Against Alzheimer's Disease Research Articles

A Novel Polysaccharide DSPP-1 from Durian Seed: Structure Characterization and Its Protective Effects Against Alzheimer's Disease in a Transgenic Caenorhabditis elegans Model.

Durian seeds are normally considered as agricultural waste in durian fruit processing, resulting in a huge waste of resources. The structure characterization of polysaccharide from durian seed and its neuroprotective effects against Alzheimer's disease (AD) in a transgenic Caenorhabditis elegans model were conducted in this study. A water-soluble polysaccharide was obtained using atmospheric pressure plasma treatment, and named DSPP-1. DSPP-1 was composed of rhamnose, galactose and galacturonic acid and its molecular weight was 3.765 × 105 Da. PDSP and DSPP-1 showed considerable antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging compared to the positive control (vitamin C). Besides, compared with the positive group (epigallocatechin gallate), PDSP and DSPP-1 exhibited the certain Abeta1 - 42 aggregation inhibitory effectiveness (p < 0.05). In contrast, DSPP-2 exerted a poor antioxidant and anti-aggregation effect (p < 0.05). In vivo results showed that DSPP-1 could decrease abnormal Aβ1-42 aggregation to delay the paralysis process of AD-nematodes. Moreover, DSPP-1 significantly improved the antioxidant enzyme activities and reduced lipid peroxidation in AD-nematodes. Taken together, these results indicated that DSPP-1 could be used as a potential natural source for the prevention and treatment of AD.

Determination of antioxidant, anticancer, antidiabetic and antimicrobial activities of Turkish red pine (Pinus brutia Ten.) bark ultrasound-assisted extract as a functional food additive

AbstractTurkish red pine (Pinus brutia Ten.) is an important tree species that grows widely in Türkiye. In this study, Box-Behnken experimental design was created and optimised for ultrasound assisted extraction of bioactive components of Turkish red pine waste bark. Extraction yield, total phenolic content (TPC), total concentrated tannin (TCT), ferric reducing antioxidant power (FRAP), and 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) were determined at experimental points. As a result of the optimisation process, optimum parameter values were found at 34.8 °C temperature, 6.5 min time and 116.3 W ultrasonic power. Under optimum conditions, the extraction efficiency was 13.16%, TPC 103.09 mg GAE/g, TCT 13.29 mg CE/g, FRAP 602.14 mg TEAC/g, and ABTS 624.51 mg TEAC/g activity results were obtained. The extracts obtained showed low in vitro toxicity against healthy cell lines (HEK-293, human embryonic kidney), proliferation of CaCo-2 (human colorectal adenocarcinoma) and MIA PaCa-2 (human pancreatic adenocarcinoma) cancer cells was significantly reduced. It was also determined that this extract has lower activity against Alzheimer's disease (AD)-associated AChE (acetylcholinesterase)-BChE (butyrylcholinesterase) than diabetes disease associated ɑ-glucosidase and ɑ-amylase. The extracts also showed significant antibacterial activity against Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Salmonella Typhimurium, and Escherichia coli.

DFT Study of Regio- and Stereoselective 13DC Reaction between Diazopropane and Substituted Chalcone Derivatives: Molecular Docking of Novel Pyrazole Derivatives as Anti-Alzheimer's Agents.

In the present work, a combination of experimental and density functional theory (DFT) investigation of the (3+2) cycloaddition reactions of diazopropane with chalcone derivatives was reported. All calculations were performed using several DFT approaches (B3LYP, M06, M06-2X) and 6-311+G(d, p) basis set. Based on the NMR, MS analyses and IRC calculations, the pyrazole derivatives are the kinetic adducts over the oxadiazoles. The use of two equivalents of diazopropane leads to thermodynamical products. A molecular docking analysis was performed to investigate the efficiency of the obtained products against selected drug targets in anti-Alzheimer ligand-receptor interactions. We revealed that the ligands selected were bound mainly to the catalytic (CAS) and peripheral (PAS) anionic sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors, respectively. The selected ligands 1, 3, 4 and P14 may act as the best inhibitors against Alzheimer's disease (AD).

