Unraveling the gut-brain connection: The association of microbiota-linked structural brain biomarkers with behavior and mental health.

AIM: The gut microbiota can influence human behavior. However, due to the massive multiple-testing problem, research into the relationship between microbiome ecosystems and the human brain faces drawbacks. This problem arises when attempting to correlate thousands of gut bacteria with thousands of brain voxels. METHODS: We performed brain magnetic resonance imaging (MRI) scans on 133 participants and applied machine-learning algorithms (Ridge regressions) combined with permutation tests. Using this approach, we were able to correlate specific gut bacterial families with brain MRI signals, circumventing the difficulties of massive multiple testing while considering sex, age, and body mass index as confounding factors. RESULTS: The relative abundance (RA) of the Selenomonadaceae, Clostridiaceae, and Veillonellaceae families in the gut was associated with altered cerebellar, visual, and frontal T2-mapping and diffusion tensor imaging measures. Conversely, decreased relative abundance of the Eubacteriaceae family was also linked to T2-mapping values in the cerebellum. Significantly, the brain regions associated with the gut microbiome were also correlated with depressive symptoms and attentional deficits. CONCLUSIONS: Our analytical strategy offers a promising approach for identifying potential brain biomarkers influenced by gut microbiota. By gathering a deeper understanding of the microbiota-brain connection, we can gain insights into the underlying mechanisms and potentially develop targeted interventions to mitigate the detrimental effects of dysbiosis on brain function and mental health.

Obesity-associated deficits in inhibitory control are phenocopied to mice through gut microbiota changes in one-carbon and aromatic amino acids metabolic pathways.

BACKGROUND: Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits. METHODS: We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics. RESULTS: An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism (thyX,dut, exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor's bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient's mice. CONCLUSION: These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts.

Resting-State Functional Connectivity Magnetic Resonance Imaging and Outcome After Acute Stroke.

Background and Purpose- Physiological effects of stroke are best assessed over entire brain networks rather than just focally at the site of structural damage. Resting-state functional magnetic resonance imaging can map functional-anatomic networks by analyzing spontaneously correlated low-frequency activity fluctuations across the brain, but its potential usefulness in predicting functional outcome after acute stroke remains unknown. We assessed the ability of resting-state functional magnetic resonance imaging to predict functional outcome after acute stroke. Methods- We scanned 37 consecutive reperfused stroke patients (age, 69±14 years; 14 females; 3-day National Institutes of Health Stroke Scale score, 6±5) on day 3 after symptom onset. After imaging preprocessing, we used a whole-brain mask to calculate the correlation coefficient matrices for every paired region using the Harvard-Oxford probabilistic atlas. To evaluate functional outcome, we applied the modified Rankin Scale at 90 days. We used region of interest analyses to explore the functional connectivity between regions and graph-computation analysis to detect differences in functional connectivity between patients with good functional outcome (modified Rankin Scale score ≤2) and those with poor outcome (modified Rankin Scale score >2). Results- Patients with good outcome had greater functional connectivity than patients with poor outcome. Although 3-day National Institutes of Health Stroke Scale score was the most accurate independent predictor of 90-day modified Rankin Scale (84.2%), adding functional connectivity increased accuracy to 94.7%. Preserved bilateral interhemispheric connectivity between the anterior inferior temporal gyrus and superior frontal gyrus and decreased connectivity between the caudate and anterior inferior temporal gyrus in the left hemisphere had the greatest impact in favoring good prognosis. Conclusions- These data suggest that information about functional connectivity from resting-state functional magnetic resonance imaging may help predict 90-day stroke outcome.

A new cognitive rehabilitation programme for patients with multiple sclerosis: the 'MS-line! Project'.

BACKGROUND: Cognitive rehabilitation is often delayed in multiple sclerosis (MS). OBJECTIVE: To develop a free and specific cognitive rehabilitation programme for MS patients to be used from early stages that does not interfere with daily living activities. METHODS: MS-line!, cognitive rehabilitation materials consisting of written, manipulative and computer-based materials with difficulty levels developed by a multidisciplinary team. RESULTS: Mathematical, problem-solving and word-based exercises were designed. Physical materials included spatial, coordination and reasoning games. Computer-based material included logic and reasoning, working memory and processing speed games. CONCLUSIONS: Cognitive rehabilitation exercises that are specific for MS patients have been successfully developed.

