Underlying mechanisms behind the neuroprotective effect of vanillic acid against diabetes-associated cognitive decline: An in vivo study in a rat model.

Hippocampal synaptic dysfunction, oxidative stress, neuroinflammation, and neuronal loss play critical roles in the pathophysiology of diabetes-associated cognitive decline (DACD). The study aimed to investigate the effects of vanillic acid (VA), a phenolic compound, against DACD and explore the potential underlying mechanisms. Following confirmation of diabetes, rats were treated with VA (50 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) for 8 consecutive weeks. The cognitive performance of the rats was evaluated using passive-avoidance and water-maze tasks. Long-term potentiation (LTP) was induced at hippocampal dentate gyrus (DG) synapses in response to high-frequency stimulation (HFS) applied to the perforant pathway (PP) to evaluate synaptic plasticity. Oxidative stress factors, inflammatory markers, and histological changes were evaluated in the rat hippocampus. This study showed that streptozotocin (STZ)-induced diabetes caused cognitive decline that was associated with inhibition of LTP induction, suppression of enzymatic antioxidant activities, enhanced lipid peroxidation, elevated levels of inflammatory proteins, and neuronal loss. Interestingly, chronic treatment with VA alleviated blood glucose levels, improved cognitive decline, ameliorated LTP impairment, modulated oxidative-antioxidative status, inhibited inflammatory response, and prevented neuronal loss in diabetic rats at a level comparable to insulin therapy. The results suggest that the antihyperglycemic, antioxidative, anti-inflammatory, and neuroplastic properties of VA may be the mechanisms behind its neuroprotective effect against DACD.

The role of the thalamus in modular functional networks in temporal lobe epilepsy with cognitive impairment.

OBJECTIVE: Cognitive deficit is common in patients with temporal lobe epilepsy (TLE). Here, we aimed to investigate the modular architecture of functional networks associated with distinct cognitive states in TLE patients together with the role of the thalamus in modular networks. METHODS: Resting-state functional magnetic resonance imaging scans were acquired from 53 TLE patients and 37 matched healthy controls. All patients received the Montreal Cognitive Assessment test and accordingly were divided into TLE patients with normal cognition (TLE-CN, n = 35) and TLE patients with cognitive impairment (TLE-CI, n = 18) groups. The modular properties of functional networks were calculated and compared including global modularity Q, modular segregation index, intramodular connections, and intermodular connections. Thalamic subdivisions corresponding to the modular networks were generated by applying a 'winner-take-all' strategy before analyzing the modular properties (participation coefficient and within-module degree z-score) of each thalamic subdivision to assess the contribution of the thalamus to modular functional networks. Relationships between network properties and cognitive performance were then further explored. RESULTS: Both TLE-CN and TLE-CI patients showed lower global modularity, as well as lower modular segregation index values for the ventral attention network and the default mode network. However, different patterns of intramodular and intermodular connections existed for different cognitive states. In addition, both TLE-CN and TLE-CI patients exhibited anomalous modular properties of functional thalamic subdivisions, with TLE-CI patients presenting a broader range of abnormalities. Cognitive performance in TLE-CI patients was not related to the modular properties of functional network but rather to the modular properties of functional thalamic subdivisions. CONCLUSIONS: The thalamus plays a prominent role in modular networks and potentially represents a key neural mechanism underlying cognitive impairment in TLE.

Loganin alleviated cognitive impairment in 3×Tg-AD mice through promoting mitophagy mediated by optineurin.