Protective effect of saffron carotenoids against amyloid beta-induced neurotoxicity in differentiated PC12 cells via the unfolded protein response and autophagy.

The preventive effect of saffron against Alzheimer's disease (AD) has been reported. Herein, we studied the effect of Cro and Crt, saffron carotenoids, on the cellular model of AD. The MTT assay, flow cytometry, and elevated p-JNK, p-Bcl-2, and c-PARP indicated the AβOs-induced apoptosis in differentiated PC12 cells. Then, the protective effects of Cro/Crt on dPC12 cells against AβOs were investigated in preventive and therapeutic modalities. Starvation was used as a positive control. RT-PCR and Western blot results revealed the reduced eIF2α phosphorylation and increased spliced-XBP1, Beclin1, LC3II, and p62, which indicate the AβOs-induced autophagic flux defect, autophagosome accumulation, and apoptosis. Cro and Crt inhibited the JNK-Bcl-2-Beclin1 pathway. They altered Beclin1 and LC3II and decreased p62 expressions, leading cells to survival. Cro and Crt altered the autophagic flux by different mechanisms. So, Cro increased the rate of autophagosome degradation more than Crt, while Crt increased the rate of autophagosome formation more than Cro. The application of 4μ8C and chloroquine as the inhibitors of XBP1 and autophagy, respectively, confirmed these results. So, augmentation of the survival branches of UPR and autophagy is involved and may serve as an effective strategy to prevent the progression of AβOs toxicity.

Mechanism of Berberis atrocarpa anthocyanin against Alzheimer's disease based on network pharmacology and experimental verification

This study aimed to explore the potential mechanism of Berberis atrocarpa Schneid. anthocyanin against Alzheimer's disease(AD) based on network pharmacology, molecular docking technology, and in vitro experiments. Databases were used to screen out the potential targets of the active components of B. atrocarpa and the targets related to AD. STRING database and Cytoscape 3.9.0 were adopted to construct a protein-protein interaction(PPI) network and carry out topological analysis of the common targets. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed on the target using the DAVID 6.8 database. Molecular docking was conducted to the active components and targets related to the nuclear factor kappa B(NF-κB)/Toll-like receptor 4(TLR4) pathway. Finally, lipopolysaccharide(LPS) was used to induce BV2 cells to establish the model of AD neuroinflammation for in vitro experimental validation. In this study, 426 potential targets of active components of B. atrocarpa and 329 drug-disease common targets were obtained, and 14 key targets were screened out by PPI network. A total of 623 items and 112 items were obtained by GO functional enrichment analysis and KEGG pathway enrichment analysis, respectively. Molecular docking results showed that NF-κB, NF-κB inhibitor(IκB), TLR4, and myeloid differentiation primary response 88(MyD88) had good binding abilities to the active components, and malvidin-3-O-glucoside had the strongest binding ability. Compared with the model group, the concentration of nitric oxide(NO) decreased at different doses of malvidin-3-O-glucoside without affecting the cell survival rate. Meanwhile, malvidin-3-O-glucoside down-regulated the protein expressions of NF-κB, IκB, TLR4, and MyD88. This study uses network pharmacology and experimental verification to preliminarily reveal that B. atrocarpa anthocyanin can inhibit LPS-induced neuroinflammation by regulating the NF-κB/TLR4 signaling pathway, thereby achieving the effect against AD, which provides a theoretical basis for the study of its pharmacodynamic material basis and mechanism.

Ganoapplins A and B with an unprecedented 6/6/6/5/6-fused pentacyclic skeleton from Ganoderma inhibit Tau pathology through activating autophagy

Ganoapplins A and B (1 and 2) with a 6/6/6/5/6-fused pentacyclic skeleton containing an aromatic E ring, were obtained from Ganoderma applanatum. Their structures were established through extensive spectroscopic analyses, quantum chemical calculations, including calculated chemical shifts with DP4 + analysis and electronic circular dichroism (ECD). A plausible biosynthetic pathway for 1 and 2 was proposed. Furthermore, their roles in activating autophagy were investigated and the cellular assays showed that 1 and 2 can inhibit tau pathology by inducing autophagy, suggesting their potential against Alzheimer’s disease (AD).

