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Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology. Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

This study was designed to evaluate whether subjects with amyloid beta (Aβ) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aβ pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer’s disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aβ+) or negative (Aβ−), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aβ+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aβ+ MCI subjects demonstrated greater worsening compared with Aβ− subjects on the ADAS-Cog over 36 months (5.66±1.47 vs −0.71±1.09, P =0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test ( P <0.05). Similar to MCI subjects, Aβ+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency ( P <0.05), whereas Aβ+ AD patients showed greater declines in verbal fluency and the MMSE ( P <0.05). Aβ+ subjects in all diagnostic groups also showed greater decline on the CDR-SB ( P <0.04), a global clinical assessment. Aβ+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aβ+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aβ− subjects do.

Cognitive impairment is a core feature of schizophrenia, which is aggravated by antipsychotics-induced metabolic disturbance and lacks effective pharmacologic treatments in clinical practice. Our previous study demonstrated the efficiency of metformin in alleviating metabolic disturbance following antipsychotic administration. Here we report that metformin could ameliorate cognitive impairment and improve functional connectivity (FC) in prefrontal regions. This is an open-labeled, evaluator-blinded study. Clinically stable patients with schizophrenia were randomly assigned to receive antipsychotics plus metformin (N = 48) or antipsychotics alone (N = 24) for 24 weeks. The improvement in cognition was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Its association with metabolic measurements, and voxel-wise whole-brain FC with dorsolateral prefrontal cortex (DLPFC) subregions as seeds were evaluated. When compared to the antipsychotics alone group, the addition of metformin resulted in significantly greater improvements in the MCCB composite score, speed of processing, working memory, verbal learning, and visual learning. A significant time × group interaction effect of increased FC between DLPFC and the anterior cingulate cortex (ACC)/middle cingulate cortex (MCC), and between DLPFC subregions were observed after metformin treatment, which was positively correlated with MCCB cognitive performance. Furthermore, the FC between left DLPFC A9/46d to right ACC/MCC significantly mediated metformin-induced speed of processing improvement; the FC between left A46 to right ACC significantly mediated metformin-induced verbal learning improvement. Collectively, these findings demonstrate that metformin can improve cognitive impairments in schizophrenia patients and is partly related to the FC changes in the DLPFC. Trial Registration: The trial was registered with ClinicalTrials.gov (NCT03271866). The full trial protocol is provided in Supplementary Material.

BackgroundHigher docosahexaenoic acid (DHA) intake is inversely correlated with relative risk of Alzheimer’s disease. The potential benefits of DHA supplementation in people with mild cognitive impairment (MCI) have not been fully examined.ObjectiveOur study aimed to assess the effect of a 24-month DHA supplementation on cognitive function and amyloid beta (Aβ)-mediated autophagy in elderly subjects with MCI.MethodsThis was a randomised, double-blind, placebo-controlled trial in Tianjin, China. A total of 240 individuals with MCI were identified and randomly divided into intervention (DHA 2 g/day, n=120) and control (corn oil as placebo, n=120) groups. Cognitive function and blood Aβ-related biomarkers were measured at baseline, 6, 12, 18 and 24 months. Data were analysed using generalised estimating equation.ResultsA total of 217 participants (DHA: 109, placebo: 108) completed the trial. During the follow-up, scores of full-scale IQ, verbal IQ and subdomains of information and digit span were significantly higher in the intervention group than the convention group (p<0.05). In the intervention group, blood Aβ-42 level and expression of Aβ protein precursor mRNA were decreased (p<0.05), while Beclin-1 and LC3-II levels and expression of LC3-II mRNA were increased (p<0.05).ConclusionDaily oral DHA supplementation (2 g/day) for 24 months may improve cognitive function and change blood biomarker-related Aβ-mediated autophagy in people with MCI. Larger longer-term confirmatory studies are warranted.Trial registration numberChiCTR-IOR-15006058.

