Physical activity (PA) is a widely accepted non-pharmacological therapy for patients with Alzheimer’s disease (AD). Existing studies have demonstrated that PA can improve cognitive function in AD patients. However, few of the meta-analyses conducted to date have included participants with a confirmed AD diagnosis that meets standardized diagnostic criteria, nor have they systematically evaluated the interactions between different intervention parameters. The aim of this study was therefore to investigate the effects of PA on cognitive function improvement in AD patients, and how different intervention parameters may influence the effect sizes.

Two investigators independently conducted systematic searches in four international databases (PubMed, Web of Science, Embase, and Cochrane Library) and two Chinese databases (China National Knowledge Infrastructure [CNKI] and VIP Database [VIP]) while adhering to PRISMA guidelines. The search was limited to randomized clinical trials (RCTs) and covered each database from its inception to March 31, 2025. The methodological quality of included studies was assessed using criteria from the Cochrane Handbook 5.1.0. All analyses were performed using Stata 15.0.

The meta-analysis included 13 RCTs with a total of 813 AD patients. PA significantly improved Mini-Mental State Examination (MMSE) scores in AD patients (Weighted Mean Difference [WMD] = 1.79, 95% CI: 1.03 to 2.55, p < 0.001). Subgroup analyses showed that interventions with moderate intensity (WMD = 2.12), a single session duration of 30 min (WMD = 2.15), a frequency of >3 times per week (WMD = 3.03), a total weekly intervention time of >120 min (WMD = 2.10), and a total intervention duration of >12 weeks (WMD = 1.95) significantly improved MMSE scores. Meta-regression analysis revealed that intervention frequency (p < 0.001) and total intervention duration (p = 0.002) were significantly correlated with improved cognitive function, while the intervention intensity (p < 0.001) and single session duration (p = 0.002) showed negative correlations.

Our findings suggest that PA interventions can improve MMSE scores and enhance cognitive function in AD patients. We recommend that PA interventions for AD patients consist of moderate-intensity, a single session duration of 30 min, a frequency of >3 times per week, a total weekly intervention time of >120 min, and a total intervention duration of >12 weeks.

CRD420250631766. https://www.crd.york.ac.uk/PROSPERO/view/CRD420250631766.

The main symptoms of Parkinson’s disease (PD) include olfactory impairment and tremor. Current treatment methods for PD generally have limitations such as short duration and severe side effects. The novel phosphodiesterase 4 (PDE4) inhibitor Roflupram (Roflu) mitigates inflammatory responses and enhances cognitive functions in individuals with neurological conditions. However, it remains unknown whether Roflu provides neuroprotection in a PD model induced by 6-hydroxydopamine (6-OHDA).

Cell viability was assessed using a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. The expression level of tyrosine hydroxylase (TH) was evaluated by immunoblotting or immunofluorescence. Lactate dehydrogenase (LDH) release was measured to assess cytotoxicity. Intracellular reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were determined using fluorescent probes.

Roflu significantly increased cell viability in 6-OHDA-treated cells, as demonstrated by both MTT assay (17.18%, p < 0.001) and flow cytometry (12.20%, p < 0.001). It also upregulated the expression level of TH by 28.53% (p < 0.05). Furthermore, Roflu reduced LDH release by 23.54% (p < 0.001), indicating decreased cellular damage. Roflu markedly suppressed 6-OHDA-induced ROS accumulation by 57.82% (p < 0.001) and enhanced mitochondrial membrane potential (MMP) by 21.07% (p < 0.01). In addition, Roflu downregulated PDE4B expression in 6-OHDA-treated cells by 88.40% (p < 0.001). Knockdown of PDE4B mimicked the protective effects of Roflu, increasing cell survival by 18.43% (p < 0.001) and reducing LDH release by 21.54% (p < 0.001). Conversely, overexpression of PDE4B completely abolished the protective effects of Roflu, reversing both the increase in cell survival and the reduction in LDH release induced by Roflu in 6-OHDA-treated cells.

Roflu has demonstrated a clear protective effect against cell damage caused by 6-OHDA, which is closely related to the inhibition of PDE4B. These findings indicate that Roflu has substantial preclinical potential as a therapeutic candidate for PD and other neurodegenerative disorders involving oxidative damage.

