was associated with changes in cortical volume, thickness, and surface area. Aβ-associated volume changes were driven by cortical surface area with or without thickness but never by thickness alone. Aβ-associated changes overlapped greatly with regions from the default mode network and were associated with lower performance in visuospatial abilities, episodic memory, and working memory., Conclusions: In cognitively normal individuals, subcortical Aβ is associated with cortical volume, and this effect was driven by surface area with or without thickness. Aβ-associated cortical changes were found in the default mode network and affected cognitive performance. Our findings demonstrate the importance of studying subcortical Aβ and cortical surface area in normal ageing.

Purpose: To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification., Methods: The data set included 57 baseline F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for supervised training of an RF classifier programmed in MATLAB., Results: A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence interval [CI], 42%-100%), specificity = 92% (CI, 64%-100%), and classification accuracy = 90% (CI, 68%-99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right anterior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees)., Conclusions: Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.

Amyloid-beta (Aβ) deposition is one of the main hallmarks of Alzheimer's disease. The study assessed the associations between cortical and subcortical 11 C-Pittsburgh Compound B (PiB) retention, namely, in the hippocampus, amygdala, putamen, caudate, pallidum, and thalamus, and subcortical morphology in cognitively normal individuals. We recruited 104 cognitive normal individuals who underwent extensive neuropsychological assessment, PiB-positron emission tomography (PET) scan, and 3-T magnetic resonance imaging (MRI) acquisition of T1-weighted images. Global, cortical, and subcortical regional PiB retention values were derived from each scan and subcortical morphology analyses were performed to investigate vertex-wise local surface and global volumes, including the hippocampal subfields volumes. We found that subcortical regional Aβ was associated with the surface of the hippocampus, thalamus, and pallidum, with changes being due to volume and shape. Hippocampal Aβ was marginally associated with volume of the whole hippocampus as well as with the CA1 subfield, subiculum, and molecular layer. Participants showing higher subcortical Aβ also showed worse cognitive performance and smaller hippocampal volumes. In contrast, global and cortical PiB uptake did not associate with any subcortical metrics. This study shows that subcortical Aβ is associated with subcortical surface morphology in cognitively normal individuals. This study highlights the importance of quantifying subcortical regional PiB retention values in these individuals., (© 2019 Wiley Periodicals, Inc.)

Introduction: Unlike for glucose, uptake of the brain's main alternative fuel, ketones, remains normal in mild cognitive impairment (MCI). Ketogenic medium chain triglycerides (kMCTs) could improve cognition in MCI by providing the brain with more fuel., Methods: Fifty-two subjects with MCI were blindly randomized to 30 g/day of kMCT or matching placebo. Brain ketone and glucose metabolism (quantified by positron emission tomography; primary outcome) and cognitive performance (secondary outcome) were assessed at baseline and 6 months later., Results: Brain ketone metabolism increased by 230% for subjects on the kMCT (P < .001) whereas brain glucose uptake remained unchanged. Measures of episodic memory, language, executive function, and processing speed improved on the kMCT versus baseline. Increased brain ketone uptake was positively related to several cognitive measures. Seventy-five percent of participants completed the intervention., Discussion: A dose of 30 g/day of kMCT taken for 6 months bypasses a significant part of the brain glucose deficit and improves several cognitive outcomes in MCI., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aβ - AD and discuss future possible treatments based on this paradigm.