A randomized, controlled, single-blind, 6-month pilot study to evaluate the efficacy of MS-Line!: a cognitive rehabilitation programme for patients with multiple sclerosis.

BACKGROUND: MS-Line! was created to provide an effective treatment for cognitive impairment in multiple sclerosis (MS) patients. OBJECTIVE: To assess the efficacy of MS-Line!. METHODS: A randomized, controlled, single-blind, 6-month pilot study. Patients were randomly assigned to an experimental group (cognitive rehabilitation with the programme) or to a control group (no cognitive rehabilitation). Randomization was stratified by cognitive impairment level. Cognitive assessment included: selective reminding test, 10/36 spatial recall test (10/36 SPART), symbol digit modalities test, paced auditory serial addition test, word list generation (WLG), FAS test, subtests of WAIS-III, Boston naming test (BNT), and trail making test (TMT). RESULTS: Forty-three patients (22 in the experimental group, 21 in the control group) were analyzed. Covariance analysis showed significant differences in 10/36 SPART (P=0.0002), 10/36 SPART delayed recall (P=0.0021), WLG (P=0.0123), LNS (P=0.0413), BNT (P=0.0007) and TMT-A (P=0.010) scores between groups. CONCLUSIONS: The study showed a significant improvement related to learning and visual memory, executive functions, attention and information processing speed, and naming ability in those patients who received cognitive rehabilitation. The results suggest that MS-Line! is effective in improving cognitive impairment in MS patients.

Multidisciplinary management of multiple sclerosis symptoms.

BACKGROUND: Effective management of multisymptomatic chronic diseases such as multiple sclerosis (MS) requires a multimodal, interdisciplinary approach. At MS clinics, numerous healthcare specialties are coordinated to provide patients with quality clinical care for all aspects of their disease. Settings and resource availability may vary between countries. Four specific specialty services from different EU countries are examined in more detail. SUMMARY: The multidisciplinary neurorehabilitation team in Rennes, France, provides specialized consultations (e.g. spasticity, urodynamic unit, devices), inpatient and outpatient intensive rehabilitation programs and therapeutic education. Management approaches are based on a patient's level of impairment as assessed by the Expanded Disability Status Scale. In Girona, Spain, neuropsychologists perform assessments as part of the neurological protocol for all patients with MS. Depending on the level of impairment and patients' characteristics (e.g. working or not working), cognitive deficits may be treated at home or at a neurorehabilitation center. In Barcelona, Spain, neuro-ophthalmologists are involved in the differential diagnosis and follow-up care of MS patients with visual disturbances; particular attention is given to patients' vision-related quality of life. Pain specialists at the Marianne Strauß Klinik in Berg, Germany, have developed a system for classifying MS pain syndromes and differentiating MS-related pain from non MS-related pain. Chronic pain management involves numerous disciplines and requires active engagement by patients in developing treatment plans. Key Messages: MS affects several body systems and patients invariably require specialized interdisciplinary support. Insight into services provided by various specialties and their fit within multidisciplinary care models at MS centers may facilitate the design or refinement of care models in other locations.

The nature of memory impairment in multiple sclerosis: understanding different patterns over the course of the disease.