Mitochondrial dysfunction is closely associated with the pathogenesis of Parkinson’s disease (PD). Lutein has been shown to exert protective effects in neurological disorders. This study aimed to investigate the ameliorative effects of lutein on mitochondrial function in PD and its underlying molecular mechanisms.

Animal and cellular PD models were established by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice and treatment of SH-SY5Y cells with 1-methyl-4-phenylpyridinium ion (MPP⁺), respectively. Motor function was assessed using the rotarod, adhesive removal, and pole tests. Mitochondrial function was evaluated using MitoSOX Red staining, JC-1 staining, and adenosine triphosphate (ATP) content measurement. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to measure the levels of relevant proteins and mRNA.

Lutein significantly ameliorated MPTP-induced motor dysfunction in PD mice, increased the number of tyrosine hydroxylase (TH)-positive neurons, and alleviated damage to striatal brain tissue. At the cellular level, lutein significantly suppressed MPP⁺-induced apoptosis of SH-SY5Y cells, upregulated the expression of B-cell lymphoma-2 (Bcl-2), and downregulated the expression of Bcl-2-associated X protein (Bax) and cleaved caspase-3. Additionally, lutein significantly reduced reactive oxygen species (ROS) levels, restored mitochondrial membrane potential, increased ATP levels, and increased the activity of mitochondrial respiratory chain complex I. At the molecular level, lutein promoted the ubiquitination of dynamin-related protein 1 (Drp1), whose degradation was impaired in the PD model. This effect was mediated by the E3 ubiquitin ligase Tripartite Motif-containing protein 31 (TRIM31), whose expression was downregulated in the disease state. Functional experiments confirmed that overexpression of TRIM31 enhanced Drp1 ubiquitination and improved mitochondrial function, whereas TRIM31 knockdown partially attenuated the therapeutic effects of lutein.

In summary, this study revealed, for the first time, that lutein alleviates PD progression by increasing Drp1 ubiquitination and degradation via TRIM31 transcription and translation, ultimately improving neuronal mitochondrial function. These findings not only elucidate a novel mechanism underlying lutein’s neuroprotective effect but also identify a potential therapeutic target and offer a new strategy for PD treatment.

Recent studies have indicated that stem cells could provide therapeutic benefits in several neurological conditions, including Alzheimer’s disease (AD). Adipose-derived stem cells (ADSCs) offer many advantages in that they are readily available from individual hosts, are robust, and secrete many factors that promote neuronal growth and homeostasis.

We transfected ADSCs with a viral construct for brain-derived neurotrophic factor (BDNF) and examined the effects of transplanting these cells into the hippocampus of 7-mo-old APPswe/PS1dE9 mice. After 6 mo, the hippocampus was examined for stem-cell survival, effects on BDNF and neprilysin-2 (NEP-2) levels, dendritic morphology using microtubule associated protein 2 (MAP2) immunohistochemistry, and amyloid plaque load.

We found that transplanted BDNF-ADSCs had survived after 6 mo. BDNF and NEP-2 levels were higher than sham controls, and dendritic architecture was improved. In addition, amyloid plaque numbers were reduced.

BDNF-ADSCs appear to confer benefits by simultaneously enhancing amyloid clearance and promoting neuronal structural repair. This multifaceted approach highlights the potential of engineering stem cells to target multiple pathophysiological hallmarks of AD, positioning BDNF-ADSCs as a powerful and synergistic cell-gene therapy strategy for this devastating disorder.

The perineuronal net (PNN) is an important extracellular environment around parvalbumin interneuron (PV IN) in the spinal cord. Chondroitin sulfate proteoglycan (CSPG) serves as a key factor mediating PNN effects on the spinal cord, primarily formed by covalently linked chondroitin sulfate glycosaminoglycan (CS-GAG) chains and diverse core proteins. Extensive research suggests that degradation of CS-GAG following nerve injury may contribute to severe spinal cord damage. Inhibiting CS-GAG degradation could enhance PNN stability and plasticity, thereby promoting recovery from nerve injury. Electroacupuncture (EA) intervention demonstrates significant neuroprotective effects, facilitating restoration of spinal cord nerve function and axonal regeneration. This study aims to observe the changes in CS-GAG and the expression of PV IN after spinal cord injury (SCI) in rats and explore the effect.