INTRODUCTION Elevated total homocysteine (tHcy) is a major predictor of brain atrophy, cognitive decline, and Alzheimer's disease (AD) progression. The VITACOG trial, a randomized, placebo‐controlled study in mild cognitive impairment (MCI), previously showed that B vitamin supplementation lowered tHcy, slowing brain atrophy and cognitive decline; however, the underlying mechanisms remained unclear. METHODS We used untargeted, multi‐platform metabolomics, with nuclear magnetic resonance and liquid chromatography‐mass spectrometry to analyze serum samples from 89 B vitamin–treated and 84 placebo‐treated MCI participants over a 2 year follow‐up period. RESULTS Multivariate modeling distinguished treated from placebo groups with 91.2 ± 1.8% accuracy. B vitamin supplementation induced significant metabolic reprogramming, lowering quinolinic acid, α‐ketoglutarate, α‐ketobutyrate, glucose, and glutamate. DISCUSSION These findings reveal that B vitamins influence metabolic pathways beyond tHcy reduction, particularly the tricarboxylic acid cycle and glutamine–glutamate cycling, critical for brain energy homeostasis and neurotransmission. This metabolic signature supports B vitamin supplementation as a strategy for slowing MCI progression. Highlights Nuclear magnetic resonance and multi‐platform liquid chromatography tandem mass spectrometry metabolomics were performed on serum samples from 89 B vitamin–treated and 84 placebo participants in the VITACOG trial. Multi‐platform metabolomics revealed B vitamin–driven metabolic reprogramming, achieving 91% classification accuracy. B vitamin supplementation modulates key neuroprotective metabolic pathways. Regulation of energy metabolism and neurotransmission by B vitamins contributes to brain health in elderly individuals. B vitamins demonstrate potential as an adjunct therapy in mild cognitive impairment, potentially mitigating progression to Alzheimer's disease.

Posdinemab is an anti-phosphorylated tau monoclonal antibody currently under investigation in early Alzheimer's disease (AD). The phase-2 Auτonomy trial (NCT04619420) enrolled participants with mild cognitive impairment (MCI) or mild AD dementia (Clinical Dementia Rating-Global Score [CDR GS] 0.5/memory box ≥0.5) with intermediate levels of tau, pre-screened using a Janssen p217+tau plasma assay and confirmed with tau Positron Emission Tomography (PET). Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) indices representing five cognitive domains were analyzed for voxelwise associations with tau PET. A brain wide map was reconstructed that reveals associations between cognitive domains and tau pathology. Neurofibrillary tangle levels from 422 randomized participants were quantified using F-MK-6240 Standardized Uptake Value Ratio (SUVR; cerebellar gray reference region). SUVR volumes were non-linearly aligned to Montreal Neurological Institute space and smoothed within a gray matter mask to a Full Width at Half Max of 12 mm. Associations with each cognitive domain were computed using Spearman rank to minimize outlier effect. For each of the 5 correlation volumes, voxel values were transformed to their rank. Finally, a domain preference map was generated by assigning to each voxel the highest ranked of the 5 domains and its corresponding Spearman correlation to enable statistical thresholding. Correlations were significant (uncorrected p <10 , False Discovery Rate q<0.01) across most of the brain for all, but the visuospatial domain, for which significant correlations were largely in right occipital cortex. The following domain associations were observed (Figure): Visuospatial to right occipital cortex, with trends of association in left occipital cortex; Language to left temporal, supramarginal, and inferior parietal; Delayed-memory to inferior temporal, fusiform, anterior cingulate, insula, and hippocampus; Attention to left middle occipital, precuneus, and bilateral frontal; Immediate-memory to bilateral middle and superior frontal, precuneus and middle temporal. In participants with intermediate tau and early AD, randomized in the Auτonomy trial, we map using a spatially unbiased analysis of tau PET, which cognitive domains are relatively most impacted by tau pathology across the brain. The ensuing maps reflect established brain functional organization. These findings demonstrate close association between presence/location of tangles and cognitive profile.