Introduction: Memory deficit is one of the most common and severe cognitive impairments in patients with multiple sclerosis and can greatly affect their quality of life. However, there is currently no agreement as to the nature of memory deficit in multiple sclerosis. Methods: This cross-sectional study, carried out at the Dr. Josep Trueta and Santa Caterina hospitals in Girona (Spain), was designed to determine the semiology of verbal memory deficit in the different stages of the disease. To this end, a modification of Rey's verbal auditory test was created by introducing two recognition trials between the five learning trials, thus monitoring what happens in terms of acquisition versus the retrieval of information during the learning phase. Linear regression models were used to evaluate verbal episodic memory performance between-groups adjusting results by age, sex, educational level, and the presence of anxiety and/or depressive symptoms. Results: 133 patients with multiple sclerosis, clinically isolated syndrome, and radiologically isolated syndrome and 55 healthy controls aged 18-65 years were assessed. It was observed that the memory processes of multiple sclerosis patients worsen with the progression of the disease. In this respect, patients in pre-diagnostic phases (radiologically isolated syndrome and clinically isolated syndrome) show no differences in verbal episodic memory compared to the healthy controls. Patients in the inflammatory stage (relapsing-remitting multiple sclerosis) show a previously learned information retrieval deficit, while patients in progressive stages (secondary progressive multiple sclerosis and primary progressive multiple sclerosis) do not even correctly acquire information. Discussion: These results provide significant information to assist in understanding the nature of memory deficits in multiple sclerosis over the course of the disease. These results are discussed in terms of possible cognitive rehabilitation strategies depending on the evolutive stage and are related to neuropathological mechanisms involved in the progression of the disease.

Differences in metacognition between multiple sclerosis phenotypes: cognitive impairment and fatigue are key factors.

Background: Cognitive impairment is present in 40-65% of patients with multiple sclerosis (pwMS). Objectively measured cognitive performance often does not match patients' subjective perception of their own performance. Objective: We aimed to compare cognitive performance and subjective perception of cognitive deficits between pwMS and healthy controls (HCs), as well as the accuracy of subjective perception. Methods: In total, 54 HC and 112 pwMS (relapsing-remitting, RRMS, and progressive PMS) underwent neuropsychological evaluation and completed perceived deficit, fatigue, and anxiety-depression scales. Participants were classified according to their consistency between subjective self-evaluation of cognitive abilities and objective cognitive performance to assess accuracy. Regression models were used to compare cognitive performance between groups and explore factors explaining inaccuracy in the estimation of cognitive performance. Results: PMS showed greater and more widespread cognitive differences with HC than RRMS. No differences were found between pwMS and HC in the perception of deficit. PMS had higher ratios of overestimators. In explaining inaccuracy, fatigue and cognitive preservation were found to be risk factors for underestimation, whereas physical disability and cognitive impairment were risk factors for overestimation. Conclusion: PwMS have metacognitive knowledge impairments. This study provides new information about metacognition, data on the prevalence of impairments over a relatively large sample of PwMS, and new insights into factors explaining it. Anosognosia, related to cognitive impairment, may be present in pwMS. Fatigue is a key factor in underestimating cognition.

Long-term clinical and radiological evolution in one case of Susac's syndrome.

Susac's syndrome is a rare idiopathic microangiopathy affecting the precapillary arterioles of the brain, retina and cochlea leading to the clinical triad of encephalopathy, retinopathy and hearing loss. The objective of this study is to describe a new case of Susac's syndrome reactivated after a 12-year period with a good response to immunosuppressive therapy. The patient was a 32-year-old woman, complaining of diplopia, right blurred vision, progressive gait disturbance, tinnitus, attention deficit, and slight memory loss. The patient was diagnosed as having Susac's syndrome and discharged with steroid therapy. After a 12-year period of clinical stability she had a relapse. Immunosuppressive therapy resulted in significant clinical and radiological improvement. Early clinical identification of Susac's syndrome is crucial for the initiation of immunosuppressive therapy and differential diagnosis. In our case, the combined use of corticosteroids and azathioprine was key in the relapse management.

Oligoclonal IgM bands are a promising biomarker for long-term cognitive outcomes in multiple sclerosis.

BACKGROUND: The presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid is associated with a more severe clinical multiple sclerosis (MS) course. OBJECTIVE: To investigate LS-OCMB as a prognostic biomarker of cognitive long-term outcomes in MS. METHODS: Ninety-nine patients underwent neuropsychological assessment. Cognitive performance between LS-OCMB- and LS-OCMB+ patients was compared adjusting by age, education, anxiety-depression, disease duration, and disability. RESULTS: LS-OCMB+ patients of ∼13 years of disease duration performed worse on Symbol Digit Modalities Test (SDMT) (p = 0.005). CONCLUSION: LS-OCMB+ perform worse on information processing speed and working memory (SDMT), suggesting that LS-OCMB could be a useful biomarker for long-term cognitive outcomes.