An SCI model was established in Sprague–Dawley rats using an Infinite Horizon (IH) impactor, and EA was applied to the Jia-ji acupoints (EX-B2). The Basso–Beattie–Bresnahan (BBB) score of SCI rats was evaluated, and electromyography (EMG) of the gastrocnemius muscle of the hind limbs was performed. The protein expression levels of CS-GAG and glutamic acid decarboxylase (GAD) were detected using western blotting, and perineuronal nets (PNN) and PV IN were observed using immunofluorescence (IF). Fiber-optic calcium imaging was used to detect and analyze PV IN activity. Adeno-associated virus containing carbohydrate sulfotransferase 11 (Chst11) was injected into T9 and T10 spinal cord spaces using a microneedle, and changes in CS-GAG in the spinal cord of SCI rats before and after EA intervention were observed.

CS-GAG and GAD expression levels were significantly decreased after SCI and PNN stability was reduced. Chondroitinase ABC (ChABC) treatment increased PV IN activity and GAD expression. EA effectively promoted an increase in CS-GAG and GAD, improved PNN stability and PV IN activity, and reversed the inhibitory effect of Chst11, thereby facilitating the rehabilitation of rats with SCI.

The mechanisms and effects of EA on SCI repair were investigated. The results revealed that EA can regulate the recovery of PNN structure and function via CS-GAG and GAD, improve PV IN activity, and reverse the inhibitory effect of Chst11 to promote SCI rehabilitation in rats.

Cerebral ischemia-reperfusion injury (CIRI) represents the most critical pathological event in the evolution of ischemic stroke (IS). Apoptosis is particularly important in CIRI pathophysiology. The interleukin-7 receptor (IL7R) is involved in various disease regulatory mechanisms; however, its specific role during CIRI remains unclear. We investigated the mechanistic function of IL7R in CIRI through a mouse model in vivo and through an astrocyte model in vitro.

C57BL/6 mice were randomly allocated to one of five groups: (1) sham; (2) transient middle cerebral artery occlusion (tMCAO); (3) tMCAO + IL7R treatment; (4) tMCAO + negative control (NC); or (5) tMCAO + IL7R + the phosphatidylinositol 3-kinase (PI3K) pathway inhibitor (LY294002) (n = 3–7 per group) to evaluate the role of IL7R in CIRI. The in vitro study groups were (1) control; (2) oxygen-glucose deprivation/reoxygenation (OGD/R); (3) OGD/R + IL7R; (4) OGD/R + NC; and (5) OGD/R + IL7R + LY294002 groups. After IL7R overexpression was induced, the resulting changes in infarct volume, neurological score, cell viability, and expression of apoptosis-related proteins were assessed.

IL7R overexpression significantly attenuated CIRI-induced apoptosis. In vivo, this intervention improved neurological function, alleviated cerebral edema, and decreased infarct volume in tMCAO mice. In vitro, after the overexpression of IL7R, flow cytometry analysis revealed a reduction in apoptosis rates post-OGD/R, whereas transmission electron microscopy revealed fewer morphological alterations associated with apoptosis. In addition, the level of Bcl-2-associated X protein (Bax) and cysteine-dependent aspartate-specific Protease-3 (caspase-3) were decreased, whereas that of B-cell lymphoma-2 (Bcl-2) was increased; these effects were reversed by LY294002.

Overexpression of IL7R was shown to alleviate CIRI by suppressing apoptosis. These findings indicate IL7R as a novel target for IS treatment.

Executive dysfunction is the most prominent feature of cognitive impairment in patients with end-stage renal disease (ESRD). The dorsolateral prefrontal cortex (DLPFC) is a central region for the regulation of executive functions. The aim of our study was to examine alterations in neural activity and functional connectivity (FC) of the DLPFC in relation to cognitive assessments and clinical indicators in patients with ESRD using the resting-state functional magnetic resonance imaging (rs-fMRI) technique, and to further predict cognitive-related brain damage in this population.

A total of 37 ESRD patients and 35 normal controls received MRI scans and neuropsychological assessments. Inter-group differences in fractional amplitude of low-frequency fluctuations (fALFF) and FC of the DLPFC were compared. Additionally, the relationships between DLPFC abnormalities and cognitive function were analyzed in ESRD patients, along with the clinical characteristics. Finally, we ascertained the potential of DLPFC abnormalities to predict cognitive-related brain damage using receiver operating characteristic (ROC) curve analysis.

