Brain atrophy in normal older adult links tooth loss and diet changes to future cognitive decline.

Several studies have found associations between poor oral health, particularly tooth loss and cognitive decline. However, the specific brain regions affected by tooth loss and the probable causes remain unclear. We conducted a population-based longitudinal cohort study in Nakajima, Nanao City, Japan. Between 2016 and 2018, 2454 residents aged ≥60 participated, covering 92.9% of the local age demographics. This study used comprehensive approach by combining detailed dental examinations, dietary assessments, magnetic resonance imaging (MRI) analysis, and cognitive evaluations. Tooth loss, even in cognitively normal individuals, is associated with parahippocampal gyrus atrophy and increased WMH volume, both of which are characteristics of dementia. Tooth loss was associated with altered dietary patterns, notably a reduction in plant-based food intake and an increase in fatty, processed food intake. This study highlights a possible preventative pathway where oral health may play a significant role in preventing the early neuropathological shifts associated with dementia.

Diffusion MRI Fiber Tractography and Benzodiazepine SPECT Imaging for Assessing Neural Damage to the Language Centers in an Elderly Patient after Successful Reperfusion Therapy.

BACKGROUND: Intravenous thrombolysis and mechanical thrombectomy are the first-line reperfusion therapies for acute ischemic stroke. Here, we describe the utility of diffusion magnetic resonance imaging (MRI) fiber tractography and 123I-iomazenil benzodiazepine receptor single-photon emission computed tomography to estimate the prognosis of post-stroke aphasia after successful reperfusion therapy. CASE REPORT: An 81-year-old man was admitted to the hospital approximately 3.5 h after the onset of symptoms, including decreased consciousness, right hemiparesis, and aphasia. An MRI revealed acute cerebral infarction due to M1 segment occlusion. Intravenous alteplase thrombolysis followed by endovascular thrombectomy resulted in recanalization of the left middle cerebral artery territory. A subsequent MRI showed no new ischemic or hemorrhagic lesions. Although the patient's motor hemiparesis gradually recovered, motor aphasia persisted. Diffusion MRI fiber tractography performed 2 weeks after admission revealed partial injury to the left arcuate fasciculus, indicated by lower fractional anisotropy values than on the contralateral side. A decreased benzodiazepine receptor density was also detected in the left perisylvian and temporoparietal cortices. The patient showed no clear signs of further improvement in the chronic stage post-stroke and was discharged to a nursing home after 3 months. CONCLUSIONS: The application of functional neuroimaging techniques to assess neuronal damage to the primary brain regions 2 weeks after reperfusion therapy for large-vessel occlusion may allow for an accurate prognosis of post-stroke aphasia. This may have a direct clinical implication for navigating subacute-to-chronic phases of rehabilitative care.

Association between Gray and White Matter Lesions and Its Involvement in Clinical Symptoms of Alzheimer's-Type Dementia.

BACKGROUND: Not only gray matter lesions (GMLs) but also white matter lesions (WMLs) can play important roles in the pathology of Alzheimer's disease (AD). The progression of cognitive impairment (CI) and behavioral and psychological symptoms of dementia (BPSD) might be caused by a concerted effect of both GML and WML. OBJECTIVE: This study aimed to investigate the association between GML and WML and how they are involved in the symptoms of CI and BPSD in dementia patients by means of imaging technology. METHODS: Patients in our memory clinic, who were diagnosed with AD-type dementia or amnestic mild cognitive impairment (aMCI) and had undergone both single-photon emission computed tomography (SPECT) and brain MRI, were consecutively enrolled (n = 156; 61 males and 95 females; 79.8 ± 7.4 years old). Symptoms of CI and BPSD were obtained from patients' medical records. For the analysis of GMLs and WMLs, SPECT data and MRI T1-weighted images were used, respectively. This study followed the Declaration of Helsinki, and all procedures were approved by the institutional ethics committee. RESULTS: According to a multivariate analysis, disorientation and disturbed attention demonstrated a relationship between the precuneus and WMLs in both hemispheres. Hyperactivity in BPSD showed multiple correlations between GMLs on both sides of the frontal cortex and WMLs. Patients with aMCI presented more multiple correlations between GMLs and WMLs compared with those with AD-type dementia regarding dementia symptoms including BPSD. CONCLUSION: The interaction between GMLs and WMLs may vary depending on the symptoms of CI and BPSD. Hyperactivity in BPSD may be affected by the functional relationship between GMLs and WMLs in the left and right hemispheres. The correlation between GMLs and WMLs may be changing in AD-type dementia and aMCI.