Microbiota alterations in proline metabolism impact depression.

The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of proline and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment.

Assessing the presence of oligoclonal IgM bands as a prognostic biomarker of cognitive decline in the early stages of multiple sclerosis.

BACKGROUND: An association has been found between the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid and a more severe clinical multiple sclerosis course. OBJECTIVE: To investigate lipid-specific oligoclonal IgM bands as a prognostic biomarker of cognitive impairment in the early stages of multiple sclerosis. METHODS: Forty-four patients underwent neuropsychological assessment at baseline and 4 years. Cognitive performance at follow-up was compared adjusting by age, education, anxiety-depression, and baseline performance. RESULTS: LS-OCMB+ patients only performed worse for Long-Term Storage in the Selective Reminding Test (p = .018). CONCLUSION: There are no remarkable cognitive differences between LS-OCMB- and LS-OCMB+ patients in the early stages of MS.

Obesity Impairs Short-Term and Working Memory through Gut Microbial Metabolism of Aromatic Amino Acids.

The gut microbiome has been linked to fear extinction learning in animal models. Here, we aimed to explore the gut microbiome and memory domains according to obesity status. A specific microbiome profile associated with short-term memory, working memory, and the volume of the hippocampus and frontal regions of the brain differentially in human subjects with and without obesity. Plasma and fecal levels of aromatic amino acids, their catabolites, and vegetable-derived compounds were longitudinally associated with short-term and working memory. Functionally, microbiota transplantation from human subjects with obesity led to decreased memory scores in mice, aligning this trait from humans with that of recipient mice. RNA sequencing of the medial prefrontal cortex of mice revealed that short-term memory associated with aromatic amino acid pathways, inflammatory genes, and clusters of bacterial species. These results highlight the potential therapeutic value of targeting the gut microbiota for memory impairment, specifically in subjects with obesity.

The Aging Imageomics Study: rationale, design and baseline characteristics of the study population.

Biomarkers of aging are urgently needed to identify individuals at high risk of developing age-associated disease or disability. Growing evidence from population-based studies points to whole-body magnetic resonance imaging's (MRI) enormous potential for quantifying subclinical disease burden and for assessing changes that occur with aging in all organ systems. The Aging Imageomics Study aims to identify biomarkers of human aging by analyzing imaging, biopsychosocial, cardiovascular, metabolomic, lipidomic, and microbiome variables. This study recruited 1030 participants aged ≥50 years (mean 67, range 50-96 years) that underwent structural and functional MRI to evaluate the brain, large blood vessels, heart, abdominal organs, fat, spine, musculoskeletal system and ultrasonography to assess carotid intima-media thickness and plaques. Patients were notified of incidental findings detected by a certified radiologist when necessary. Extensive data were also collected on anthropometrics, demographics, health history, neuropsychology, employment, income, family status, exposure to air pollution and cardiovascular status. In addition, several types of samples were gathered to allow for microbiome, metabolomic and lipidomic profiling. Using big data techniques to analyze all the data points from biological phenotyping together with health records and lifestyle measures, we aim to cultivate a deeper understanding about various biological factors (and combinations thereof) that underlie healthy and unhealthy aging.

A clinical registry of dementia based on the principle of epidemiological surveillance.

BACKGROUND: Traditional epidemiological studies do not allow elucidating the reality of referral and diagnosis patterns of dementia in routine clinical practice within a defined territory. This information is useful and necessary in order to plan and allocate healthcare resources. This paper presents the results from a dementia case registry based on epidemiological surveillance fundamentals. METHODS: Standardised registry of dementia diagnoses made in 2007 by specialised care centres in the Health Region of Girona (RSG) (Spain), which encompasses an area of 5,517 sq. km and a reference population of 690,207 inhabitants. RESULTS: 577 cases of dementia were registered, of which 60.7% corresponded to cases of Alzheimer's disease. Presenile dementia accounted for 9.3% of the cases. Mean time between the onset of symptoms and clinical diagnosis was 2.4 years and the severity of the dementia was mild in 60.7% of the cases. High blood pressure, a family history of dementia, dislipidemia, and a past history of depression were the most common conditions prior to the onset of the disease (>20%). CONCLUSION: The ReDeGi is a viable epidemiological surveillance device that provides information about the clinical and demographic characteristics of patients diagnosed with dementia in a defined geographical area.