ETHNOPHARMACOLOGICAL RELEVANCE: Corni Fructus is a traditional Chinese herb and widely applied for treatment of age-related disorders in China. Iridoid glycoside was considered as the active ingredient of Corni Fructus. Loganin is one of the major iridoid glycosides and quality control components of Corni Fructus. Emerging evidence emphasized the beneficial effect of loganin on neurodegenerative disorders, such as Alzheimer's disease (AD). However, the detailed mechanism underlying the neuroprotective action of loganin remains to be unraveled. AIM OF THE STUDY: To explore the improvement of loganin on cognitive impairment in 3 × Tg-AD mice and reveal the potential mechanism. MATERIALS AND METHODS: Eight-month 3 × Tg-AD male mice were intraperitoneally injected with loganin (20 and 40 mg/kg) for consecutive 21 days. Behavioral tests were used to evaluated the cognition-enhancing effects of loganin, and Nissl staining and thioflavine S staining were performed to analyze neuronal survival and Aß pathology. Western blot analysis, transmission electron microscopy and immunofluorescence were utilized to explore the molecular mechanism of loganin in AD mice involved mitochondrial dynamics and mitophagy. Aß25-35-induced SH-SY5Y cells were applied to verify the potential mechanism in vitro. RESULTS: Loganin significantly mitigated the learning and memory deficit and amyloid ß-protein (Aß) deposition, and recovered synaptic ultrastructure in 3 × Tg-AD mice. Perturbed mitochondrial dynamics characterized by excessive fission and insufficient fusion were restored after loganin treatment. Meanwhile, loganin reversed the increase of mitophagy markers (LC3II, p62, PINK1 and Parkin) and mitochondrial markers (TOM20 and COXIV) in hippocampus of AD mice, and enhanced the location of optineurin (OPTN, a well-known mitophagy receptor) to mitochondria. Accumulated PINK1, Parkin, p62 and LC3II were also revealed in Aß25-35-induced SH-SY5Y cells, which were ameliorated by loganin. Increased OPTN in Aß25-35-treated SH-SY5Y cells was further upregulated by loganin incubation, along with the reduction of mitochondrial ROSand elevation ofmitochondrial membrane potential (MMP). Conversely, OPTN silence neutralized the effect of loganin on mitophagy and mitochondrial function, which is consistent with the finding that loganin presented strong affinity with OPTN measured by molecular docking in silico. CONCLUSIONS: Our observations confirmed that loganin enhanced cognitive function and alleviated AD pathology probably by promoting OPTN-mediated mitophagy,. Loganin might be a potential drug candidate for AD therapy via targeting mitophagy.

Phospholipase D1 Attenuation Therapeutics Promotes Resilience against Synaptotoxicity in 12-Month-Old 3xTg-AD Mouse Model of Progressive Neurodegeneration.

Abrogating synaptotoxicity in age-related neurodegenerative disorders is an extremely promising area of research with significant neurotherapeutic implications in tauopathies including Alzheimer's disease (AD). Our studies using human clinical samples and mouse models demonstrated that aberrantly elevated phospholipase D1 (PLD1) is associated with amyloid beta (Aß) and tau-driven synaptic dysfunction and underlying memory deficits. While knocking out the lipolytic PLD1 gene is not detrimental to survival across species, elevated expression is implicated in cancer, cardiovascular conditions and neuropathologies, leading to the successful development of well-tolerated mammalian PLD isoform-specific small molecule inhibitors. Here, we address the importance of PLD1 attenuation, achieved using repeated 1 mg/kg of VU0155069 (VU01) intraperitoneally every alternate day for a month in 3xTg-AD mice beginning only from ~11 months of age (with greater influence of tau-driven insults) compared to age-matched vehicle (0.9% saline)-injected siblings. A multimodal approach involving behavior, electrophysiology and biochemistry corroborate the impact of this pre-clinical therapeutic intervention. VU01 proved efficacious in preventing in later stage AD-like cognitive decline affecting perirhinal cortex-, hippocampal- and amygdala-dependent behaviors. Glutamate-dependent HFS-LTP and LFS-LTD improved. Dendritic spine morphology showed the preservation of mushroom and filamentous spine characteristics. Differential PLD1 immunofluorescence and co-localization with Aß were noted.

Reduced power and phase-locking values were accompanied by thalamus, putamen, and hippocampus atrophy in Parkinson's disease with mild cognitive impairment: an event-related oscillation study.