Impact of hs-CRP concentration on brain structure alterations and cognitive trajectory in Alzheimer's disease.

Introduction: Present study was to investigate hs-CRP concentration, brain structural alterations, and cognitive function in the context of AD [Subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD]. Methods: We retrospectively included 313 patients (Mean age = 76.40 years, 59 SCD, 101 MCI, 153 AD) in a cross-sectional analysis and 91 patients (Mean age = 75.83 years, 12 SCD, 43 MCI, 36 AD) in a longitudinal analysis. Multivariable linear regression was conducted to investigate the relationship between hs-CRP concentration and brain structural alterations, and cognitive function, respectively. Results: Hs-CRP was positively associated with gray matter volume in the left fusiform (ß = 0.16, pFDR = 0.023) and the left parahippocampal gyrus (ß = 0.16, pFDR = 0.029). Post hoc analysis revealed that these associations were mainly driven by patients with MCI and AD. The interaction of diagnosis and CRP was significantly associated with annual cognitive changes (ß = 0.43, p = 0.008). Among these patients with AD, lower baseline CRP was correlated with greater future cognitive decline (r = -0.41, p = 0.013). Conclusion: Our study suggests that increased hs-CRP level may exert protective effect on brain structure alterations and future cognitive changes among patients already with cognitive impairment.

Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study: Rationale, Design, and Background.

The Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study (TMM Brain MRI Study) was established to collect multimodal information through neuroimaging and neuropsychological assessments to evaluate the cognitive function and mental health of residents who experienced the Great East Japan Earthquake (GEJE) and associated tsunami. The study also aimed to promote advances in personalized healthcare and medicine related to mental health and cognitive function among the general population. We recruited participants for the first (baseline) survey starting in July 2014, enrolling individuals who were participating in either the TMM Community-Based Cohort Study (TMM CommCohort Study) or the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). We collected multiple magnetic resonance imaging (MRI) sequences, including 3D T1-weighted sequences, magnetic resonance angiography (MRA), diffusion tensor imaging (DTI), pseudo-continuous arterial spin labeling (pCASL), and three-dimensional fluid-attenuated inversion recovery (FLAIR) sequences. To assess neuropsychological status, we used both questionnaire- and interview-based rating scales. The former assessments included the Tri-axial Coping Scale, Impact of Event Scale in Japanese, Profile of Mood States, and 15-item Depression, Anxiety, and Stress Scale, whereas the latter assessments included the Mini-Mental State Examination, Japanese version. A total of 12,164 individuals were recruited for the first (baseline) survey, including those unable to complete all assessments. In parallel, we returned the MRI results to the participants and subsequently shared the MRI data through the TMM Biobank. At present, the second (first follow-up) survey of the study started in October 2019 is underway. In this study, we established a large and comprehensive database that included robust neuroimaging data as well as psychological and cognitive assessment data. In combination with genomic and omics data already contained in the TMM Biobank database, these data could provide new insights into the relationships of pathological processes with neuropsychological disorders, including age-related cognitive impairment.

Pretreatment with tadalafil attenuates cardiotoxicity induced by combretastatin A4 disodium phosphate in rats.