Cholinesterase Inhibiting Terpenoid from Albizia kalkora

Albizia kalkora is potent source of phytocompounds. In recent phytochemical investigation one new triterpenoid Albizinoic acid A was isolated from the chloroform soluble fraction of medicinal plant Albizia kalkora. The structure was elucidated by physical, chemical, and spectroscopic analysis (FT-IR, 1Dandamp; 2D-NMR, Mass spectrometry). This bioactive compound exhibited inhibitory potential against Alzheimer’s disease (AD) causing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). IC50 of Albizinoic acid A against cholinesterase were found 25.3and#177; 0.02, AChE and 19.0and#177;0.03, BChE while galanthamine as a positive control (0.5 and#177; 0.05, AChE and 8.5and#177;0.01, BChE). This enzymes assay indicated that Albizinoic acid A has great potential of pharmacological characteristics.

Munronin V with 7/7/6 tricarbocyclic framework from Munronia henryi harms inhibits tau pathology by activating autophagy.

Munronin V (1), isolated from Munronia henryi Harms, is the first example, to the best of our knowledge, of an unprecedented 7/7/6 tricarbocyclic framework featuring an unusual A,B-seco-limonoid ring. The structures of munronin V were established from extensive spectroscopic and electronic circular dichroism (ECD) analyses. The novel A,B-seco with two seven-membered lactones was formed as a result of Baeyer-Villiger oxidation. Compound 1 activated autophagy and inhibited Tau pathology as revealed by flow cytometric analyses, confocal imaging analysis and western blotting, and this effect was mediated by transcription factor EB (TFEB). These findings suggested that 1 might have potential as a compound for combating Alzheimer's disease.

An in situ-triggered and chemi-excited photooxygenation system for Aβ aggregates

Photooxygenation of Aβ protein has emerged as an effective and promising strategy against Alzheimer’s disease (AD). However, the penetration depth of excitation light into the skull and brain is limited, which restricts its further development. In this work, for the first time, we report an in situ-triggered and chemi-excited photooxygenation system capable of photooxygenating aggregated Aβ without the need for an external excitation source. A photosensitizer (BD-6-3) has been designed and synthesized that could mediate photooxidative degradation of Aβ aggregates under white light. BD-6-3 and bis[2,4,5-trichloro-6-(pentoxycarbonyl) phenyl] ester were loaded in mesoporous silica nanoparticles, which were in turn decorated with lactoferrin to afford the in situ-triggered and chemi-excited photooxygenation system Lf@6-3. It could be activated by the high concentration of H2O2 in the pathological microenvironment of AD to produce chemiluminescence. Singlet oxygen (1O2) produced can photooxygenate Aβ aggregates, thereby inactivating them and suppressing their neurotoxic effect.

Suppression of Amyloid-β Adsorption on Endoplasmic Reticulum Stress-Mimicking Membranes by α-Tocopherol and α-Tocotrienol

Two forms of hydrophobic vitamin E (VE), α-tocopherol (Toc) and α-tocotrienol (Toc3), have been proposed to be effective against Alzheimer's disease (AD), the etiology of which is thought to involve endoplasmic reticulum (ER) stress. However, previous studies reported conflicting effects of Toc and Toc3 on the risk of AD. We prepared liposomes mimicking the phase separation of the ER membrane (solid-ordered/liquid-disordered phase separation) and studied how VE can influence the interaction between amyloid-β (Aβ) and the ER membrane. We found that Toc could inhibit the formation of the solid-ordered phase more significantly than Toc3. Furthermore, Aβ protofibril adsorption on ER stress-mimicking membranes was more strongly suppressed by Toc compared with Toc3. Therefore, we concluded that VE can relieve ER stress by destabilizing the solid-ordered phase of the ER membrane and subsequently reducing the amount of Aβ adsorbed on the membrane. Moreover, Toc exerted a stronger effect than Toc3.

Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve.

Several lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them. We systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE). Regarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM. Our results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology.