ESRD patients exhibited decreased fALFF in the bilateral DLPFC (p < 0.05, false discovery rate [FDR] corrected). These also showed abnormal FC with the frontoparietal cortex, cingulate cortex, cerebellar posterior lobe, inferior temporal gyrus, and rolandic operculum (p < 0.05, FDR corrected). Several alterations in the DLPFC were associated with cognitive assessments (p < 0.05) in ESRD patients, and were also correlated with the levels of uric acid and hemoglobin (p < 0.05). Importantly, ROC curve analysis showed the fALFF value of left DLPFC, and FC between right DLPFC and right middle frontal gyrus effectively predicted cognitive-related brain damage in patients with ESRD.

This study demonstrated that the DLPFC is an important pathological brain region associated with the cognitive impairment of ESRD patients. Our results provide neuroimaging insights to further understand neural mechanisms of cognitive decline in this population.

Maternal diabetes increases the risk of neurodevelopmental alterations in the offspring, yet the molecular links to early corticogenesis remain unclear. During corticogenesis, radial migration is a coordinated process regulated by Reelin signaling and its disruption has been associated with abnormal cortical patterning. We reanalyze dorsal telencephalon transcriptomes from embryonic day 12 (E12) non-neural tube-defect rat embryos to identify canonical pathways perturbed by maternal hyperglycemia.

Gene expression profiles from the dorsal prosencephalon at E12 from control and streptozotocin-treated dams (50 mg/kg at E5.5) were interrogated with Ingenuity Pathway Analysis (IPA). We then assessed Reelin pathway components using quantitative reverse transcription polymerase chain reaction (RT-qPCR), immunohistochemistry, and immunoblotting at E12 and E16, and examined postnatal cytoarchitecture/morphology in the primary motor cortex (M1) at postnatal day zero (P0) and P21 using hematoxylin-eosin and Golgi-Cox staining. All analyses excluded embryos with neural tube defects (NTD) to avoid cofounding by gross malformations.

IPA revealed Reelin signaling in neurons as the only canonical pathway with a non-zero activation z-score, predicting inhibition in E12 embryos from diabetic rats. Concordantly, protein levels of Reelin (RELN), apolipoprotein E receptor 2/low-density lipoprotein receptor-related protein 8 (ApoER2/LRP8), very low-density lipoprotein receptor (VLDLR), and Disabled Homolog 1 (DAB1) were reduced at E12/E16 (all p < 0.05). N-cadherin (N-CAD) showed disrupted radial localization along the ventricular-pial axis despite unchanged total abundance, consistent with impaired neuron-radial glia adhesion/polarity. Postnatally, the M1 showed increased layer I cellularity, ectopic pyramidal neurons, and aberrant laminar organization.

Maternal hyperglycemia is associated with attenuation of the Reelin signaling pathway and N-CAD mislocalization, providing a mechanistic framework for defective neuronal migration and abnormal lamination that persist into early postnatal life. Focusing on NTD-negative embryos isolates the pathway-specific effects of maternal hyperglycemia and nominates Reelin-pathway hypofunction as a candidate driver of altered fetal cortical patterning.

Epilepsy is a complex neurological disorder marked by recurrent, unprovoked seizures. Ferroptosis is characterized by the accumulation of oxidative stress and is associated with the occurrence and development of epilepsy. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has demonstrated neuroprotective properties in various neurodegenerative conditions. In this study, we examined the antiepileptic efficacy of TUDCA and sought to elucidate its underlying mechanisms of action.

The antiepileptic effects of TUDCA were evaluated using electroencephalogram recordings, behavioral testing, and immunohistochemistry in a Lithium chloride (LiCl)- Pilocarpine (Pilo)-induced epilepsy rat model, alongside a glutamate-induced neuronal cell model. Neuronal ferroptosis was assessed through western blotting and immunofluorescence.

In vivo, TUDCA significantly alleviated both seizure severity and neuronal damage by inhibiting oxidative stress and ferroptosis. In vitro, TUDCA similarly exerted neuroprotective effects and effectively suppressed neuronal ferroptosis.

TUDCA mitigates epilepsy through the suppression of ferroptosis, suggesting its potential as a therapeutic agent for epilepsy treatment.

To investigate topological brain network properties, intra- and inter-network network patterns, rich-club organization, structural-functional coupling, and their associations with cognitive impairment in elderly patients with cerebral small vessel disease (CSVD).