Combretastatin A4 disodium phosphate (CA4DP) is a prodrug of combretastatin A4 (CA4), a microtubule-disassembling agent that exhibits antitumor effects by inhibiting tumor cell proliferation and inducing morphological changes and apoptosis in vascular endothelial cells in tumors. However, cardiotoxicity induced by ischemia and hypertension is a severe adverse event. In this study, we focused on the fact that phosphodiesterase (PDE) 5 inhibitors dilate the heart and peripheral blood vessels and aimed to investigate whether co-administration of tadalafil, a PDE5 inhibitor, can attenuate cardiotoxicity without altering the antitumor effect of CA4DP. To investigate cardiotoxicity, CA4DP and/or tadalafil were administered to rats, and blood pressure, echocardiography, histopathology, and cGMP concentration in the myocardium were examined. Administration of CA4DP increased systolic blood pressure, decreased cardiac function, lowered cGMP levels in the myocardium, and led to necrosis of myocardial cells. Co-administration of tadalafil attenuated these CA4DP-induced changes. To investigate the antitumor effect, canine mammary carcinoma cell lines (CHMp-13a) and human umbilical vein endothelial cells were cultured with CA4 and/or tadalafil, and cell proliferation and endothelial vascular tube disruption were examined. CHMp-13a cells were transplanted into nude mice and treated with CA4DP and/or tadalafil. CA4-induced inhibition of cell proliferation and disruption of the endothelial vascular tube were not affected by co-treatment with tadalafil, and the antitumor effects of CA4DP in xenograft mice were not reduced by co-administration of tadalafil. These results revealed that myocardial damage induced by CA4DP was attenuated by co-administration of tadalafil while maintaining antitumor efficacy.

Association Between Frequency of Social Contact and Brain Atrophy in Community-Dwelling Older People Without Dementia: The JPSC-AD Study.

BACKGROUND AND OBJECTIVES: Epidemiologic evidence has shown that social isolation, a low frequency of social contact with others, is associated with the risk of dementia and late-life depressive symptoms. Therefore, we hypothesized that low frequency of social contact may be involved in brain atrophy, and depressive symptoms may play some role in this relationship. We aimed to evaluate the association between low frequency of social contact and the volumes of various brain regions and to assess the extent to which depressive symptoms mediate these relationships from a large population-based multisite cohort study. METHODS: Dementia-free community-dwelling Japanese aged 65 years or older underwent brain MRI scans and a comprehensive health examination. Frequency of contact with noncohabiting relatives and friends was determined by asking a single question with 4 categories: everyday, several times a week, several times a month, and seldom. Total and regional brain volumes, intracranial volume (ICV), and white matter lesion volume were estimated using FreeSurfer software. The associations between frequency of social contact and brain volumes per ICV were examined using analyses of covariance. Mediation analyses were conducted to calculate the proportion of the associations explained by depressive symptoms. RESULTS: We included 8,896 participants. The multivariable-adjusted mean of the total brain volume in the group with the lowest frequency of social contact was significantly lower compared with that in the group with the highest frequency of social contact (67.3% vs 67.8%), with a significant increasing trend across the groups (p value for trend <0.001). The white matter lesion volume increased significantly with lower frequency of social contact (0.30% in the lowest frequency group vs 0.26% in the highest frequency group, p value for trend <0.001). Lower frequency of social contact was associated with smaller volumes in the temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala (all q values of false discovery rate correction <0.05). The relationships seemed to be partly mediated by depressive symptoms, which accounted for 15%-29% of the observed associations. DISCUSSION: Lower frequency of social contact was associated with decreased total and cognitive function-related regional brain volumes. In addition, depressive symptoms partially explained the association in community-dwelling older people without dementia in Japan.

CKD, Brain Atrophy, and White Matter Lesion Volume: The Japan Prospective Studies Collaboration for Aging and Dementia.