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder accompanied by mild cognitive impairment (MCI) as a crucial nonmotor manifestation. Event-related oscillations (EROs) are suggested to reflect cognitive status associated with subcortical structures in neurodegenerative conditions. In this study, 36 individuals with PD-MCI and 32 PD-CN were compared with 60 healthy control (HC) participants using visual EROs by measures of event-related spectral perturbation and inter-trial coherence, along with subcortical gray matter volumes based on the FIRST algorithm. Cross-correlations among electrophysiological, neuropsychological, and structural parameters were investigated exploratively. Both PD-MCI and PD-CN patients had diminished delta and alpha phase-locking than HC, however, electrophysiological abnormalities were more pronounced in PD-MCI over frontal, central, parietal, and temporal locations in almost all frequency bands, accompanied by bilateral thalamus, hippocampus, and right putamen atrophy. PD-CN had lower hippocampal volumes than HC, without exhibiting any subcortical differences from PD-MCI. Lastly, EROs showed low-to-high correlations with structural and neuropsychological measures. These findings may highlight the complex interplay between electrophysiological, neuropsychological, and structural parameters in detected abnormalities of PD-CN and PD-MCI.

Asiatic Acid Fabricated Nanoconstructs to Mitigate Amyloid Beta1-42 Induced Injury in SH-SY5Y Cells In-Vitro and Ameliorates Cognitive Impairment by Dual Cholinesterase Inhibition and Attenuation of Oxidative Stress In-Vivo.

PURPOSE: Asiatic acid (AA) is reported for its neuroprotective potential in Alzheimer's disease (AD). This present work aimed to develop AA loaded nanostructured lipid carriers (AAN) for targeting the delivery of AA into the brain and ameliorating the cognitive deficits in AD rats. METHODS: AAN was optimized using the Box-Behnken design, considering 3 factors (soya lecithin, tween 80, and high pressure homogenizer (HPH) pressure) as independent variables while particle size (PS), zeta potential (ZP) and entrapment efficiency (EE) were dependent variables. Cytotoxicity assay and internalization studies of AAN were evaluated in SH-SY5Y cells and further neuroprotective efficiency on intracellular amyloid beta (Aß) aggregation was evaluated in Aß 1-42 treated cells with thioflavin T (ThT). The behavioral acquisition effects were evaluated in Aß 1-42 (5 µg/ 5 µL, intracerebroventricular (ICV), unilateral) induced AD model followed by the histology and quantification of neurotransmitters levels. RESULTS: The optimized AAN revealed desired PS (44.1 ± 12.4 nm), ZP (- 47.1 ± 0.017 mv) and EE (73.41 ± 2.53%) for brain targeting delivery of AA. In-vitro, AAN exhibited better neuroprotective potential than AA suspension (AAS). AA content was 1.28 folds and 2.99 folds heightened in plasma and brain respectively after the i.p. administration of AAN as compared to AAS. The results of pharmacodynamic studies manifested the AAN treatment significantly (p < 0.05) ameliorated the cognitive deficits. CONCLUSIONS: Hence, developed AAN has neuroprotective potential and should be further considered as an unconventional platform in preclinical model for the management of AD.

Cognitive Decline Related to Diet Pattern and Nutritional Adequacy in Alzheimer's Disease Using Surface-Based Morphometry.

Dietary pattern (DP) results in nutrition adequacy and may influence cognitive decline and cortical atrophy in Alzheimer's disease (AD). The study explored DP in 248 patients with AD. Two neurobehavioral assessments (intervals 13.4 months) and two cortical thickness measurements derived from magnetic resonance images (intervals 26.5 months) were collected as outcome measures. Reduced rank regression was used to assess the groups of DPs and a linear mixed-effect model to explore the cortical neurodegenerative patterns. At screening, underweight body mass index (BMI) was related to significant higher lipid profile, impaired cognitive function, smaller cortical thickness, lower protein DP factor loading scores and the non-spouse caregiver status. Higher mini-mental state examination (MMSE) scores were related to the DP of coffee/tea, compared to the lipid/sugar or protein DP group. The underweighted-BMI group had faster cortical thickness atrophy in the pregenual and lateral temporal cortex, while the correlations between cortical thickness degeneration and high HbA1C or low B12 and folate levels were localized in the medial and lateral prefrontal cortex. The predictive model suggested that factors related to MMSE score were related to the caregiver status. In conclusion, normal or overweight BMI, coffee/tea DP group and living with a spouse were considered as protective factors for better cognitive outcomes in patients with AD. The influence of glucose, B12 and folate on the cortical degeneration was spatially distinct from the pattern of AD degeneration.