How does APOE genotype moderate the relationship between physical activity and Alzheimer’s disease risk? A novel integrative model

AbstractBackgroundEvidence suggests that physical activity (PA) confers protection against Alzheimer’s disease (AD), while the Apolipoprotein E (APOE) ε4 allele represents the greatest genetic risk factor. Extensive research has thus far failed to establish whether frequent PA can mitigate the increased AD risk associated with APOE ε4. Studies looking at various AD‐related traits (e.g., amyloid beta burden or cortical atrophy) might show diverse results because the biological pathways involved are differentially influenced by PA, APOE ε4 carriage and their interaction. In order to bridge these discrepancies, the aim of this theoretical article is to propose a novel model of how PA and APOE ε4 carriage, independently and in combination, may alter well‐established molecular mechanisms underlying AD pathogenesis.MethodAvailable literature was searched to investigate how PA and APOE ε4 carriage, independently and in combination, may alter several molecular pathways involved in AD pathogenesis. The reviewed mechanisms include amyloid beta (Aβ) and tau deposition and clearance, neuronal resilience and neurogenesis, lipid function and cerebrovascular alterations, brain immune response, and glucose metabolism.ResultWe have identified potential pathways through which the beneficial effects of PA might offset some of the detrimental outcomes of APOE ε4 carriage. Nonetheless, PA does not seem to be able to entirely prevent or revert the noxious effects of genetic risk. Our integrative model includes evidence‐based and theoretical synergistic interactions across mechanisms, and a proposal of testable hypotheses for future studies.ConclusionPA influences a wide array of molecular targets involved in AD neuropathology. A better understanding of where, when and most importantly, how, PA decreases AD risk in the presence of the APOE ε4 allele is essential to formulate combined therapeutic approaches.

Suppression of Selective Voltage-Gated Calcium Channels Alleviates Neuronal Degeneration and Dysfunction through Glutathione S-Transferase-Mediated Oxidative Stress Resistance in a Caenorhabditis elegans Model of Alzheimer's Disease.

Calcium homeostasis plays a vital role in protecting against Alzheimer's disease (AD). In this study, amyloid-β (Aβ)-induced C. elegans models of AD were used to elucidate the mechanisms underlying calcium homeostasis in AD. Calcium acetate increased the intracellular calcium content, exacerbated Aβ 1-42 aggregation, which is closely associated with oxidative stress, aggravated neuronal degeneration and dysfunction, and shortened the lifespan of the C. elegans models. Ethylene glycol tetraacetic acid (EGTA) and nimodipine were used to decrease the intracellular calcium content. Both EGTA and nimodipine showed remarkable inhibitory effects on Aβ 1-42 aggregations by increasing oxidative stress resistance. Moreover, both compounds significantly delayed the onset of Aβ-induced paralysis, rescued memory deficits, ameliorated behavioral dysfunction, decreased the vulnerability of two major (GABAergic and dopaminergic) neurons and synapses, and extended the lifespan of the C. elegans AD models. Furthermore, RNA sequencing of nimodipine-treated worms revealed numerous downstream differentially expressed genes related to calcium signaling. Nimodipine-induced inhibition of selective voltage-gated calcium channels was shown to activate other calcium channels of the plasma membrane (clhm-1) and endoplasmic reticulum (unc-68), in addition to sodium-calcium exchanger channels (ncx-1). These channels collaborated to activate downstream events to resist oxidative stress through glutathione S-transferase activity mediated by HPGD and skn-1, as verified by RNA interference. These results may be applied for the treatment of Alzheimer's disease.

Synthesis of deoxy-Andrographolide Triazolyl Glycoconjugates for the Treatment of Alzheimer's Disease.

A new andrographolide-based terminal alkyne 3 was synthesized in good yield from deoxy-andrographolide 2, obtained from a natural compound andrographolide 1, which in turn was isolated from the leaves of the plant Andrographis paniculata. Copper(I)-catalyzed azide-alkyne cycloaddition reaction of alkyne 3 with azido-sugars 4a-f furnished a library of andrographolide-fastened triazolyl glycoconjugates 5a-f in good yields. The structures of these semisynthetic andrographolide derivatives were established by Fourier transform infrared, NMR, and mass spectroscopy. The compounds 5a-f were further evaluated against Alzheimer's disease (AD) using a scopolamine (SCOP)-induced memory impairment mice model. It was observed that antioxidant and anticholinesterase properties of these compounds contribute significantly toward their remarkable potential to improve cognitive functioning.