Rationale & Objective: Chronic kidney disease, defined by albuminuria and/or reduced estimated glomerular filtration rate (eGFR), has been reported to be associated with brain atrophy and/or higher white matter lesion volume (WMLV), but there are few large-scale population-based studies assessing this issue. This study aimed to examine the associations between the urinary albumin-creatinine ratio (UACR) and eGFR levels and brain atrophy and WMLV in a large-scale community-dwelling older population of Japanese. Study Design: Population-based cross-sectional study. Setting & Participants: A total of 8,630 dementia-free community-dwelling Japanese aged greater than or equal to 65 years underwent brain magnetic resonance imaging scanning and screening examination of health status in 2016-2018. Exposures: UACR and eGFR levels. Outcomes: The total brain volume (TBV)-to-intracranial volume (ICV) ratio (TBV/ICV), the regional brain volume-to-TBV ratio, and the WMLV-to-ICV ratio (WMLV/ICV). Analytical Approach: The associations of UACR and eGFR levels with the TBV/ICV, the regional brain volume-to-TBV ratio, and the WMLV/ICV were assessed by using an analysis of covariance. Results: Higher UACR levels were significantly associated with lower TBV/ICV and higher geometric mean values of the WMLV/ICV (P for trend = 0.009 and <0.001, respectively). Lower eGFR levels were significantly associated with lower TBV/ICV, but not clearly associated with WMLV/ICV. In addition, higher UACR levels, but not lower eGFR, were significantly associated with lower temporal cortex volume-to-TBV ratio and lower hippocampal volume-to-TBV ratio. Limitations: Cross-sectional study, misclassification of UACR or eGFR levels, generalizability to other ethnicities and younger populations, and residual confounding factors. Conclusions: The present study demonstrated that higher UACR was associated with brain atrophy, especially in the temporal cortex and hippocampus, and with increased WMLV. These findings suggest that chronic kidney disease is involved in the progression of morphologic brain changes associated with cognitive impairment.

Efficacy of a mixture of Ginkgo biloba, sesame, and turmeric on cognitive function in healthy adults: Study protocol for a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Ginkgo biloba extract (GBE) reportedly ameliorates cognitive function in patients with chronic cerebrovascular insufficiency. However, its efficacy in healthy adults is ambiguous. It was reported that concentrations of terpene lactones, active components of GBE that are present in very low concentrations in the brain, were significantly increased following administration of a mixture of GBE, sesame seed, and turmeric (GBE/MST) in mice. This study aims to investigate the effectiveness of GBE/MST on the cognitive function of healthy adults by comparing it with that of GBE alone. METHODS: Altogether, 159 participants providing informed consent will be recruited from a population of healthy adults aged 20-64 years. Normal cognitive function at baseline will be confirmed using the Japanese version of the Montreal Cognitive Assessment battery. Participants will be randomly assigned in a double-blind manner to the GBE/MST, GBE, and placebo groups in a 1:1:1 ratio. The Wechsler Memory Scale, Trail Making Test, and Stroop Color and Word Test will be used to assess the memory and executive functions at baseline and at the endpoint (24 weeks). For biological assessment, resting state functional magnetic resonance imaging (rs-fMRI) will be performed simultaneously with the neuropsychological tests. DISCUSSION: This study aims to obtain data that can help compare the profile changes in memory and executive functions among participants consuming GBE/MST, GBE alone, and placebo for 24 weeks. Alterations in the default mode network will be evaluated by comparing the rs-fMRI findings between baseline and 24 weeks in the aforementioned groups. Our results may clarify the impact of GBE on cognitive function and the functional mechanism behind altered cognitive function induced by GBE components. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; registration number: UMIN000043494). This information can be searched on the website of the International Clinical Trials Registry Platform Search Portal of the World Health Organization under the Japan Primary Registries Network.

Co-administration of JQ1, a bromodomain-containing protein 4 inhibitor, enhances the antitumor effect of combretastatin A4, a microtubule inhibitor, while attenuating its cardiotoxicity.