Acupuncture Treatment Modulate Regional Homogeneity of Dorsal Lateral Prefrontal Cortex in Patients with Amnesic Mild Cognitive Impairment.

BACKGROUND: Although acupuncture is widely used to improve cognitive and memory in the amnesic mild cognitive impairment (aMCI) patients with impressive effectiveness, its neural mechanism remains largely unclear. OBJECTIVE: We aimed to explore functional magnetic resonance imaging (fMRI) mechanism of acupuncture for aMCI. METHODS: A randomized, controlled, single-blind research was performed. A total of 46 aMCI patients were randomly assigned into verum and sham acupuncture group, who received a total of 24 times treatments (3 times/week, 8 weeks). Clinical evaluation and fMRI scanning were performed at baseline and after treatment for all aMCI patients. The interaction effects and inter-group effects of regional homogeneity (ReHo) were performed using mixed effect models, and the correlations between clinical improvement and neuroimaging changes before and after verum acupuncture treatment were analyzed using Pearson correlations. RESULTS: As a result, interaction effects showed increased ReHo value in left dorsal lateral prefrontal cortex (DLPFC), increased functional connectivity between left DLPFC and left precuneus, and decreased functional connectivity between left DLPFC and left inferior temporal gyrus after verum acupuncture but inversely after sham acupuncture in the aMCI. Condition effects showed increased ReHo in right lingual gyrus, and bilateral post-central gyrus after verum and sham acupuncture in the aMCI. In addition, the changed Montreal Cognitive Assessment scores in verum acupuncture group were significantly correlated with changed ReHo values in left DLPFC. CONCLUSION: Together, our findings further confirmed that acupuncture could be used as a promising complementary therapy for aMCI by modulating function of left DLPFC to improve cognitive symptoms.

Abnormal Functional Connectivity of Thalamic Subdivisions in Alzheimer's Disease: A Functional Magnetic Resonance Imaging Study.

Alzheimer's disease (AD) is characterized by global cognitive impairment in multiple cognitive domains. Thalamic dysfunction during AD progression has been reported. However, there are limited studies regarding dysfunction in the functional connectivity (FC) of thalamic subdivisions and the relationship between such dysfunction and clinical assessments. This study examined dysfunction in the FC of thalamic subdivisions and determined the relationship between such dysfunction and clinical assessments. Forty-eight patients with AD and 47 matched healthy controls were recruited and assessed with scales for multiple cognitive domains. Group-wise comparisons of FC with thalamic subdivisions as seed points were conducted to identify abnormal cerebral regions. Moreover, correlation analysis was conducted to evaluate the relationship between abnormal FC and cognitive performance. Decreased FC of the intralaminar and medial nuclei with the left precuneus was observed in patients but not in heathy controls. The abnormal FC of the medial nuclei with the left precuneus was correlated with the Mini Mental State Examination score in the patient group. Using the FC values showing between-group differences, the linear support vector machine classifier achieved quite good in accuracy, sensitivity, specificity and area under the curve. Dysfunction in the FC of the intralaminar and medial thalamus with the precuneus may comprise a potential neural substrate for cognitive impairment during AD progression, which in turn may provide new treatment targets.

Transcranial photobiomodulation (laser) therapy for cognitive impairment: A review of molecular mechanisms and potential application to canine cognitive dysfunction (CCD).

Alzheimer's disease (AD) is a common degenerative brain disorder of aging people which shares many clinical and pathological features with canine cognitive dysfunction (CCD). CCD is considered a naturally occurring model of human AD. Transcranial photobiomodulation therapy (tPBMT), also known as transcranial laser therapy, entails delivering photons of near infrared to infrared light from the skin surface of the scalp to the underlying brain. Specific molecular cellular receptors, called chromophores, absorb this energy, and use it to initiate biological reactions with potential therapeutic benefit. Improvement in cognitive ability using tPBMT has been documented in rodent AD models and human clinical trials. The purposes of this review are to provide an overview of the suspected molecular mechanisms of action of tPBMT for the treatment of cognitive decline and to propose potential application of this treatment modality for dogs affected by CCD.