CSF proteome profiling across the Alzheimer's disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels.

Development of disease-modifying therapies against Alzheimer's disease (AD) requires biomarkers reflecting the diverse pathological pathways specific for AD. We measured 665 proteins in 797 cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment with abnormal amyloid (MCI(Aβ+): n = 50), AD-dementia (n = 230), non-AD dementias (n = 322) and cognitively unimpaired controls (n = 195) using proximity ligation-based immunoassays. Here we identified >100 CSF proteins dysregulated in MCI(Aβ+) or AD compared to controls or non-AD dementias. Proteins dysregulated in MCI(Aβ+) were primarily related to protein catabolism, energy metabolism and oxidative stress, whereas those specifically dysregulated in AD dementia were related to cell remodeling, vascular function and immune system. Classification modeling unveiled biomarker panels discriminating clinical groups with high accuracies (area under the curve (AUC): 0.85-0.99), which were translated into custom multiplex assays and validated in external and independent cohorts (AUC: 0.8-0.99). Overall, this study provides novel pathophysiological leads delineating the multifactorial nature of AD and potential biomarker tools for diagnostic settings or clinical trials.

Near-Infrared Photooxygenation Theranostics Used for the Specific Mapping and Modulating of Amyloid-β Aggregation.

The photooxygenation of amyloid-β (Aβ) protein is considered a promising strategy against Alzheimer's disease (AD). The inhibition of Aβ aggregation or depolymerization of Aβ aggregates can effectively alleviate and improve the condition of AD. Herein, we report a series of "off-on" near-infrared quinolinium photosensitizers (QM20-QM22) based on D-π-A structures using a target-sensing catalyst activation (TaSCAc) strategy. They exhibit turn-on fluorescence when bonded to Aβ aggregates and generate singlet oxygen to achieve the specific imaging and photooxygenation of Aβ aggregates, leading to attenuated Aβ aggregates, enhancing their clearance through the microglial lysosomal pathway, decreasing their neurotoxicity. This study will shed light on the development of the photooxygenation of misfolded proteins for the treatment of neurodegenerative diseases.

Transcranial deep-tissue phototherapy for Alzheimer's disease using low-dose X-ray-activated long-afterglow scintillators

Non-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-β (Aβ) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aβ oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Here, we report an Aβ targeted, low-dose X-ray-excitable long-afterglow scintillator (ScNPs@RB/Ab) for efficient deep-brain phototherapy. We demonstrate that the as-synthesized ScNPs@RB/Ab is capable of converting X-rays into visible light to activate the photosensitizers of rose bengal (RB) for Aβ oxygenation through the scalp and skull. We show that the ScNPs@RB/Ab persistently emitting visible luminescence can substantially minimize the risk of excessive X-ray exposure dosage. Importantly, peptide KLVFFAED-functionalized ScNPs@RB/Ab shows a blood–brain barrier permeability. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aβ burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects. Our study paves a new pathway to develop high-efficiency transcranial AD phototherapy. Statement of significanceNon-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-β (Aβ) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aβ oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Herein, we report an Aβ targeted, low-dose X-ray-excitable long-afterglow scintillators (ScNPs@RB/Ab) for efficient deep-brain phototherapy. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aβ burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects.

Treadmill Exercise Improves PINK1/Parkin-Mediated Mitophagy Activity Against Alzheimer's Disease Pathologies by Upregulated SIRT1-FOXO1/3 Axis in APP/PS1 Mice.