Combretastatin A4 (CA4) inhibits microtubule polymerization, and clinical trials of the prodrug, CA4 disodium phosphate (CA4DP), as an anti-cancer agent have been conducted. However, CA4DP has not been marketed to date because the margin between the effective dose and the cardiotoxic dose is insufficient. Meanwhile, bromodomain-containing protein 4 (BRD4) has been reported to be required for recovery from mitotic arrests induced by anti-microtubule drugs. BRD4 has also been reported to be involved in the progression of heart failure. Therefore, we hypothesized that the combined use of CA4DP with BRD4 inhibitors can enhance the antitumor effect and attenuate CA4DP-induced cardiotoxicity. In this study, the antitumor effect and cardiotoxicity caused by the co-administration of CA4DP with JQ1, a BRD4 inhibitor, were evaluated. CA4 or JQ1 alone reduced the viability of cultured canine mammary tumor cells (CHMp-13a). Viability was further reduced by co-administration, through the suppression of c-Myc. BRD4 positivity in CHMp-13a cytoplasm showed a significant increase when treated with CA4 alone, while the increase was not significant following co-administration. In CHMp-13a xenograft-transplanted mice, co-administration of CA4DP and JQ1 suppressed tumor growth significantly. In CA4DP-induced cardiac injury model rats, echocardiography showed a CA4DP-induced decrease in cardiac function and histopathology showed cardiomyocyte necrosis. Meanwhile, these cardiac changes tended to be milder following the co-administration of CA4DP and JQ1. These results suggest that CA4DP-JQ1 co-administration enhances the antitumor effect of CA4DP while attenuating its cardiotoxicity and therefore potentially open the doors to the development of a novel cancer chemotherapy with reduced cardiotoxicity risks.

Impact of atrial fibrillation on the cognitive decline in Alzheimer's disease.

BACKGROUND: Atrial fibrillation (AF) is a strong risk factor for Alzheimer's disease (AD) independent of ischemic stroke. However, the clinicopathological impact of AF on the severity of AD has not been well elucidated. We aimed to investigate the clinical differences between dementia patients with AF and those without AF by means of imaging data. METHODS: Following approval from the institutional ethics committee, patients with newly diagnosed AD or amnestic mild cognitive impairment (aMCI) were retrospectively screened (n = 170, 79.5 ± 7.4 years old). Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Based on the MRI data, the cerebral volume, cerebral microbleeds (CMBs), periventricular white matter lesions (WMLs), and deep WMLs were evaluated. The regional cerebral blood flow (rCBF) was measured using 123I-IMP SPECT. RESULTS: Of the patients, 14 (8.2%) and 156 (91.8%) had AF (AF group) and sinus rhythm (SR group), respectively. The AF group had significantly lower MMSE scores than the SR group (average [standard deviation (SD)]: 19.4 [4.4] and 22.0 [4.4], respectively; p = 0.0347). Cerebral volume and CMBs did not differ between the two groups. The periventricular WMLs, but not the deep WMLs, were significantly larger in the AF group than in the SR group (mean [SD] mL: 6.85 [3.78] and 4.37 [3.21], respectively; p = 0.0070). However, there was no significant difference in rCBF in the areas related to AD pathology between the two groups. CONCLUSION: AD and aMCI patients with AF showed worse cognitive decline along with larger periventricular WMLs compared to those with SR, although the reduction of rCBF was not different between patients with AF and SR. The white matter lesions may be a more important pathology than the impairment of cerebral blood flow in dementia patients with AF. A larger study is needed to confirm our findings in the future.

Impact of constipation on progression of Alzheimer's disease: A retrospective study.

BACKGROUND AND PURPOSE: In terms of the gut-brain axis, constipation has been considered to be an important factor of neurodegenerative diseases, although the exact mechanism is still controversial. Herein, we aimed to investigate the contribution of constipation to the progression of dementia in a retrospective study. METHODS: Patients of Alzheimer's disease(AD) and amnestic mild cognitive impairment were consecutively screened between January 2015 and December 2020, and those of whom brain MRI and neuropsychological tests were performed twice were enrolled in this study. Participants were classified into with constipation (Cons[+], n = 20) and without constipation (Cons[-], n = 64) groups. Laboratory data at the first visit were used. Regression analysis was performed in MMSE, ADAS-Cog, and the volumes of hippocampus on MRI-MPRAGE images and deep white matter lesions (DWMLs) on MRI-FLAIR images obtained at two different time points. RESULTS: The main finding was that the Cons[+] group showed 2.7 times faster decline in cognitive impairment compared with the Cons[-] group, that is, the liner coefficients of ADAS-Cog were 2.3544 points/year in the Cons[+] and 0.8592 points/year in the Cons[-] groups. Ancillary, changes of DWMLs showed significant correlation with the time span (p < 0.01), and the liner coefficients of DWMLs were 24.48 ml/year in the Cons[+] and 14.83 ml/year in the Cons[-] group, although annual rate of hippocampal atrophy was not different between the two groups. Moreover, serum homocysteine level at baseline was significantly higher in the Cons[+] group than Cons[-] group (14.6 ± 6.4 and 11.5 ± 4.2 nmol/ml, respectively: p = 0.03). CONCLUSION: There is a significant correlation between constipation and faster progression of AD symptoms along with expansion of DWMLs.