IL-33 and IL-10 Serum Levels Increase in MCI Patients Following Homotaurine Treatment.

Homotaurine is a potential therapeutic compound for treatment of Alzheimer's disease (AD), but its efficacy is still under investigation. Emerging data have shown that other than neuroprotective, homotaurine is endowed with anti-inflammatory activities, though with still unclear underlying mechanisms. Inflammation plays a critical role in the pathogenesis of AD and we previously suggested that homotaurine supplementation in patients with amnestic mild cognitive impairment (MCI) plays beneficial effects associated to a decrease in the circulating levels of the pro-inflammatory cytokine IL-18. Here we report that MCI patients supplemented with homotaurine for 12 months show elevated serum levels of IL-10 and IL-33, as compared to baseline, in addition to the described IL-18 decrease. Furthermore, we observed a significant positive correlation between IL-10 and IL-33 levels after treatment but not at the baseline, underlining the effectiveness of the compound in modulating both cytokines in an inter-related fashion and in regulating the pro/anti-inflammation balance. Furthermore, the elevation of both IL-10 and IL-33 is significantly associated with an improvement of episodic memory of treated patients, as measured by the Delayed Verbal Ray Test. In conclusion, our results confirm that homotaurine treatment exerts an overall anti-inflammatory action in MCI patients, based not only on the down-regulation of pro-inflammatory IL-18, but also on up-regulation of the anti-inflammatory IL-33 and IL-10 cytokines, which in turn are associated with an amelioration of patient's cognitive functions. Future studies should be addressed to investigate the molecular mechanisms of homotaurine anti-inflammatory activity and its therapeutic exploitation in early AD.

Yoga Prevents Gray Matter Atrophy in Women at Risk for Alzheimer's Disease: A Randomized Controlled Trial.

BACKGROUND: Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRFs) are known risk factors for developing Alzheimer's disease (AD). We previously demonstrated that yoga improved depression, resilience, memory and executive functions, increased hippocampal choline concentrations, and modulated brain connectivity in older adults with mild cognitive impairment. OBJECTIVE: In this study (NCT03503669), we investigated brain gray matter volume (GMV) changes in older women with SCD and CVRFs following three months of yoga compared to memory enhancement training (MET). METHODS: Eleven women (mean age = 61.45, SD = 6.58) with CVRF and SCD completed twelve weeks of Kundalini Yoga and Kirtan Kriya (KY + KK) while eleven women (mean age = 64.55, SD = 6.41) underwent MET. Anxiety, resilience, stress, and depression were assessed at baseline and 12 weeks, as were T1-weighted MRI scans (Siemens 3T Prisma scanner). We used Freesurfer 6.0 and tested group differences in GMV change, applying Monte-Carlo simulations with alpha = 0.05. Region-of-interest analysis was performed for hippocampus and amygdala. RESULTS: Compared to KY + KK, MET showed reductions in GMV in left prefrontal, pre- and post-central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices, the banks of the superior temporal sulcus, and the pars opercularis. Right hippocampal volume increased after yoga but did not survive corrections. CONCLUSION: Yoga training may offer neuroprotective effects compared to MET in preventing neurodegenerative changes and cognitive decline, even over short time intervals. Future analyses will address changes in functional connectivity in both groups.

Centella asiatica Alleviates AlCl3-induced Cognitive Impairment, Oxidative Stress, and Neurodegeneration by Modulating Cholinergic Activity and Oxidative Burden in Rat Brain.