Although treadmill exercise is effective against Alzheimer's disease (AD), the molecular mechanisms underlying these effects are not fully understood. Recent literature has linked the accumulation of damaged mitochondria and defective mitophagy to AD progression. Here, we determined that abnormally activated PINK1/Parkin pathway-mediated mitophagy plays an important role in AD progression and pathogenesis in 6-month-old APP/PS1 mice. We used the lysosomal inhibitor chloroquine and demonstrated that a 12-week treadmill exercise program improved mitochondrial function, decreased accumulation of β-amyloid plaques, and ameliorated loss of learning and memory ability by enhancing PINK1/Parkin-mediated mitophagy activity in the hippocampus of APP/PS1 mice. Moreover, using the SIRT1 inhibitor EX527, we found that 12weeks of treadmill exercise rescued PINK1/Parkin-mediated mitophagy by activating the SIRT1-FOXO1/3 axis in the hippocampus of APP/PS1 mice. These findings reveal that activating PINK1/Parkin-mediated mitophagy is a promising strategy for AD treatment, and that the SIRT1-FOXO1/3 axis is a potential candidate for the development of mitophagy enhancers.

Efficacy of methylphenidate for the treatment of apathy in patients with Alzheimer's disease: a systematic review and meta-analysis of randomized controlled studies.

Despite the reported efficacy of methylphenidate (MET) against Alzheimer's disease (AD)-associated apathy, a recent larger clinical trial was not included in pooled analysis. This study aimed at investigating the efficacy of MET for attenuating apathy in patients diagnosed with AD. The PubMed, Cochrane Library, and EMBASE databases were searched from inception until March, 2022 to identify randomized controlled trials (RCTs). The primary outcome was apathy improvement assessed with the Neuropsychiatric Inventory (NPI) apathy subscale, Apathy Evaluation Scale (AES), or Clinical Global Impressions of Change scale (CGI-C apathy). Meta-analysis of four RCTs revealed an improvement in apathy among patients receiving MET compared to placebo (MD = - 5.12, p = 0.04, three trials, 144 participants) at follow-ups of 1-3months assessed with AES score. Despite the absence of improvement on NPI-apathy subscale at follow-ups of 1-2months (MD = - 0.74, p = 0.37, three trials, 265 participants), significant improvement was noted at follow-ups of 6months (MD = - 1.4, p = 0.02, one trial, 180 participants). Assessment with CGI-C apathy revealed no significant association between improvement in apathy with MET use (RR = 1.38, p = 0.05, three trials, 265 participants). No significant differences in global cognitive function (using the Mini Mental State Exam) or adverse events were noted between the two groups. While AES score suggested an early attenuation effect of MET on apathy in different domains, the NPI-apathy subscale did not show early improvement in apathy until the 6-month follow-up. Further studies with longer follow-ups are needed to elucidate the efficacy of MET for relieving caregiver burden and improving global functional performance.

Combined Effects of Synaptic and Axonal Integrity on Longitudinal Gray Matter Atrophy in Cognitively Unimpaired Adults.

Synaptic dysfunction and degeneration is a predominant feature of brain aging, and synaptic preservation buffers against Alzheimer disease (AD) protein-related brain atrophy. We tested whether CSF synaptic protein concentrations similarly moderate the effects of axonal injury, indexed by CSF neurofilament light [NfL]), on brain atrophy in clinically normal adults. Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (mean scan [follow-up] = 2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 25 [SNAP-25], neurogranin, growth-associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau181/Aβ42 ratio; reflecting AD proteinopathy). Ten bilateral temporoparietal gray matter region of interest (ROIs) shown to be sensitive to clinical AD were summed to generate a composite temporoparietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporoparietal trajectories, controlling for ptau181/Aβ42 ratios. Forty-six clinically normal older adults (mean age = 70 years; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL (r range: 0.10-0.36). Higher baseline NfL, but not ptau181/Aβ42 ratios, predicted steeper temporoparietal atrophy (NfL × time: β = -0.08, p < 0.001; ptau181/Aβ42 × time: β = -0.02, p = 0.31). SNAP-25, neurogranin, and GAP-43 significantly moderated NfL-related atrophy trajectories (-0.07 ≤ β's ≥ -0.06, p's < 0.05) such that NfL was associated with temporoparietal atrophy at high (more abnormal) but not low (more normal) synaptic protein concentrations. At high NfL concentrations, atrophy trajectories were 1.5-4.5 times weaker when synaptic protein concentrations were low (β range: -0.21 to -0.07) than high (β range: -0.33 to -0.30). The association between baseline CSF NfL and longitudinal temporoparietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions.