Risk factors and cognitive correlates of white matter hyperintensities in ethnically diverse populations without dementia: The COSMIC consortium.

INTRODUCTION: White matter hyperintensities (WMHs) are an important imaging marker for cerebral small vessel diseases, but their risk factors and cognitive associations have not been well documented in populations of different ethnicities and/or from different geographical regions. METHODS: We investigated how WMHs were associated with vascular risk factors and cognition in both Whites and Asians, using data from five population-based cohorts of non-demented older individuals from Australia, Singapore, South Korea, and Sweden (N = 1946). WMH volumes (whole brain, periventricular, and deep) were quantified with UBO Detector and harmonized using the ComBat model. We also harmonized various vascular risk factors and scores for global cognition and individual cognitive domains. RESULTS: Factors associated with larger whole brain WMH volumes included diabetes, hypertension, stroke, current smoking, body mass index, higher alcohol intake, and insufficient physical activity. Hypertension and stroke had stronger associations with WMH volumes in Whites than in Asians. No associations between WMH volumes and cognitive performance were found after correction for multiple testing. CONCLUSION: The current study highlights ethnic differences in the contributions of vascular risk factors to WMHs.

Risk factors and cognitive correlates of white matter hyperintensities in ethnically diverse populations without dementia: the COSMIC consortium.

INTRODUCTION: White matter hyperintensities (WMH) are an important imaging marker for cerebral small vessel diseases, but their risk factors and cognitive associations have not been well-documented in populations of different ethnicities and/or from different geographical regions. METHOD: Magnetic resonance imaging data of five population-based cohorts of non-demented older individuals from Australia, Singapore, South Korea, and Sweden (N = 1,946) were examined for WMH and their associations with vascular risk factors and cognition. RESULT: Factors associated with larger whole brain WMH volumes included diabetes, hypertension, stroke, current smoking, body mass index, higher alcohol intake and insufficient physical activity. Participants with moderate or higher physical activity had less WMH than those who never exercised, but the former two groups did not differ. Hypertension and stroke had stronger associations with WMH volumes in the White, compared to Asian subsample. DISCUSSION: The current study highlighted the ethnic differences in the contributions of vascular risk factors to WMH.

Risk of a first clinical diagnosis of central nervous system demyelination in relation to human herpesviruses in the context of Epstein-Barr virus.

BACKGROUND AND PURPOSE: Epstein-Barr virus (EBV) is implicated in multiple sclerosis (MS) risk; evidence for other herpesviruses is inconsistent. Here, we test blood markers of infection with human herpesvirus 6 (HHV-6), varicella zoster virus (VZV), and cytomegalovirus (CMV) as risk factors for a first clinical diagnosis of central nervous system demyelination (FCD) in the context of markers of EBV infection. METHODS: In the Ausimmune case-control study, cases had an FCD, and population controls were matched on age, sex, and study region. We quantified HHV-6- and VZV-DNA load in whole blood and HHV-6, VZV, and CMV antibodies in serum. Conditional logistic regression tested associations with FCD risk, adjusting for Epstein-Barr nuclear antigen (EBNA) IgG, EBV-DNA load, and other covariates. RESULTS: In 204 FCD cases and 215 matched controls, only HHV-6-DNA load (positive vs. negative) was associated with FCD risk (adjusted odds ratio = 2.20, 95% confidence interval = 1.08-4.46, p = 0.03). Only EBNA IgG and HHV-6-DNA positivity were retained in a predictive model of FCD risk; the combination had a stronger association than either alone. CMV-specific IgG concentration modified the association between an MS risk-related human leucocyte antigen gene and FCD risk. Six cases and one control had very high HHV-6-DNA load (>1.0 × 106 copies/mL). CONCLUSIONS: HHV-6-DNA positivity and high load (possibly due to inherited HHV-6 chromosomal integration) were associated with increased FCD risk, particularly in association with markers of EBV infection. With growing interest in prevention/management of MS through EBV-related pathways, there should be additional consideration of the role of HHV-6 infection.

Understanding the FLASH effect to unravel the potential of ultra-high dose rate irradiation.

A reemergence of research implementing radiation delivery at ultra-high dose rates (UHDRs) has triggered intense interest in the radiation sciences and has opened a new field of investigation in radiobiology. Much of the promise of UHDR irradiation involves the FLASH effect, an in vivo biological response observed to maintain anti-tumor efficacy without the normal tissue complications associated with standard dose rates. The FLASH effect has been validated primarily, using intermediate energy electron beams able to deliver high doses (>7 Gy) in a very short period of time (<200 ms), but has also been found with photon and proton beams. The clinical implications of this new area of research are highly significant, as FLASH radiotherapy (FLASH-RT) has the potential to enhance the therapeutic index, opening new possibilities for eradicating radio-resistant tumors without toxicity. As pioneers in this field, our group has developed a multidisciplinary research team focused on investigating the mechanisms and clinical translation of the FLASH effect. Here, we review the field of UHDR, from the physico-chemical to the biological mechanisms.

Association Between Time Spent Outdoors and Risk of Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: This study aims to determine the contributions of sun exposure and ultraviolet radiation (UVR) exposure to risk of pediatric-onset multiple sclerosis (MS). METHODS: Children with MS and controls recruited from multiple centers in the United States were matched on sex and age. Multivariable conditional logistic regression was used to investigate the association of time spent outdoors daily in summer, use of sun protection, and ambient summer UVR dose in the year before birth and the year before diagnosis with MS risk, with adjustment for sex, age, race, birth season, child's skin color, mother's education, tobacco smoke exposure, being overweight, and Epstein-Barr virus infection. RESULTS: Three hundred thirty-two children with MS (median disease duration 7.3 months) and 534 controls were included after matching on sex and age. In a fully adjusted model, compared to spending <30 minutes outdoors daily during the most recent summer, greater time spent outdoors was associated with a marked reduction in the odds of developing MS, with evidence of dose-response (30 minutes-1 hour: adjusted odds ratio [AOR] 0.48, 95% confidence interval [CI] 0.23-0.99, p = 0.05; 1-2 hours: AOR 0.19, 95% CI 0.09-0.40, p < 0.001). Higher summer ambient UVR dose was also protective for MS (AOR 0.76 per 1 kJ/m2, 95% CI 0.62-0.94, p = 0.01). DISCUSSION: If this is a causal association, spending more time in the sun during summer may be strongly protective against developing pediatric MS, as well as residing in a sunnier location.

Associations of loneliness, belongingness and health behaviors with psychological distress and wellbeing during COVID-19.

BACKGROUND: The aim of this study was to assess the effects of loneliness, belongingness and other modifiable factors on psychological distress and wellbeing and whether the effects of COVID-19 modulated these relationships. METHODS: The current study reported on 1217 participants aged 18 years or older who completed an online survey from 28 to 31 March 2020. Survey measures included demographic characteristics; exposure to COVID-19; impact of COVID-19 on employment, finance, and work and social adjustment; loneliness, thwarted belongingness, and health behavior changes as modifiable factors. Outcome measures were psychological distress and wellbeing. RESULTS: Linear regression models revealed that COVID-19 related work and social adjustment difficulties, financial distress, loneliness, thwarted belongingness, eating a less healthy diet poorer sleep and being female were all associated with increased psychological distress and reduced wellbeing (p < 0.05). Psychological distress was more elevated for those with high difficulties adjusting to COVID-19 and high levels of thwarted belongingness (p < 0.005). Similarly, as COVID-19 related work and social adjustment difficulties increased, wellbeing reduced. This was more pronounced in those who felt lower levels of loneliness (p < 0.0001). Other interactions between COVID-19 impacts were observed with gender and poorer diet for psychological distress and cigarette use, age and gender for wellbeing (p < 0.05). LIMITATIONS: The study was cross-sectional, preventing causal interpretation of the relationships. CONCLUSION: Modifiable factors, age and gender had significant impacts on psychological distress and wellbeing. Public health and policy approaches to improving social, economic and lifestyle factors may mitigate the negative mental health effects of the pandemic and its restrictions.

Commissioning of an ultra-high dose rate pulsed electron beam medical LINAC for FLASH RT preclinical animal experiments and future clinical human protocols.

PURPOSE: To present the acceptance and the commissioning, to define the reference dose, and to prepare the reference data for a quality assessment (QA) program of an ultra-high dose rate (UHDR) electron device in order to validate it for preclinical animal FLASH radiotherapy (FLASH RT) experiments and for FLASH RT clinical human protocols. METHODS: The Mobetron® device was evaluated with electron beams of 9 MeV in conventional (CONV) mode and of 6 and 9 MeV in UHDR mode (nominal energy). The acceptance was performed according to the acceptance protocol of the company. The commissioning consisted of determining the short- and long-term stability of the device, the measurement of percent depth dose curves (PDDs) and profiles at two different positions (with two different dose per pulse regimen) and for different collimator sizes, and the evaluation of the variability of these parameters when changing the pulse width and pulse repetition frequency. Measurements were performed using a redundant and validated dosimetric strategy with alanine and radiochromic films, as well as Advanced Markus ionization chamber for some measurements. RESULTS: The acceptance tests were all within the tolerances of the company's acceptance protocol. The linearity with pulse width was within 1.5% in all cases. The pulse repetition frequency did not affect the delivered dose more than 2% in all cases but 90 Hz, for which the larger difference was 3.8%. The reference dosimetry showed a good agreement within the alanine and films with variations of 2.2% or less. The short-term (resp. long-term) stability was less than 1.0% (resp. 1.8%) and was the same in both CONV and UHDR modes. PDDs, profiles, and reference dosimetry were measured at two positions, providing data for two specific dose rates (about 9 Gy/pulse and 3 Gy/pulse). Maximal beam size was 4 and 6 cm at 90% isodose in the two positions tested. There was no difference between CONV and UHDR mode in the beam characteristics tested. CONCLUSIONS: The device is commissioned for FLASH RT preclinical biological experiments as well as FLASH RT clinical human protocols.

Efficiency of the RADPAD Surgical Cap in Reducing Brain Exposure During Pacemaker and Defibrillator Implantation.

OBJECTIVES: This study sought to investigate the RADPAD No Brainer (Worldwide Innovation and Technologies, Overland Park, Kansas) efficiency in reducing brain exposure to scattered radiation. BACKGROUND: Cranial radioprotective caps such as the RADPAD No Brainer are being marketed as devices that significantly reduce operator's brain exposure to scattered radiation. However, the efficiency of the RADPAD No Brainer in reducing brain exposure in clinical practice remains unknown to date. METHODS: Five electrophysiologists performing device implantations over a 2-month period wore the RADPAD cap with 2 strips of 11 thermoluminescent dosimeter pellets covering the front head above and under the shielded cap. Phantom measurements and Monte Carlo simulations were performed to further investigate brain dose distribution. RESULTS: Our study showed that the right half of the operators' front head was the most exposed region during left subpectoral device implantation; the RADPAD cap attenuated the skin front-head exposure but provided no protection to the brain. The exposure of the anterior part of the brain was decreased by a factor of 4.5 compared with the front-head skin value thanks to the skull. The RADPAD cap worn as a protruding horizontal plane, however, reduced brain exposure by a factor of 1.7 (interquartile range: 1.3 to 1.9). CONCLUSIONS: During device implantation, the RADPAD No Brainer decreased the skin front head exposure but had no impact on brain dose distribution. The RADPAD No Brainer worn as a horizontal plane worn around the neck reduces brain exposure and confirms that the exposure comes from upward scattered radiation.

Midlife susceptibility to the effects of poor diet on diabetes risk.

OBJECTIVE: Type 2 diabetes mellitus (T2D) prevalence continues to increase, and age of incidence continues to decrease. More information is needed to target interventions to the ages where they can be most effective. The objective of this study was to explore the degree to which the association between diet and T2D incidence changes through adulthood. METHODS: Participants were a large number (N = 2818) of community living adults in Canberra and Queanbeyan, Australia across three cohorts; young (20-24 followed to 32-36), mid-life (40-44 followed to 52-56) and late-life (60-64 followed to 72-76). Self-report dietary pattern scores at baseline and diabetes incidence across 12 years follow-up were measured, alongside confounders of caloric intake, sex, smoking status, years of education, hypertension, BMI and physical activity. RESULTS: Cox proportional hazards indicated that neither Western nor Prudent dietary pattern scores were significantly associated with T2D incidence when confounders were included in the model. Unadjusted estimates suggested a positive association between Western dietary pattern scores and subsequent diabetes incidence (HR = 1.40, 95% CI [1.18, 1.64]). Compared with the mid-life cohort, a higher Western dietary pattern score posed a lower risk for incident T2D in the young cohort (unadjusted HR = 0.46, 95% CI [0.22, 0.96]), who also had significantly lower BMI and higher physical activity. No such significant effects were found for the late-life cohort. CONCLUSIONS: Our findings indicate that mid-life may be a period of heightened vulnerability to the effects of an unhealthy diet on diabetes risk, but this effect is attenuated when risk factors related to diet, such as adiposity, are taken into account.

An Internet-Based Intervention Augmented With a Diet and Physical Activity Consultation to Decrease the Risk of Dementia in At-Risk Adults in a Primary Care Setting: Pragmatic Randomized Controlled Trial.

BACKGROUND: There is a need to develop interventions to reduce the risk of dementia in the community by addressing lifestyle factors and chronic diseases over the adult life course. OBJECTIVE: This study aims to evaluate a multidomain dementia risk reduction intervention, Body Brain Life in General Practice (BBL-GP), targeting at-risk adults in primary care. METHODS: A pragmatic, parallel, three-arm randomized trial involving 125 adults aged 18 years or older (86/125, 68.8% female) with a BMI of ≥25 kg/m2 or a chronic health condition recruited from general practices was conducted. The arms included (1) BBL-GP, a web-based intervention augmented with an in-person diet and physical activity consultation; (2) a single clinician-led group, Lifestyle Modification Program (LMP); and (3) a web-based control. The primary outcome was the Australian National University Alzheimer Disease Risk Index Short Form (ANU-ADRI-SF). RESULTS: Baseline assessments were conducted on 128 participants. A total of 125 participants were randomized to 3 groups (BBL-GP=42, LMP=41, and control=42). At immediate, week 18, week 36, and week 62 follow-ups, the completion rates were 43% (18/42), 57% (24/42), 48% (20/42), and 48% (20/42), respectively, for the BBL-GP group; 71% (29/41), 68% (28/41), 68% (28/41), and 51% (21/41), respectively, for the LMP group; and 62% (26/42), 69% (29/42), 60% (25/42), and 60% (25/42), respectively, for the control group. The primary outcome of the ANU-ADRI-SF score was lower for the BBL-GP group than the control group at all follow-ups. These comparisons were all significant at the 5% level for estimates adjusted for baseline differences (immediate: difference in means -3.86, 95% CI -6.81 to -0.90, P=.01; week 18: difference in means -4.05, 95% CI -6.81 to -1.28, P<.001; week 36: difference in means -4.99, 95% CI -8.04 to -1.94, P<.001; and week 62: difference in means -4.62, 95% CI -7.62 to -1.62, P<.001). CONCLUSIONS: A web-based multidomain dementia risk reduction program augmented with allied health consultations administered within the general practice context can reduce dementia risk exposure for at least 15 months. This study was limited by a small sample size, and replication on a larger sample with longer follow-up will strengthen the results. TRIAL REGISTRATION: Australian clinical trials registration number (ACTRN): 12616000868482; https://anzctr.org.au/ACTRN12616000868482.aspx.

Determinants of cognitive performance and decline in 20 diverse ethno-regional groups: A COSMIC collaboration cohort study.

BACKGROUND: With no effective treatments for cognitive decline or dementia, improving the evidence base for modifiable risk factors is a research priority. This study investigated associations between risk factors and late-life cognitive decline on a global scale, including comparisons between ethno-regional groups. METHODS AND FINDINGS: We harmonized longitudinal data from 20 population-based cohorts from 15 countries over 5 continents, including 48,522 individuals (58.4% women) aged 54-105 (mean = 72.7) years and without dementia at baseline. Studies had 2-15 years of follow-up. The risk factors investigated were age, sex, education, alcohol consumption, anxiety, apolipoprotein E ε4 allele (APOE*4) status, atrial fibrillation, blood pressure and pulse pressure, body mass index, cardiovascular disease, depression, diabetes, self-rated health, high cholesterol, hypertension, peripheral vascular disease, physical activity, smoking, and history of stroke. Associations with risk factors were determined for a global cognitive composite outcome (memory, language, processing speed, and executive functioning tests) and Mini-Mental State Examination score. Individual participant data meta-analyses of multivariable linear mixed model results pooled across cohorts revealed that for at least 1 cognitive outcome, age (B = -0.1, SE = 0.01), APOE*4 carriage (B = -0.31, SE = 0.11), depression (B = -0.11, SE = 0.06), diabetes (B = -0.23, SE = 0.10), current smoking (B = -0.20, SE = 0.08), and history of stroke (B = -0.22, SE = 0.09) were independently associated with poorer cognitive performance (p < 0.05 for all), and higher levels of education (B = 0.12, SE = 0.02) and vigorous physical activity (B = 0.17, SE = 0.06) were associated with better performance (p < 0.01 for both). Age (B = -0.07, SE = 0.01), APOE*4 carriage (B = -0.41, SE = 0.18), and diabetes (B = -0.18, SE = 0.10) were independently associated with faster cognitive decline (p < 0.05 for all). Different effects between Asian people and white people included stronger associations for Asian people between ever smoking and poorer cognition (group by risk factor interaction: B = -0.24, SE = 0.12), and between diabetes and cognitive decline (B = -0.66, SE = 0.27; p < 0.05 for both). Limitations of our study include a loss or distortion of risk factor data with harmonization, and not investigating factors at midlife. CONCLUSIONS: These results suggest that education, smoking, physical activity, diabetes, and stroke are all modifiable factors associated with cognitive decline. If these factors are determined to be causal, controlling them could minimize worldwide levels of cognitive decline. However, any global prevention strategy may need to consider ethno-regional differences.

Of fractal and Fourier: A measure for local shape complexity for neurological applications.

BACKGROUND: Local shape complexity can be biologically meaningful as a marker of disease, trauma, or change in brain structure over time. Fractal dimensionality (FD) is currently the dominant measure of local shape complexity used in neuroimaging but its limitations are not well understood. NEW METHOD: Elliptical Fourier harmonic power requirement (HPR) may provide complementary information to FD. We benchmarked the performance of FD and HPR on a series of simulated shapes, systematically manipulating aspects of local shape complexity, and a series of clinical contours (glioma tumour cores and stroke lesions from the BRATS and ATLAS datasets). HPR was calculated as the point of 99.9% harmonic power. FD was calculated at six resolutions (8 × 8, 16 × 16, 32 × 32, 64 × 64, 128 × 128, and 256 × 256), by using an approach which computationally indexes the complexity of the shape boundary (i.e. the number of cells defining the contour) relative to the total grid size. RESULTS AND COMPARISON WITH EXISTING METHODS: PR and FD were moderately positively correlated (r ≈ 0.2 to 0.8 depending on shape properties), and both were sensitive to the frequency and amplitude of local complexity. FD was most biased by rotation, while HPR was more biased by global shape features such as deep invaginations. FD indicated an aggregate measure of complexity across the whole contour, while HPR indicated the point of highest complexity. CONCLUSIONS: The HPR index provides conceptually distinct local complexity information from the current FD standard. Future research will benefit from using these complementary measures.

Protocol for a pragmatic randomised controlled trial of Body Brain Life-General Practice and a Lifestyle Modification Programme to decrease dementia risk exposure in a primary care setting.

INTRODUCTION: It has been estimated that a 10%-25% reduction in seven key risk factors could potentially prevent 1.1-3.0 million Alzheimer's disease cases globally. In addition, as dementia is preceded by more subtle cognitive deficits which have substantial social and economic impact, effective preventative interventions would likely have more extensive benefits. The current study evaluates in primary care a multidomain risk-reduction intervention targeting adults with high risk of developing dementia. METHODS AND ANALYSIS: A randomised controlled trial (RCT) is being conducted to evaluate three intervention programmes using a pragmatic approach suitable to the clinic: (1) a 12-week online and face-to-face dementia risk-reduction intervention (Body Brain Life-General Practice (BBL-GP)); (2) a 6-week face-to-face group lifestyle modification programme (LMP); and (3) a 12-week email-only programme providing general health information. We aim to recruit 240 participants, aged 18 and over, to undergo a comprehensive cognitive and physical assessment at baseline and follow-ups (postintervention, 18, 36 and 62 weeks). The primary outcome is dementia risk measured with the modified version of the Australian National University-Alzheimer's Disease Risk Index Short Form. Secondary outcomes are cognitive function measured with Trails A and B, and the Digit Symbol Modalities Test; physical activity with moderate-vigorous physical activity and the International Physical Activity Questionnaire; depression with the Centre for Epidemiological Studies Depression; cost evaluation with the 12-item Short Form Health Survey, Framingham Coronary Heart Disease Risk Score and Australian Type 2 Diabetes Risk Assessment Tool; diet quality with the Australian Recommended Food Score; and sleep quality with the Pittsburgh Sleep Quality Index. ETHICS AND DISSEMINATION: This RCT is a novel pragmatic intervention applied in a primary care setting to reduce the dementia risk exposure in adults at high risk. If successful, BBL-GP and LMP will provide a versatile, evidence-based package that can be easily and quickly rolled out to other primary care settings and which can be scaled up at relatively low cost compared with other strategies involving intensive interventions. TRIAL REGISTRATION NUMBER: ACTRN12616000868482.

General Practice Clinical Data Help Identify Dementia Hotspots: A Novel Geospatial Analysis Approach.

We have a poor understanding of whether dementia clusters geographically, how this occurs, and how dementia may relate to socio-demographic factors. To shed light on these important questions, this study aimed to compute a dementia risk score for individuals to assess spatial variation of dementia risk, identify significant clusters (hotspots), and explore their association with socioeconomic status. We used clinical records from 16 general practices (468 Statistical Area level 1 s, N = 14,746) from the city of west Adelaide, Australia for the duration of 1 January 2012 to 31 December 2014. Dementia risk was estimated using The Australian National University-Alzheimer's Disease Risk Index. Hotspot analyses were applied to examine potential clusters in dementia risk at small area level. Significant hotspots were observed in eastern and southern areas while coldspots were observed in the western area within the study perimeter. Additionally, significant hotspots were observed in low socio-economic communities. We found dementia risk scores increased with age, sex (female), high cholesterol, no physical activity, living alone (widow, divorced, separated, or never married), and co-morbidities such as diabetes and depression. Similarly, smoking was associated with a lower dementia risk score. The identification of dementia risk clusters may provide insight into possible geographical variations in risk factors for dementia and quantify these risks at the community level. As such, this research may enable policy makers to tailor early prevention strategies to the correct individuals within their precise locations.

Cancer and Cognitive Function: The PATH Through Life Project.

BACKGROUND: A limited number of studies have shown that cancer diagnosis plays a protective role in Alzheimer's disease. However, the effect of the cancer diagnosis on general cognitive function/cognitive decline has not been previously examined. The aim of this study was to investigate the relationship between cancer diagnosis and cognitive function and mild cognitive impairment/disorders (MCI/MCD), adjusting for cancer treatments. METHODS: These data were drawn from the Personality and Total Health (PATH) Through Life Study, a population-based Australian cohort study. A total of 2,547 participants (age range 60-66 years; 48.4% women) who answered cancer-related questions were included in analyses. Random effects linear and logistic models were used to analyze 8-year follow-up data. RESULTS: Participants who were diagnosed with cancer at or prior to baseline (n = 166) had higher levels of physical conditions and depression compared with those who received cancer diagnoses during follow-ups (n = 346) and those who reported no cancer history (n = 2,035). A main effect suggested an improvement in processing speed (p < .01), working memory (p < .05), and simple reaction time (p < .05) for those who received the cancer diagnosis after baseline when compared with those without a cancer diagnosis. However, these group differences were no longer significant when adjusted for cancer treatments. Those with a cancer diagnosis at or prior to baseline reported poorer processing speed when compared with those without a cancer diagnosis, even after adjusting for the treatments. CONCLUSIONS: A cancer diagnosis alone did not play a protective role for cognitive function and cognitive impairment in this population of older community-living individuals.

A longitudinal examination of the relationship between cannabis use and cognitive function in mid-life adults.

BACKGROUND: The relationship between cannabis use and cognitive function in mid-life has rarely been examined despite verbal learning deficits in young adults. METHOD: A longitudinal cohort study of 1,897 Australians recruited at 40-46 years of age and followed up 4 years (94%) and 8 years (87%) later. Random effects regression was used to assess within- and between-person associations between cannabis use and cognitive function across waves of data, and examine whether age-related changes in cognitive performance were modified by cannabis use. The first list of the California Verbal Learning Test (immediate and delayed recall), Symbol Digit Modality Test, Digit Backwards, simple and choice reaction time tasks, were administered at each wave. The Spot-the-Word test was used to assess premorbid verbal ability. Self-reported cannabis use in the past year (no use, < weekly use,≥weekly use) was assessed at each wave. FINDINGS: Participants who used cannabis≥weekly had worse immediate recall (b=-0.68, p=0.014) and showed a trend toward worse delayed recall (b=-0.55, p=0.062) compared to non-users after adjusting for correlates of cannabis use and premorbid verbal ability. These effects were due to between-person differences. There were no significant within-person associations between cannabis use and recall, nor was there evidence of greater cognitive decline in cannabis users with age. CONCLUSIONS: Mid-life cannabis users had poorer verbal recall than non-users, but this was not related to their current level of cannabis use, and cannabis use was not associated with accelerated cognitive decline.

Higher fasting plasma glucose is associated with striatal and hippocampal shape differences: the 2sweet project.

OBJECTIVE: Previous studies have demonstrated associations between higher normal fasting plasma glucose levels (NFG) (<6.1 mmol/L), type 2 diabetes (T2D) and hippocampal atrophy and other cerebral abnormalities. Little is known about the association between plasma glucose and the striatum despite sensorimotor deficits being implicated in T2D. This study aimed to investigate the relationship between plasma glucose levels and striatal and hippocampal morphology using vertex-based shape analysis. DESIGN: A population-based, cross-sectional study. SETTING: Canberra and Queanbeyan, Australia. PARTICIPANTS: 287 cognitively healthy individuals (mean age 63 years, 132 female, 273 Caucasian) with (n=261) or without T2D (n=26), selected from 2551 participants taking part in the Personality & Total Health (PATH) Through Life study by availability of glucose data, MRI scan, and absence of gross brain abnormalities and cognitive impairment. OUTCOME MEASURES: Fasting plasma glucose was measured at first assessment, and MRI images were collected 8 years later. Shape differences indicating outward and inward deformation at the hippocampus and the striatum were examined with FMRIB Software Library-Integrated Registration and Segmentation Toolbox (FSL-FIRST) after controlling for sociodemographic and health variables. RESULTS: Higher plasma glucose was associated with shape differences indicating inward deformation, particularly at the caudate and putamen, among participants with NFG after controlling for age, sex, body mass index (BMI), hypertension, smoking and depressive symptoms. Those with T2D showed shape differences indicating inward deformation at the right hippocampus and bilateral striatum, but outward deformation at the left hippocampus, compared with participants with NFG. CONCLUSIONS: These findings further emphasize the importance of early monitoring and management of plasma glucose levels, even within the normal range, as a risk factor for cerebral atrophy.

Partition Model-Based 99mTc-MAA SPECT/CT Predictive Dosimetry Compared with 90Y TOF PET/CT Posttreatment Dosimetry in Radioembolization of Hepatocellular Carcinoma: A Quantitative Agreement Comparison.

90Y-microsphere selective internal radiation therapy (SIRT) is a valuable treatment in unresectable hepatocellular carcinoma (HCC). Partition-model predictive dosimetry relies on differential tumor-to-nontumor perfusion evaluated on pretreatment 99mTc-macroaggregated albumin (MAA) SPECT/CT. The aim of this study was to evaluate agreement between the predictive dosimetry of 99mTc-MAA SPECT/CT and posttreatment dosimetry based on 90Y time-of-flight (TOF) PET/CT. METHODS: We compared the 99mTc-MAA SPECT/CT results for 27 treatment sessions (25 HCC patients, 41 tumors) with 90Y SIRT (7 glass spheres, 20 resin spheres) and the posttreatment 90Y TOF PET/CT results. Three-dimensional voxelized dose maps were computed from the 99mTc-MAA SPECT/CT and 90Y TOF PET/CT data. Mean absorbed dose ([Formula: see text]) was evaluated to compute the predicted-to-actual dose ratio ([Formula: see text]) in tumor volumes (TVs) and nontumor volumes (NTVs) for glass and resin spheres. The Lin concordance ([Formula: see text]) was used to measure accuracy ([Formula: see text]) and precision (ρ). RESULTS: Administered activity ranged from 0.8 to 1.9 GBq for glass spheres and from 0.6 to 3.4 GBq for resin spheres, and the respective TVs ranged from 2 to 125 mL and from 6 to 1,828 mL. The mean dose [Formula: see text] was 240 Gy for glass and 122 Gy for resin in TVs and 72 Gy for glass and 47 Gy for resin in NTVs. [Formula: see text] was 1.46 ± 0.58 (0.65-2.53) for glass and 1.16 ± 0.41 (0.54-2.54) for resin, and the respective values for [Formula: see text] were 0.88 ± 0.15 (0.56-1.00) and 0.86 ± 0.2 (0.58-1.35). DR variability was substantially lower in NTVs than in TVs. The Lin concordance between [Formula: see text] and [Formula: see text] (resin) was significantly better for tumors larger than 150 mL than for tumors 150 mL or smaller ([Formula: see text] = 0.93 and [Formula: see text] = 0.95 vs. [Formula: see text] = 0.57 and [Formula: see text] = 0.93; P < 0.05). CONCLUSION: In 90Y radioembolization of HCC, predictive dosimetry based on 99mTc-MAA SPECT/CT provided good estimates of absorbed doses calculated from posttreatment 90Y TOF PET/CT for tumor and nontumor tissues. The low variability of [Formula: see text] demonstrates that pretreatment dosimetry is particularly suitable for minimizing radiation-induced hepatotoxicity.

The Effect of Diabetes Medication on Cognitive Function: Evidence from the PATH Through Life Study.

Objective. To examine the effect of diabetes treatment on change of measures of specific cognitive domains over 4 years. Research Design and Methods. The sample was drawn from a population-based cohort study in Australia (the PATH Through Life Study) and comprised 1814 individuals aged 65-69 years at first measurement, of whom 211 were diagnosed with diabetes. Cognitive function was measured using 10 neuropsychological tests. The effect of type of diabetes treatment (diet, oral hypoglycemic agents, and insulin) on measures of specific cognitive domains was assessed using Generalized Linear Models adjusted for age, sex, education, smoking, physical activity level, BMI, and hypertension. Results. Comparison of cognitive function between diabetes treatment groups showed no significant effect of type of pharmacological treatment on cognitive function compared to diet only group or no diabetes group. Of those on oral hypoglycaemic treatment only, participants who used metformin alone had better cognitive function at baseline for the domains of verbal learning, working memory, and executive function compared to participants on other forms of diabetic treatment. Conclusion. This study did not observe significant effect from type of pharmacological treatment for diabetes on cognitive function except that participants who only used metformin showed significant protective effect from metformin on domain of verbal learning, working memory, and executive function.

Heavy cannabis users at elevated risk of stroke: evidence from a general population survey.

OBJECTIVE: Case reports and hospital-based case-control studies suggest that cannabis use may increase the risk of stroke. We examined the risk of non-fatal stroke or transient ischemic attack (TIA) among cannabis users in the general community. METHOD: A general population survey of Australians aged 20-24 years (n=2,383), 40-44 years (n=2,525) and 60-64 years (n=2,547) was used to determine the odds of lifetime stroke or TIA among participants who had smoked cannabis in the past year while adjusting for other stroke risk factors. RESULTS: There were 153 stroke/TIA cases (2.1%). After adjusting for age cohort, past year cannabis users (n=1,043) had 3.3 times the rate of stroke/TIA (95% CI 1.8-6.3, p<0.001). The incidence rate ratio (IRR) reduced to 2.3 after adjustment for covariates related to stroke, including tobacco smoking (95% CI 1.1-4.5). Elevated stroke/TIA was specific to participants who used cannabis weekly or more often (IRR 4.7, 95% CI 2.1-10.7) with no elevation among participants who used cannabis less often. CONCLUSIONS: Heavy cannabis users in the general community have a higher rate of non-fatal stroke or transient ischemic attack than non-cannabis users.