Aluminum (Al) is linked to the development of many neurological disorders such as Alzheimer's disease (AD), Parkinson's disease, and autism. Centella asiatica (CA) is a regenerating herb traditionally used to stimulate memory. This study was designed to assess the neuroprotective role of ethanolic extract of CA (CAE) in AlCl3-induced neurological conditions in rats. Adult rats were chronically treated with AlCl3 (100 mg/kg b.w./day) for 60 days to establish the dementia model, and co-administration of CAE was evaluated for its ability to attenuate the toxic effect of AlCl3. CAE was given orally at a dose of 150 and 300 mg/kg b.w./day, for 60 days. The behavioral performances of rats were tested through Y-maze and open field tests. Lipid peroxidation, superoxide dismutase, and catalase activity were evaluated to measure oxidative stress; and acetylcholinesterase (AChE) activity was assessed to evaluate cholinergic dysfunction in the rat brain. H&E staining was used to assess structural abnormalities in the cortex and hippocampus. The result showed that AlCl3 induces cognitive dysfunction (impaired learning and memory, anxiety, diminished locomotor activity), oxidative stress, cholinergic impairment, and histopathological alteration in the rat brain. Co-administration of CAE with AlCl3 markedly protects the brain from AlCl3-induced cognitive dysfunction, oxidative stress, AChE activity, and cytoarchitectural alterations. Furthermore, 15 days CAE treatment after 45 days AlCl3 administration markedly ameliorates the AlCl3-induced neurotoxicity indicating its potential for therapeutic use.

Salvianolic acid A relieves cognitive disorder after chronic cerebral ischemia: Involvement of Drd2/Cryab/NF-κB pathway.

Chronic cerebral ischemia (CCI) refers to long-term hypoperfusion of cerebral blood flow with the main clinical manifestations of progressive cognitive impairment. The pathological mechanism of CCI is complex, and there is a lack of effective treatments. Salvianolic acid A (SalA) is a neuroprotective extract of Salvia miltiorrhiza with the effects of anti-inflammation and anti-apoptosis. In this study, the effect of SalA on cognitive function and Drd2/Cryab/NF-κB signaling pathway in rats with CCI was investigated. Morris water maze and open field test were used to observe the effects of SalA on the cognitive function of CCI rats. The pathological changes in the brain were observed by HE, Nissl, and LFB staining. TUNEL staining, enzyme-linked immunosorbent assay, and western blot analysis were used to detect the inflammatory and apoptosis in the cortex and hippocampus. The expression of Drd2/Cryab/NF-κB pathway-related molecules and Drd2 localization were detected by western blotting and dual immunofluorescence, respectively. SH-SY5Y cells were exposed to chronic hypoglycemic and hypoxic injury in vitro, and Drd2 inhibitor haloperidol was used to verify the involved pathway. The results showed that SalA could improve the cognitive function of CCI rats, reduce pathological damage of cortex and hippocampus, inhibit neuroinflammation and apoptosis, and suppress the activation of NF-κB by regulating Drd2/Cryab pathway. And SalA inhibited NF-κB activation and nuclear translocation in SH-SY5Y cells by upregulating Drd2/Cryab pathway, which was reversed by haloperidol interference. In conclusion, SalA could relieve CCI-induced cognitive impairment in rats, at least partly through the Drd2/Cryab/NF-κB pathway.

The Role of Melatonin on Behavioral Changes and Concomitant Oxidative Stress in icvAß1-42 Rat Model with Pinealectomy.

One of the pathological hallmarks of Alzheimer's disease (AD) associated with its progression that contributes to ß-amyloid (Aß) generation is oxidative stress (OS). Clinical data suggest that melatonin is a potent antioxidant that might be effective in the adjunctive therapy of this neurodegenerative disease. The present study aimed to explore the role of melatonin on behavioral changes and markers of OS in three rat models, namely, pinealectomy (pin) model of melatonin deficit, intracerebroventricular (icv)Aß1-42 model of AD, and combination of both pin and Aß1-42 model (pin+icvAß1-42). The chronic injection with vehicle/melatonin (50 mg/kg, i.p. for 40 days) started on the same day of sham/pin and icv vehicle/Aß1-42 infusion procedures. Anxiety in the open field and the elevated plus-maze test and cognitive responses in the object recognition test were tested between the 30th-35th day after the surgical procedures. Markers of OS in the frontal cortex (FC) and hippocampus were detected by the ELISA method. Melatonin treatment corrected the exacerbated anxiety response only in the pin+icvAß1-42 model while it alleviated the cognitive impairment in the three models. Pinealectomy disturbed the antioxidant system via enhanced SOD activity and decreased GSH levels both in the FC and hippocampus. The Aß1-42 model decreased the SOD activity in the FC and elevated the MDA level in the two brain structures. The pin+icvAß1-42 model impaired the antioxidant system and elevated lipid peroxidation. Melatonin supplementation restored only the elevated MDA level of icvAß1-42 and pin+icvAß1-42 model in the hippocampus. In conclusion, our study reveals that the pin+icvAß1-42 rat model triggers more pronounced anxiety and alterations in markers of OS that may be associated with melatonin deficit concomitant to icvAß1-42-induced AD pathology.

Cortical Thickness and Serum NfL Explain Cognitive Dysfunction in Newly Diagnosed Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To determine the relative importance of global or regional MRI and blood markers of neurodegeneration and neuroaxonal injury in predicting cognitive performance for recently diagnosed patients with multiple sclerosis (MS). METHODS: Thirty-five newly diagnosed patients with relapsing-remitting MS (RRMS) and 23 healthy controls (HCs) simultaneously completed a full clinical and neuropsychological assessment, structural brain MRI, and serum neurofilament light chain (sNfL) level test. Linear regression analyses were performed to determine which global or regional measures of gray matter (GM) atrophy and cortical thickness (CT), in combination with sNfL levels and clinical scores, are most strongly related to neuropsychological impairment. RESULTS: Compared with HCs, patients with MS showed bilateral thalamic GM atrophy (left, p = 0.033; right, p = 0.047) and diminished CT, particularly in the right superior and transverse temporal gyri (p = 0.045; p = 0.037). Regional atrophy failed to add predictive variance, whereas anxiety symptoms, sNfL, and global CT were the best predictors (R2 = 0.404; p < 0.001) of cognitive outcomes, with temporal thickness accounting for greater variance in cognitive deficits than global CT. DISCUSSION: Thalamic GM atrophy and thinning in temporal regions represent a distinctive MRI trait in the early stages of MS. Although sNfL levels alone do not clearly differentiate HCs and patients with RRMS, in combination with global and regional CT, sNfL levels can better explain the presence of underlying cognitive deficits. Hence, cortical thinning and sNfL increases can be considered 2 parallel neurodegenerative markers in the pathogenesis of progression in newly diagnosed patients with MS.

Grey Matter Loss at Different Stages of Cognitive Decline: A Role for the Thalamus in Developing Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive impairment and large loss of grey matter volume and is the most prevalent form of dementia worldwide. Mild cognitive impairment (MCI) is the stage that precedes the AD dementia stage, but individuals with MCI do not always convert to the AD dementia stage, and it remains unclear why. OBJECTIVE: We aimed to assess grey matter loss across the brain at different stages of the clinical continuum of AD to gain a better understanding of disease progression. METHODS: In this large-cohort study (N = 1,386) using neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative, voxel-based morphometry analyses were performed between healthy controls, individuals with early and late and AD dementia stage. RESULTS: Clear patterns of grey matter loss in mostly hippocampal and temporal regions were found across clinical stages, though not yet in early MCI. In contrast, thalamic volume loss seems one of the first signs of cognitive decline already during early MCI, whereas this volume loss does not further progress from late MCI to AD dementia stage. AD dementia stage converters already show grey matter loss in hippocampal and mid-temporal areas as well as the posterior thalamus (pulvinar) and angular gyrus at baseline. CONCLUSION: This study confirms the role of temporal brain regions in AD development and suggests additional involvement of the thalamus/pulvinar and angular gyrus that may be linked to visuospatial, attentional, and memory related problems in both early MCI and AD dementia stage conversion.

Progressive Neurochemical Abnormalities in Cognitive and Motor Subgroups of Amyotrophic Lateral Sclerosis: A Prospective Multicenter Study.

OBJECTIVE: To evaluate progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) by assessing alterations in N-acetylaspartate (NAA) ratios in the motor and prefrontal cortex within clinical subgroups of ALS. METHODS: Seventy-six patients with ALS and 59 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium. Participants underwent serial clinical evaluations and magnetic resonance spectroscopy at baseline and 4 and 8 months using a harmonized protocol across 5 centers. NAA ratios were quantified in the motor cortex and prefrontal cortex. Patients were stratified into subgroups based on disease progression rate, upper motor neuron (UMN) signs, and cognitive status. Linear mixed models were used for baseline and longitudinal comparisons of NAA metabolite ratios. RESULTS: Patients with ALS had reduced NAA ratios in the motor cortex at baseline (p < 0.001). Ratios were lower in those with more rapid disease progression and greater UMN signs (p < 0.05). A longitudinal decline in NAA ratios was observed in the motor cortex in the rapidly progressing (p < 0.01) and high UMN burden (p < 0.01) cohorts. The severity of UMN signs did not change significantly over time. NAA ratios were reduced in the prefrontal cortex only in cognitively impaired patients (p < 0.05); prefrontal cortex metabolites did not change over time. CONCLUSIONS: Progressive degeneration of the motor cortex in ALS is associated with more aggressive clinical presentations. These findings provide biological evidence of variable spatial and temporal cerebral degeneration linked to the disease heterogeneity of ALS. The use of standardized imaging protocols may have a role in clinical trials for patient selection or subgrouping. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that MRS NAA metabolite ratios of the motor cortex are associated with more rapid disease progression and greater UMN signs in patients with ALS. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02405182.

GW9508 ameliorates cognitive dysfunction via the external treatment of encephalopathy in Aß1-42 induced mouse model of Alzheimer's disease.

The functions and mechanisms of GPR40 receptor to ameliorating the Alzheimer's disease (AD) by external treatment of encephalopathy remain unknown. In present study, the typical Aß1-42 induced mice model was applied to explore the functions and mechanisms of GPR40 receptor by external treatment of encephalopathy in AD. GPR40 agonist GW9508 and antagonist GW1100 were given by i.g injection to activate/inhibit the GPR40 receptor respectively in the gut of AD mouse which illustrated the function and mechanism of GPR40 receptor in ameliorating AD symptoms by external treatment of encephalopathy. A series of behavioral experiments were used to investigate the cognitive function and memory ability of mice, while molecular biology experiments such as Western blot, ELISA, flow cytometry were used to detect the corresponding changes of signaling pathways. The results revealed that intragastric administrated GW9508 could significantly ameliorate cognitive deficits of AD mouse, up-regulate the expression levels of gut-brain peptides both in blood circulation and hypothalamus thus up-regulate the expression levels of α-MSH in hypothalamus, while the negative autophagy-related proteins and inflammation-related proteins were down-regulated correspondingly. Meanwhile, GW9508 could also inhibit the pathological process of neuroinflammation in microglia. GW1100 reversed the effects of GW9508 significantly. These results suggested that GPR40 was an underlying therapeutic target for the external treatment of encephalopathy related to AD and GPR40 agonist could be explored as the emerging AD therapeutic drug.

Fatty acids and beyond: Age and Alzheimer's disease related changes in lipids reveal the neuro-nutraceutical potential of lipids in cognition.

Lipids are essential in maintaining brain function, and lipid profiles have been reported to be altered in aged and Alzheimer's disease (AD) brains as compared to healthy mature brains. Both age and AD share common metabolic hallmarks such as increased oxidative stress and perturbed metabolic function, and age remains the most strongly correlated risk factor for AD, a neurodegenerative disease. A major accompanying pathological symptom of these conditions is cognitive impairment, which is linked with changes in lipid metabolism. Thus, nutraceuticals that affect brain lipid metabolism or lipid levels as a whole have the potential to ameliorate cognitive decline. Lipid analyses and lipidomic studies reveal changes in specific lipid types with aging and AD, which can identify potential lipid-based nutraceuticals to restore the brain to a healthy lipid phenotype. The brain lipid profile can be influenced directly with dietary administration of lipids themselves, although because of synergistic effects of nutrients it may be more useful to consider a multi-component diet rather than single nutrient supplementation. Gut microbiota also serve as a source of beneficial lipids, and the value of treatments that manipulate the composition of gut microbiome should not be ignored. Lastly, instead of direct supplementation, compounds that affect pathways involved with lipid metabolism should also be considered as a way of manipulating lipid levels to improve cognition. In this review, we briefly discuss the role of lipids in the brain, the changing lipid profile in AD, current research on lipid-based nutraceuticals and their therapeutic potential to combat cognitive impairment.