Background: Benzodiazepines are among the most commonly prescribed drugs for anxiety disorders. While they are indicated as adjunctive treatment for short-term use according to clinical practice guidelines, previous studies have shown patterns of long-term use of benzodiazepines, which is problematic due to side effects, dependence and potential of abuse. The aims of this study were to examine among a large sample of primary care adults suffering from anxiety disorders: 1) benzodiazepine use patterns; and 2) correlates of long-term benzodiazepine use., Methods: Data were drawn from the "Dialogue" project, a large primary care study conducted in 64 primary care clinics in the province of Quebec, Canada. Following a mental health screening in waiting rooms, patients at risk of anxiety or depression completed the Composite International Diagnostic Interview-Simplified (CIDIS). A sample of 740 adults meeting DSM-IV criteria for Generalized Anxiety Disorder, Panic Disorder or Social Anxiety Disorder in the past 12 months took part in this study., Results: Benzodiazepines were used by 22.6% of participants with anxiety disorders in our primary care sample. A large majority of benzodiazepine users (88.4%) met our indicator of long-term use, as defined by utilization for more than 12 weeks including regular and as-needed use. Based on a logistic regression model, individual correlates associated with long-term benzodiazepine use included: being 30 years or older, having a comorbid physical illness, meeting criteria for comorbid agoraphobia, reporting the use of sleep-aids, and concurrent SSRI utilization., Limitation: Data collection with self-reported questionnaires may be subject to information bias., Conclusions: Despite knowledge of the risks of long-term use of benzodiazepines, this remains a pervasive problem. Clinicians need to be mindful of patterns and risk factors leading to long-term use of benzodiazepines in patients with anxiety disorders. Results of this study should raise awareness regarding appropriate prescription practices for benzodiazepines, including decision-making in initiation, duration of prescription, and use of strategies for discontinuation in current long-term benzodiazepine users.

Introduction: Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimer's disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly β-hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI., Objective: To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD., Methods: 24 CTL, 20 MCI and 19AD of similar age and metabolic phenotype underwent a dual-tracer PET and MRI protocol. The uptake rate constants and cerebral metabolic rate of glucose (K Glu , CMR Glu ) and acetoacetate (K AcAc , CMR AcAc ) were evaluated with PET using [ 18 F]-fluorodeoxyglucose ([ 18 F]-FDG), a glucose analogue, and [ 11 C]-acetoacetate ([ 11 C]-AcAc), a ketone PET tracer. Regional brain volume and cortical thickness were evaluated by T1-weighted MRI., Results: In AD compared to CTL, CMR Glu was ~11% lower in the frontal, parietal, temporal lobes and in the cingulate gyrus (p<0.05). K Glu was ~15% lower in these same regions and also in subcortical regions. In MCI compared to CTL, ~7% glucose hypometabolism was present in the cingulate gyrus. Neither regional nor whole brain CMR AcAc or K AcAc were significantly different between CTL and MCI or AD. Reduced gray matter volume and cortical thinning were widespread in AD compared to CTL, whereas, in MCI compared to CTL, volumes were reduced only in the temporal cortex and cortical thinning was most apparent in temporal and cingulate regions., Discussion: This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD and demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

AP@LZ is an electronic organiser that was designed to support the day-to-day activities of persons with Alzheimer's disease. To assess the potential of this technology, three participants (NI, JB, RD) were approached to take part in the study. They benefited from a structured cognitive intervention to learn how to operate AP@LZ; the intervention included the following learning stages: Acquisition, Application and Adaptation. Pre- and post-intervention measures were collected. NI, for whom a longitudinal study was conducted, still continued to use AP@LZ 24 months post-intervention. JB and RD also showed a gradual improvement in their performance throughout the intervention phase (sessions 1 to 19 for JB: performance increased from 50 to 100%; sessions 1 to 25 for RD: from 56 to 89%). The results of the use of AP@LZ in activities of daily living suggest that the application was beneficial for three persons with Alzheimer's disease whose profiles differed notably (age, cognitive and social profiles). Thus, results indicate that they were all able to learn how to operate AP@LZ's functions and to use them in their activities of daily living. Cognitive intervention appears to play an important role for the promotion of learning and adoption of such technology.

New technologies, such as tablet computers, present great potential to support the day-to-day living of persons with Alzheimer's disease (AD). However, whether people with AD can learn how to use a tablet properly in daily life remains to be demonstrated. A single case study was conducted with a 65-year-old woman with AD. A specific and structured intervention tailored to her needs was conceptualised for the use of a calendar application on a tablet computer according to the following learning stages: Acquisition, Application and Adaptation. In spite of her severe episodic memory deficit, she showed progressive learning of the tablet application during the intervention phase. Furthermore, data compiled over 12 months post-use show that she used the tablet successfully in her day-to-day life. She was even able to transfer her newly acquired ability to other available applications designed to monitor regular purchases, consult various recipes and play games. Tablet computers thereby offer a promising avenue for cognitive rehabilitation for persons with AD. This success was mainly achieved through a one-on-one individual programme tailored to this person. The limits and constraints of utilising tablet computers for persons with AD are discussed.