Glycated Hemoglobin, but not Insulin Sensitivity, is Associated with Memory in Subjects with Obesity.

OBJECTIVE: Obesity has been related to later-life dementia. Serum glucose levels and insulin resistance are known to influence cognition in individuals with diabetes. This study aimed to evaluate memory function in middle-aged individuals with obesity in association with glucose metabolism and brain iron content. METHODS: This was a cross-sectional case-control study including 121 participants aged 27.2 to 66.6 years (56 without obesity, 65 with obesity) stratified according to sex and menopausal status. Insulin sensitivity, body composition, brain iron content, and memory function were evaluated by euglycemic hyperinsulinemic clamp, dual-energy x-ray absorptiometry, magnetic resonance relaxometry (R2*), and California Verbal Learning Test, respectively. RESULTS: Women with obesity, but not men, had lower scores in some California Verbal Learning Tests in association with metabolic parameters and increased brain iron content compared with controls. Fasting plasma glucose, glycated hemoglobin (HbA1c; within normal range), and R2* were negatively associated with memory scores, whereas insulin sensitivity showed positive associations. Remarkably, only HbA1c levels and R2* in the right inferior fronto-orbital region remained significant after controlling for age, sex, education, and BMI. CONCLUSIONS: Impairments in memory function in middle-aged women with obesity are associated with HbA1c levels and brain iron content independently of insulin sensitivity. These results may have implications in the design of therapeutic strategies in women with obesity.

Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48).

OBJECTIVE: To describe a new spinocerebellar ataxia (SCA48) characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA. METHODS: This is a descriptive study of a family that has been followed for more than a decade with periodic neurologic and neuropsychological examinations, MRI, brain SPECT perfusion, and genetic analysis. Whole exome sequencing was performed in 3 affected and 1 unaffected family member and subsequently validated by linkage analysis of chromosome 16p13.3. RESULTS: Six patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with vermian and hemispheric cerebellar atrophy, suggesting a continuum from a dysexecutive syndrome slowly evolving to a complete and severe CCAS with late truncal ataxia. Three presymptomatic patients showed focal cerebellar atrophy in the vermian, paravermian, and the medial part of cerebellar lobes VI and VII, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum. Among the candidate variants, only the frameshift heterozygous c.823_824delCT STUB1 (p.L275Dfs*16) pathogenic variant cosegregated with the disease. The p.L275Dfs*16 heterozygous STUB1 pathogenic variant leads to neurodegeneration and atrophy in cognition- and emotion-related cerebellar areas and reinforces the importance of STUB1 in maintaining cognitive cerebellar function. CONCLUSIONS: We report a heterozygous STUB1 pathogenic genetic variant causing dominant cerebellar ataxia. Since recessive mutations in STUB1 gene have been previously associated with SCAR16, these findings suggest a previously undescribed SCA locus (SCA48; MIM# 618093).

Adherence to Clinical Practice Guidelines during Dementia Work-Up in a Real-World Setting: A Study from the Registry of Dementias of Girona.

BACKGROUND: There are several position statements and clinical practice guidelines (CPG) for diagnosing dementia. OBJECTIVE: Our aims were to evaluate the adherence to CPG among specialists in the 7 memory clinics included in the Registry of Dementias of Girona (ReDeGi), and to compare the results between 2007-2011 and 2012-2015. We also determined the time and number of visits required to achieve a diagnosis, the supplementary tests ordered, and the drugs prescribed according to dementia subtypes. METHODS: Medical charts of a stratified random sample of 475 ReDeGi cases were reviewed. Basic dementia work-up was evaluated using as a reference evidence-based CPG. An Index of Adherence (AI) was calculated using the following items in the medical chart: cognitive symptomatology; functional disability evaluation; physical examination; neurological examination; psychiatric examination; brief cognitive examination; activities of daily living performance examination; blood test; structural neuroimaging (CT-scan or MRI). RESULTS: The mean AI to CPG among specialists was of 8.2 points, and it improved from 7.9 points in 2007-2011 to 8.5 points in 2012-2015 (Cohen's d = 0.46). A lower adherence was detected in the most severe cases. A dementia diagnosis required 3.5 visits, regardless of the subtype of dementia, although milder cases required more time, more visits, and more supplementary tests than severe cases. CONCLUSION: The adherence to CPG in the catchment area of the ReDeGi is high, and an epidemiological surveillance system such as the ReDeGi may help in improving it. Dementia guidelines should establish procedures adapted to clinical practice, with simplified recommendations for most severe cases.

Trends in the Prescription and Long-Term Utilization of Antidementia Drugs Among Patients with Alzheimer's Disease in Spain: A Cohort Study Using the Registry of Dementias of Girona.

BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) and the N-methyl D-aspartate-antagonist memantine are indicated for the symptomatic treatment of Alzheimer's disease (AD). OBJECTIVES: Our aims were to describe the baseline characteristics of patients with AD according to prescription of these treatments after the diagnostic work-up to describe long-term trends in the use of these medications and to identify baseline characteristics associated with the frequency of use of each treatment. METHODS: This was a cohort study with a sample of 2992 patients with AD recorded in the Registry of Dementias of Girona (ReDeGi) between 2007 and 2014. Consumption of AChEIs and memantine was assessed using the Pharmacy Unit database from the Public Catalan Healthcare Service. We used generalized estimating equation analyses to identify the baseline characteristics associated with the consumption of AChEIs and memantine over time. RESULTS: Most of the patients (70.4%; 95% confidence interval [CI] 68.7-72.0) were prescribed antidementia medication at the time of diagnosis. Of these, 75.0% (95% CI 73.1-76.8) were prescribed AChEIs, 14.7% (95% CI 13.2-16.3) were prescribed an AChEI plus memantine, and 10.3% (95% CI 9.0-11.6) were prescribed memantine. Advanced age reduced the likelihood of AChEI consumption. Mild dementia severity increased the use of AChEIs, and moderate-advanced dementia increased the likelihood of memantine consumption. After diagnosis, the likelihood of AChEI consumption decreased from the first year until the fifth, whereas the likelihood of memantine consumption, either alone or in combination with AChEIs, increased. CONCLUSIONS: Antidementia drug use in this study showed the initial use of AChEIs alone with later use of AChEIs in combination with memantine and memantine alone in older patients with severe AD. Our findings are in agreement with current clinical practice guidelines for the pharmacological treatment of AD.

The Gut Metagenome Changes in Parallel to Waist Circumference, Brain Iron Deposition, and Cognitive Function.

Context: Microbiota perturbations seem to exert modulatory effects on emotional behavior, stress-, and pain-modulation systems in adult animals; however, limited information is available in humans. Objective: To study potential relationships among the gut metagenome, brain microstructure, and cognitive performance in middle-aged, apparently healthy, obese and nonobese subjects after weight changes. Design: This is a longitudinal study over a 2-year period. Setting: A tertiary public hospital. Patients or Other Participants: Thirty-five (18 obese) apparently healthy subjects. Intervention(s): Diet counseling was provided to all subjects. Obese subjects were followed every 6 months. Main Outcome Measure(s): Brain relaxometry (using magnetic resonance R2*), cognitive performance (by means of cognitive tests), and gut microbiome composition (shotgun). Results: R2* increased in both obese and nonobese subjects, independent of weight variations. Changes in waist circumference, but not in body mass index, were associated with brain iron deposition (R2*) in the striatum, amygdala, and hippocampus in parallel to visual-spatial constructional ability and circulating beta amyloid Aß42 levels. These changes were linked to shifts in gut microbiome in which the relative abundance of bacteria belonging to Caldiserica and Thermodesulfobacteria phyla were reciprocally associated with raised R2* in different brain nuclei. Of note, the increase in bacteria belonging to Tenericutes phylum was parallel to decreased R2* gain in the striatum, serum Aß42 levels, and spared visual-spatial constructional ability. Interestingly, metagenome functions associated with circulating and brain iron stores are involved in bacterial generation of siderophores. Conclusions: Changes in the gut metagenome are associated longitudinally with cognitive function and brain iron deposition.