Mild cognitive impairment, dementia and osteoporosis are common diseases of ageing and, with the increasingly ageing global population, are increasing in prevalence. These conditions are closely associated, with shared risk factors, common underlying biological mechanisms and potential direct causal pathways. In this review, the epidemiological and mechanistic links between mild cognitive impairment, dementia and skeletal health are explored. Discussion will focus on how changes in brain and bone signalling can underly associations between these conditions, and will consider the molecular and cellular drivers in the context of inflammation and the gut microbiome. There is a complex interplay between nutritional changes, which may precede or follow the onset of mild cognitive impairment (MCI) or dementia, and bone health. Polypharmacy is common in patients with MCI or dementia, and there are difficult prescribing decisions to be made due to the elevated risk of falls associated with many drugs used for associated problems, which can consequently increase fracture risk. Some medications prescribed for cognitive impairment may directly impact bone health. In addition, patients may have difficulty remembering medication without assistance, meaning that osteoporosis drugs may be prescribed but not taken. Cognitive impairment may be improved or delayed by physical activity and exercise, and there is evidence for the additional benefits of physical activity on falls and fractures. Research gaps and priorities with the aim of reducing the burden of osteoporosis and fractures in people with MCI or dementia will also be discussed.

Mild Cognitive Impairment (MCI) is a frequent precursor to Alzheimer's dementia (AD). Mitochondrial dysfunction, marked by reduced cytochrome c oxidase (CCO) activity and lower ATP production, is linked to these neurodegenerative diseases. This study evaluates transcranial photobiomodulation (tPBM), a non-invasive technique using near-infrared light to stimulate mitochondrial CCO, potentially enhancing neuronal energy and cognitive function in individuals with MCI. Twenty patients with mild cognitive impairment (MCI) were randomly assigned to an active treatment group (n = 10) or a sham control group (n = 10) using visually identical devices to maintain blinding. Participants completed daily home-based tPBM sessions for 6 weeks. Pre- and post-treatment assessments included cognitive tests (MMSE, TMT-A & B, CVLT-II) and biomarker evaluations (blood samples via ELISA). Neuroimaging included proton magnetic resonance spectroscopy (¹H-MRS) of the posterior cingulate cortex (PCC) and whole-brain structural and resting-state functional MRI. Change scores were calculated by subtracting baseline from post-treatment values. Compliance exceeded 98% in both groups, and tPBM was well-tolerated. The active tPBM group showed significantly greater post-treatment improvements from baseline (p < 0.05) compared to the sham group, including: (1) better recognition memory (higher long-delay hits, fewer false positives on the CVLT-II); (2) improved cognition (higher MMSE); (3) faster processing speed (shorter TMT-B times); (4) decreased plasma IL-6 levels; (5) higher choline/creatine ratio and a trend toward increased myoinositol/creatine in the PCC; (6) increased left nucleus-accumbens volume; and (7) enhanced functional connectivity within the DMN and between the caudate and DMN, along with decreased FC within the limbic network. Daily, home-based tPBM is a well-tolerated and feasible intervention that led to significant improvements in both cognitive function and biological markers in individuals with MCI. The active tPBM group demonstrated enhanced cognition, recognition memory, and processing speed, alongside reductions in inflammation and structural and functional brain changes, including increased neuroplasticity and alterations in brain connectivity. These findings suggest that tPBM may promote neuronal function and brain network modifications, particularly within the default mode network and limbic regions, providing evidence for its potential as a therapeutic approach in the early stages of Alzheimer's disease.

Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination increased the ability of conventional DTI measures to detect associations between tissue diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content and mean diffusivity measured along the cingulum were independently associated with changes in verbal fluency. This suggests that both tissue modifications and an increase in interstitial isotropic water would contribute to cognitive decline. These observations reinforce the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.