Association of the prefrailty with global brain atrophy and white matter lesions among cognitively unimpaired older adults: the Nakajima study.

Physical frailty has been associated with adverse outcomes such as dementia. However, the underlying structural brain abnormalities of physical frailty are unclear. We investigated the relationship between physical frailty and structural brain abnormalities in 670 cognitively unimpaired individuals (mean age 70.1 years). Total brain volume (TBV), hippocampal volume (HV), total white matter hypointensities volume (WMHV), and estimated total intracranial volume (eTIV) on the 3D T1-weighted images were automatically computed using FreeSurfer software. Participants were divided into two states of physical frailty (robust vs. prefrail) based on the revised Japanese version of the Cardiovascular Health Study criteria. The multivariable-adjusted mean values of the TBV-to-eTIV ratio was significantly decreased, whereas that of the WMHV-to-eTIV ratio was significantly increased in the prefrail group compared with the robust group. Slowness, one of the components of physical frailty, was significantly associated with reduced TBV-to-eTIV and HV-to-eTIV ratios, and slowness and weakness were significantly associated with an increased WMHV-to-eTIV ratio. Our results suggest that the prefrail state is significantly associated with global brain atrophy and white matter hypointensities. Furthermore, slowness was significantly associated with hippocampal atrophy.

Impact of Catheter Ablation on Brain Microstructure and Blood Flow Alterations for Cognitive Improvements in Patients with Atrial Fibrillation: A Pilot Longitudinal Study.

Atrial fibrillation (AF) predisposes patients to develop cognitive decline and dementia. Clinical and epidemiological data propose that catheter ablation may provide further benefit to improve neurocognitive function in patients with AF, but the underlying mechanism is poorly available. Here, we conducted a pilot prospective study to investigate whether AF ablation can alter regional cerebral blood flow (rCBF) and brain microstructures, using multimodal magnetic resonance imaging (MRI) technique. Eight patients (63 ± 7 years) with persistent AF underwent arterial-spin labeling (ASL) perfusion, 3D T1-structural images and cognitive test batteries before and 6 months after intervention. ASL and structural MR images were spatially normalized, and the rCBF and cortical thickness of different brain areas were compared between pre- and 6-month post-treatment. Cognitive-psychological function was improved, and rCBF was significantly increased in the left posterior cingulate cortex (PCC) (p = 0.013), whereas decreased cortical thickness was found in the left posterior insular cortex (p = 0.023). Given that the PCC is a strategic site in the limbic system, while the insular cortex is known to play an important part in the central autonomic nervous system, our findings extend the hypothesis that autonomic system alterations are an important mechanism explaining the positive effect of AF ablation on cognitive function.

Perceived social isolation is correlated with brain structure and cognitive trajectory in Alzheimer's disease.

Both objective and perceived social isolations were associated with future cognitive decline and increase risk of Alzheimer's disease (AD). However, the impacts of perceived social isolation depending on different clinical stages of AD have not been elucidated. The aim of this study was to investigate the influence of perceived social isolation or loneliness on brain structure and future cognitive trajectories in patients who are living with or are at risk for AD. A total of 176 elderly patients (mean age of 78 years) who had complaint of memory problems (39 subjective cognitive decline [SCD], 53 mild cognitive impairment [MCI], 84 AD) underwent structural MRI and neuropsychological testing. Loneliness was measured by one binary item question "Do you often feel lonely?." Voxel-based morphometry was conducted to evaluate regional gray matter volume (rGMV) difference associated with loneliness in each group. To evaluate individual differences in cognitive trajectories based on loneliness, subgroup analysis was performed in 51 patients with AD (n = 23) and pre-dementia status (SCD-MCI, n = 28) using the longitudinal scores of Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog). Whole brain VBM analysis comparing lonely to non-lonely patients revealed loneliness was associated with decreased rGMV in bilateral thalamus in SCD patients and in the left middle occipital gyrus and the cerebellar vermal lobules I - V in MCI patients. Annual change of ADAS-Jcog in patients who reported loneliness was significantly greater comparing to these non-lonely in SCD-MCI group, but not in AD group. Our results indicate that perceived social isolation, or loneliness, might be a comorbid symptom of patients with SCD or MCI, which makes them more vulnerable to the neuropathology of future AD progression.

Higher-resolution quantification of white matter hypointensities by large-scale transfer learning from 2D images on the JPSC-AD cohort.

White matter lesions (WML) commonly occur in older brains and are quantifiable on MRI, often used as a biomarker in Aging research. Although algorithms are regularly proposed that identify these lesions from T2-fluid-attenuated inversion recovery (FLAIR) sequences, none so far can estimate lesions directly from T1-weighted images with acceptable accuracy. Since 3D T1 is a polyvalent and higher-resolution sequence, it could be beneficial to obtain the distribution of WML directly from it. However a serious difficulty, both for algorithms and human, can be found in the ambiguities of brain signal intensity in T1 images. This manuscript shows that a cross-domain ConvNet (Convolutional Neural Network) approach can help solve this problem. Still, this is non-trivial, as it would appear to require a large and varied dataset (for robustness) labelled at the same high resolution (for spatial accuracy). Instead, our model was taught from two-dimensional FLAIR images with a loss function designed to handle the super-resolution need. And crucially, we leveraged a very large training set for this task, the recently assembled, multi-sites Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) cohort. We describe the two-step procedure that we followed to handle such a large number of imperfectly labeled samples. A large-scale accuracy evaluation conducted against FreeSurfer 7, and a further visual expert rating revealed that WML segmentation from our ConvNet was consistently better. Finally, we made a directly usable software program based on that trained ConvNet model, available at https://github.com/bthyreau/deep-T1-WMH.

Altruistic Social Activity, Depressive Symptoms, and Brain Regional Gray Matter Volume: Voxel-Based Morphometry Analysis From 8,695 Old Adults.

Altruistic social activity, such as giving support to others, has shown protective benefits on dementia risk and cognitive decline. However, the pathological mechanism is unclear. In the present study, we investigated the association between altruistic social activity and brain regional gray matter. Furthermore, to explore the psychological interplay in altruistic social activity, we tested mediating effect of depressive symptoms on brain regional gray matter. We performed a cross-sectional voxel-based morphology (VBM) analysis including 8 695 old adults (72.9 ± 6.1 years) from Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) Cohort. We measured altruistic social activities by self-report questionnaires, depressive symptoms by Geriatric Depression Scale (GDS)-short version. We employed the whole-brain VBM method to detect relevant structural properties related to altruistic social activity. We then performed multiple regression models to detect the mediating effect of depressive symptoms on particular brain regional gray matter volume while adjusting possible physical and social lifestyle covariables. We found that altruistic social activity is associated with larger gray matter volume in posterior insula, middle cingulate gyrus, hippocampus, thalamus, superior temporal gyrus, anterior orbital gyrus, and middle occipital gyrus. Depressive symptoms mediated over 10% on altruistic social activity and hippocampus volume, over 20% on altruistic social activity and cingulate gyrus volume. Our results indicated that altruistic social activity might preserve brain regional gray matter which are sensitive to aging and cognitive decline. Meanwhile, this association may be explained by indirect effect on depressive symptoms, suggesting that altruistic social activity may mitigate the neuropathology of dementia.

Impact of medium-chain triglycerides on gait performance and brain metabolic network in healthy older adults: a double-blind, randomized controlled study.

Nutritional supplementation with medium-chain triglycerides (MCTs) has the potential to increase memory function in elderly patients with frailty and dementia. Our aim was to investigate the effects of MCT on cognitive and gait functions and their relationships with focal brain metabolism and functional connectivity even in healthy older adults. Participants were blindly randomized and allocated to two groups: 18 g/day of MCT oil and matching placebo formula (control) administered as a jelly stick (6 g/pack, ingested three times a day). Gait analysis during the 6-m walk test, cognition, brain focal glucose metabolism quantified by 18F-fluorodeocyglucose positron emission tomography, and magnetic resonance imaging-based functional connectivity were assessed before and after a 3-month intervention. Sixty-three healthy, normal adults (females and males) were included. Compared with the control group, the MCT group showed better balance ability, as represented by the lower Lissajous index (23.1 ± 14.4 vs. 31.3 ± 18.9; P < 0.01), although no time × group interaction was observed in cognitive and other gait parameters. Moreover, MCT led to suppressed glucose metabolism in the right sensorimotor cortex compared with the control (P < 0.001), which was related to improved balance (r = 0.37; P = 0.04) along with increased functional connectivity from the ipsilateral cerebellar hemisphere. In conclusion, a 3-month MCT supplementation improves walking balance by suppressing glucose metabolism, which suggests the involvement of the cerebro-cerebellar network. This may reflect, at least in part, the inverse reaction of the ketogenic switch as a beneficial effect of long-term MCT dietary treatment.

Alzheimer's Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet.

Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated with Alzheimer's disease (AD). This is partly due to insulin resistance in the brain. Insulin signaling and the number of insulin receptors may decline in the brain of T2DM patients, resulting in impaired synaptic formation, neuronal plasticity, and mitochondrial metabolism. In AD patients, hypometabolism of glucose in the brain is observed before the onset of symptoms. Amyloid-ß accumulation, a main pathology of AD, also relates to impaired insulin action and glucose metabolism, although ketone metabolism is not affected. Therefore, the shift from glucose metabolism to ketone metabolism may be a reasonable pathway for neuronal protection. To promote ketone metabolism, medium-chain triglyceride (MCT) oil and a ketogenic diet could be introduced as an alternative source of energy in the brain of AD patients.

Defining the Optimal Method for Measuring Metabolic Tumor Volume on Preoperative 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography as a Prognostic Predictor in Patients With Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Metabolic tumor volume (MTV) on 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a promising prognostic predictor in pancreatic ductal adenocarcinoma (PDAC). However, the optimal segmentation method and threshold value to determine MTV for PDAC are still unclear. We explored the optimal method and threshold value for the prognostic value of MTV measured on pre-treatment 18F-FDG-PET/CT. METHODS: Seventy-three patients with resected PDAC who underwent 18F FDG-PET/CT before surgical resection were enrolled. MTV values of the tumor were measured on FDG-PET/CT by the two fixed-threshold methods using threshold values as 2.0, 2.5, 3.0, and 3.5 for the absolute method and 35%, 40%, 42%, 45%, and 50% for the relative method. Receiver operating characteristic curve analysis for prediction of 1-year survival rates was conducted for determining the optimal threshold values, and we selected the optimal method and threshold value considering area under the curve. The prognostic values of each FDG-PET/CT parameter for disease-specific survival and recurrence-free survival were assessed with Kaplan-Meier method and Cox proportional hazard models. RESULTS: In receiver operating characteristic curve analysis, MTV by the fixed-absolute threshold method based on a threshold value of 3.5 (MTV3.5) performed best in our study with area under the curve 0.724, sensitivity of 65%, and specificity of 75%. In univariate and multivariate analyses, MTV3.5 was significantly associated with disease-specific and recurrence-free survival. CONCLUSIONS: MTV3.5 by absolute threshold on pre-treatment FDG-PET/CT was the best independent prognostic predictor in resectable PDAC compared with other absolute threshold values and relative threshold values.