A total of 264 participants were enrolled: 60 healthy controls, 93 CSVD patients without mild cognitive impairment (CSVD-NMCI), and 111 CSVD patients with MCI (CSVD-MCI). All underwent neuropsychological testing and multimodal magnetic resonance imaging (MRI). Structural and functional networks were constructed, and graph theory was applied to assess global and local topology. Associations among network metrics, default mode network (DMN), frontoparietal control network (FPCN), dorsal attention network (DAN), rich-club connectivity, structural connectivity (SC)–functional connectivity (FC) coupling, and cognitive scores were examined.

CSVD patients exhibited significant global and nodal topological disruption (p < 0.05, Bonferroni correction). In CSVD-MCI, FC was reduced within the DMN and DAN but increased within the FPCN. FC within the DAN and between DMN–DAN was positively correlated with Auditory Verbal Learning Test (AVLT) performance. SC-FC coupling was significantly higher in CSVD-MCI than in CSVD-NMCI and controls (p < 0.05). Rich-club, feeder, and local connections were markedly impaired in CSVD-MCI and correlated with AVLT and Symbol Digit Modalities Test scores.

CSVD is associated with decreased network efficiency and elevated SC-FC coupling. Altered FC in the FPCN, DMN, and DAN may indicate compensatory mechanisms, whereas rich-club disruption may be key evidence for cognitive impairment. These findings provide novel insights into network dysfunction underlying cognitive decline in CSVD.

Parkinson’s Disease (PD) is a neurological condition characterized by motor symptoms that fluctuate throughout the day depending on medication. Continuous and objective monitoring is essential, but conventional clinical assessments are episodic and subjective, while wearable and video-based solutions may raise privacy concerns. This study aims to develop a real-time, privacy-preserving deep learning framework that utilizes 2D skeleton pose data to simultaneously classify medication states (ON or OFF) and continuously estimate motor symptom severity.

To enable privacy-preserving and real-time monitoring of Parkinson’s motor fluctuations, a Multi-Scale Temporal Attention-Transformer Network (MS-TATNet) was developed based on 2D skeleton pose data collected from the REal-world Mobility Activities in Parkinson’s disease dataset (REMAP) dataset. The MS-TATNet captures complex, variable, and multi-scale temporal dynamics of PD motor symptoms through a multi-scale temporal convolutional network, scaled dot-product attention mechanism, stacked transformer encoder blocks with a multi-head self-attention mechanism, temporal pooling layer, softmax classifier, and regression layer.

The experimental results demonstrate that the MS-TATNet achieved 99.63% accuracy, 99.50% recall, 99.33% specificity, and 99.67% F1-score for medication state classification. For continuous severity estimation, the predicted scores showed a Pearson correlation coefficient of 0.97 with clinical assessments.

Thus, this work highlights the MS-TATNet’s potential for scalable, privacy-preserving remote monitoring of PD.

The protective Icelandic mutation in the amyloid precursor protein (APP) gene, APP^A673T, identified in Icelandic and other Nordic populations is associated with a significantly lower risk of developing Alzheimer’s disease (AD). Conflicting results have been reported for the human APP^A673T mutation in various knock-in models of AD, but the effect of the mouse APP^A673T form in 5× familial AD (5×FAD) mice has never been investigated.

We crossed C57Bl6/J mice expressing a single point mutation edited into the murine APP gene via Clustered Regularly Interspaced Short Palindromic Repeats–CRISPR-associated (CRISPR-Cas) gene editing, termed mAPP^A673T, with 5×FAD mice that overexpress human APP carrying the Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations as well as human presenilin-1 (PS1) with two mutations (M146L and L286V); the resulting mice were termed 5×FAD × mAPP^A673T mice. We investigated amyloid beta-protein (Aβ) pathology in 5×FAD × mAPP^A673T, 5×FAD and their respective controls, mAPP^A673T, and C57Bl6/J wild type mice, at 6-months of age using immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay (ELISA).

We found a moderate yet significant reduction in Aβ plaque size in male 5×FAD × mAPP^A673T compared with 5×FAD mice. No differences were observed for soluble/insoluble Aβ40 and Aβ42 levels per se, but lower plaque count/area was found in 5×FAD × mAPP^A673T mice when Aβ42/Aβ40 ratios were low, suggesting a genotype-dependent sensitivity to Aβ aggregation and accumulation.

The mAPP^A673T mutation has the potential to modify Aβ pathology in 5×FAD mice at the age of 6 months.