The high metabolic demand of neuronal tissue, coupled with its relatively low energy storage capacity, requires that increases in neuronal activation are quickly matched with increased blood flow to ensure efficient supply of oxygen and nutrients to the tissue. For this to occur, dilation of nearby arterioles must be coordinated with the dilation of larger upstream feeding arteries. As it stands, the exact spatial extent of such dilation in humans is unknown. Using non-invasive time-of-flight magnetic resonance angiography in healthy participants, we developed an automatic methodology for reconstructing cerebral arterial vessels and quantifying their diameter on a voxel-by-voxel basis. Specifically, we isolated the posterior cerebral artery (PCA) supplying each occipital lobe and quantified its vasodilation induced by visual stimulation. Stimulus-induced changes were strongest (∼30%) near primary visual cortex and progressively decreased in a non-linear fashion as a function of distance. Surprisingly, weak - albeit significant - changes (∼2%) were observed ∼70 mm from the visual cortex. This demonstrates that visual stimulation modulates vascular tone along the bulk of the PCA segment, and thus may have important implications for our understanding of functional hyperemia in healthy and diseased states.

Background: In Alzheimer's disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement., Objective: To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults., Methods: Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention., Results: Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization., Conclusion: Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.

Introduction: Midlife hypertension is associated with dementia in longitudinal studies while chronic hypotension in the elderly is associated with dementia onset. Orthostatic hypotension could influence cognitive performance in the elderly. The objective of this study was to assess the relationship between orthostatic hypotension and cognitive functions., Methods: Consecutive participants with complete neuropsychological evaluation from a Memory Clinic were included. Orthostatic hypotension (OH) was defined by a fall≥20/10mmHg systolic/diastolic pressure. Participants were classified into one of 3 groups: 1) subjective cognitive impairment (SCI), 2) mild cognitive impairment (MCI), and 3) dementia. Neuropsychological tests were analyzed for patients with and without OH., Results: One hundred and twenty participants were included, of which 16 (13%) were classified as SCI, 42 (35%) as MCI, and 63 (52%) with dementia. Prevalence of OH was 0% for the SCI group, 26% (n=11) for the MCI group, and 38% (n=24) for the dementia group. Age, sex, education, and brief cognitive test scores (MMSE & MoCA) were not different between groups with or without OH. In the MCI group, OH was associated with lower cognitive performance in several executive functions tests: visual working memory (p<0.001), processing speed (p=0.006), Stroop flexibility (p=0.030) and Trail-Making Test part B (p=0.024). There was no difference in episodic memory performance. OH was associated with a diagnosis of hypertension and the use of antihypertensive medication. No differences were observed in vascular brain injury between groups with and without OH., Conclusions: This study found that orthostatic hypotension prevalence is correlated to severity of cognitive deficits in a Memory Clinic. In MCI, OH is associated with lower performance in executive functions. OH could represent an under-recognized correlate of cognitive performance., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Calibrated fMRI based on arterial spin-labeling (ASL) and blood oxygen-dependent contrast (BOLD), combined with periods of hypercapnia and hyperoxia, can provide information on cerebrovascular reactivity (CVR), resting blood flow (CBF), oxygen extraction fraction (OEF), and resting oxidative metabolism (CMRO 2 ). Vascular and metabolic integrity are believed to be affected in Alzheimer's disease (AD), thus, the use of calibrated fMRI in AD may help understand the disease and monitor therapeutic responses in future clinical trials. In the present work, we applied a calibrated fMRI approach referred to as Quantitative O2 (QUO2) in a cohort of probable AD dementia and age-matched control participants. The resulting CBF, OEF and CMRO 2 values fell within the range from previous studies using positron emission tomography (PET) with 15 O labeling. Moreover, the typical parietotemporal pattern of hypoperfusion and hypometabolism in AD was observed, especially in the precuneus, a particularly vulnerable region. We detected no deficit in frontal CBF, nor in whole grey matter CVR, which supports the hypothesis that the effects observed were associated specifically with AD rather than generalized vascular disease. Some key pitfalls affecting both ASL and BOLD methods were encountered, such as prolonged arterial transit times (particularly in the occipital lobe), the presence of susceptibility artifacts obscuring medial temporal regions, and the challenges associated with the hypercapnic manipulation in AD patients and elderly participants. The present results are encouraging and demonstrate the promise of calibrated fMRI measurements as potential biomarkers in AD. Although CMRO 2 can be imaged with 15 O PET, the QUO2 method uses more widely available imaging infrastructure, avoids exposure to ionizing radiation, and integrates with other MRI-based measures of brain structure and function.

Background: Accumulating evidence points to the superiority of the MoCA over the MMSE as a cognitive screening tool. To facilitate the transition from the MMSE to the MoCA in clinical and research settings, authors have developed MMSE-MoCA conversion tables. However, it is unknown whether a conversion table generated from Alzheimer's disease (AD) patients would apply to patients with other dementia subtypes like vascular dementia or frontotemporal dementia. Furthermore, the reliability and accuracy of MMSE-MoCA conversion tables has not been properly evaluated., Method: We retrospectively examined the MMSE-MoCA relationship in a large multicenter sample gathered from 3 Memory Clinics in Quebec, Canada (1492 patients). We produced an MMSE-MoCA conversion table using the equi-percentile method with log-linear smoothing. We then cross-validated our conversion table with the ADNI dataset (1202 patients) and evaluated its accuracy for future predictions., Results: The MMSE-MoCA conversion table is consistent with previously published tables and has an intra-class correlation of 0.633 with the ADNI sample. However, we found that the MMSE-MoCA relationship is significantly modified by diagnosis (P < .01), with dementia subtypes associated with a dysexecutive syndrome showing a trend towards higher MMSE than other dementia syndromes for a given MoCA score. The large width of 95% confidence interval (CI) for a new prediction suggests questionable reliability for clinical use., Conclusion: In this study, we validated a conversion table between MMSE and MoCA using a large multicenter sample. Our results suggest caution in interpreting the tables in heterogeneous clinical populations, as the MMSE-MoCA relationship may be different across dementia subtypes., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Background: Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disease (AD). Little is known about the implication of the brain's two main fuels, glucose and ketones (acetoacetate), associated with thesebenefits., Objective: To determine whether aerobic exercise training modifies brain energy metabolism in mild AD., Methods: In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu) and acetoacetate (CMRacac) using neuroimaging and cognitive testing were done before and after the Walking program., Results: Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6±0.4 versus 0.2±0.1 μmol/100 g/min; p = 0.01). Plasma acetoacetate concentration and the blood-to-brain acetoacetate influx rate constant were also increased by 2-3-fold (all p≤0.03). CMRglu was unchanged after Walking (28.0±0.1 μmol/100 g/min; p = 0.96). There was a tendency toward improvement in the Stroop-color naming test (-10% completion time, p = 0.06). Performance on the Trail Making A&B tests was also directly related to plasma acetoacetate and CMRacac (all p≤0.01)., Conclusion: In mild AD, aerobic training improved brain energy metabolism by increasing ketone uptake and utilization while maintaining brain glucose uptake, and could potentially be associated with some cognitive improvement.

We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer's disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain's main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain's main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal.

Our primary objective in this study was to quantify whole brain and regional cerebral metabolic rates of glucose (CMRg) in young and older adults in order to determine age-normalized reference CMRg values for healthy older adults with normal cognition for age. Our secondary objectives were to--(i) report a broader range of metabolic and endocrine parameters including body fat composition that could form the basis for the concept of a 'metabolic phenotype' in cognitively normal, older adults, and (ii) to assess whether medications commonly used to control blood lipids, blood pressure or thyroxine affect CMRg values in older adults. Cognition assessed by a battery of tests was normal for age and education in both groups. Compared to the young group (25 years old; n = 34), the older group (72 years old; n = 41) had ~14% lower CMRg (μmol/100 g/min) specifically in the frontal cortex, and 18% lower CMRg in the caudate. Lower grey matter volume and cortical thickness was widespread in the older group. These differences in CMRg, grey matter volume and cortical thickness were present in the absence of any known evidence for prodromal Alzheimer's disease (AD). Percent total body fat was positively correlated with CMRg in many brain regions but only in the older group. Before and after controlling for body fat, HOMA2-IR was significantly positively correlated to CMRg in several brain regions in the older group. These data show that compared to a healthy younger adult, the metabolic phenotype of a cognitively-normal 72 year old person includes similar plasma glucose, insulin, cholesterol, triglycerides and TSH, higher hemoglobin A1c and percent body fat, lower CMRg in the superior frontal cortex and caudate, but the same CMRg in the hippocampus and white matter. Age-normalization of cognitive test results is standard practice and we would suggest that regional CMRg in cognitively healthy older adults should also be age-normalized.

Senile amyloid plaques are one of the main hallmarks of Alzheimer's disease (AD). They correspond to insoluble deposits of amyloid-β peptides (Aβ) and are responsible for the inflammatory response and neurodegeneration that lead to loss of memory. Recent data suggest that Aβ possess antimicrobial and anti-viral activity in vitro. Here, we have used cocultures of neuroglioma (H4) and glioblastoma (U118-MG) cells as a minimal in vitro model to investigate whether Aβ is produced by neuroglioma cells and whether this could result in protective anti-viral activity against HSV-1 infection. Results showed that H4 cells secreted Aβ42 in response to HSV-1 challenge and that U118-MG cells could rapidly internalize Aβ42. Production of pro-inflammatory cytokines TNFα and IL-1β by H4 and U118-MG cells occurred under basal conditions but infection of the cells with HSV-1 did not significantly upregulate production. Both cell lines produced low levels of IFNα. However, extraneous Aβ42 induced strong production of these cytokines. A combination of Aβ42 and HSV-1 induced production of pro-inflammatory cytokines TNFα and IL-1β, and IFNα in the cell lines. The reported anti-viral protection of Aβ42 was revealed in transfer experiments involving conditioned medium (CM) of HSV-1-infected H4 cells. CM conferred Aβ-dependent protection against HSV-1 replication in de novo cultures of H4 cells challenged with HSV-1. Type 1 interferons did not play a role in these assays. Our data established that H4 neuroglioma cells produced Aβ42 in response to HSV-1 infection thus inhibiting secondary replication. This mechanism may play a role in the etiology of AD.

Purpose: Generalized Anxiety Disorder (GAD) is a common mental disorder in the primary care setting, marked by persistent anxiety and worries. The aims of this study were to: 1) examine mental health services utilisation in a large sample of primary care patients; 2) explore detection of GAD and minimal standards for pharmacological and psychological treatment adequacy based on recommendation from clinical practice guidelines; 3) examine correlates of treatment adequacy, i.e. predisposing, enabling and needs factors according to the Behavioural Model of Health Care Use., Methods: A sample of 373 adults meeting DSM-IV criteria for Generalized Anxiety Disorder in the past 12 months took part in this study. Data were drawn from the "Dialogue" project, a large primary care study conducted in 67 primary care clinics in Quebec, Canada. Following a mental health screening in medical clinics (n = 14833), patients at risk of anxiety or depression completed the Composite International Diagnostic Interview-Simplified (CIDIS). Multilevel logistic regression models were developed to examine correlates of treatment adequacy for pharmacological and psychological treatments., Results: Results indicate that 52.5 % of participants were recognized as having GAD by a healthcare professional in the past 12 months, and 36.2 % of the sample received a pharmacological (24.4 %) and/or psychological treatment (19.2 %) meeting indicators based on clinical practice guidelines recommendations. The detection of GAD by a health professional and the presence of comorbid depression were associated with overall treatment adequacy., Conclusions: This study suggests that further efforts towards GAD detection could lead to an increase in the delivery of evidence-based treatments. Key targets for improvement in treatment adequacy include regular follow up of patients with a GAD medication and access to psychotherapy from the primary care setting.