Resveratrol differentially affects MMP-9 release from neurons and glia; implications for therapeutic efficacy.

Resveratrol, a naturally occurring polyphenol that activates sirtuin 1 (SIRT1), has been shown to reduce overall levels of matrix metalloprotease-9 (MMP-9) in cerebrospinal fluid (CSF) samples from patients with Alzheimer's dementia (AD). Depending on the site of release, however, MMP-9 has the potential to improve or impair cognition. In particular, its release from microglia or pericytes proximal to the blood brain barrier can damage the basement membrane, while neuronal activity-dependent release of this protease from glutamatergic neurons can instead promote dendritic spine expansion and long-term potentiation of synaptic plasticity. In the present study, we test the hypothesis that resveratrol reduces overall MMP-9 levels in CSF samples from patients with APOE4, an allele associated with increased glial inflammation. We also examine the possibility that resveratrol reduces inflammation-associated MMP release from cultured glia but spares neuronal activity-dependent release from cultured cortical neurons. We observe that resveratrol decreases overall levels of MMP-2 and MMP-9 in CSF samples from AD patients. Resveratrol also reduces CSF levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), glial-derived protein that restricts long-term potentiation of synaptic transmission, in individuals homozygous for APOE4. Consistent with these results, we observe that resveratrol reduces basal and lipopolysaccharide (LPS)-stimulated MMP and TIMP-1 release from cultured microglia and astrocytes. In contrast, however, resveratrol does not inhibit release of MMP-9 from cortical neurons. Overall, these results are consistent with the possibility that while resveratrol reduces potentially maladaptive MMP and TIMP-1 release from activated glia, neuroplasticity-promoting MMP release from neurons is spared. In contrast, resveratrol reduces release of neurocan and brevican, extracellular matrix components that restrict neuroplasticity, from both neurons and glia. These data underscore the diversity of resveratrol's actions with respect to affected cell types and molecular targets and also suggest that further studies may be warranted to determine if its effects on glial MMP release could make it a useful adjunct for AD- and/or anti-amyloid therapy-related damage to the blood brain barrier.

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

INTRODUCTION: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aß) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. METHODS: Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 µg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aß positron emission tomography (PET) scans at 18 to 24 months. RESULTS: CAD106 induced measurable serum Aß immunoglobulin G titers in 41/42 participants, slower rates of Aß plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic). DISCUSSION: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aß active immunotherapies in individuals at risk for AD. HIGHLIGHTS: This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease.

BACKGROUND: Monoclonal antibodies that target amyloid-beta (Aß) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aß IgG1 monoclonal antibody with highest affinity for aggregated Aß that has been tested for the treatment of Alzheimer's disease. METHODS: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. RESULTS: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aß42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. CONCLUSIONS: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).

The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.

INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort.

INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

Matrix disequilibrium in Alzheimer's disease and conditions that increase Alzheimer's disease risk.

Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.

Inhibition of discoidin domain receptor (DDR)-1 with nilotinib alters CSF miRNAs and is associated with reduced inflammation and vascular fibrosis in Alzheimer's disease.

Discoidin Domain Receptor (DDR)-1 is activated by collagen. Nilotinib is a tyrosine kinase inhibitor that is FDA-approved for leukemia and potently inhibits DDR-1. Individuals diagnosed with mild-moderate Alzheimer's disease (AD) treated with nilotinib (versus placebo) for 12 months showed reduction of amyloid plaque and cerebrospinal fluid (CSF) amyloid, and attenuation of hippocampal volume loss. However, the mechanisms are unclear. Here, we explored unbiased next generation whole genome miRNA sequencing from AD patients CSF and miRNAs were matched with their corresponding mRNAs using gene ontology. Changes in CSF miRNAs were confirmed via measurement of CSF DDR1 activity and plasma levels of AD biomarkers. Approximately 1050 miRNAs are detected in the CSF but only 17 miRNAs are specifically altered between baseline and 12-month treatment with nilotinib versus placebo. Treatment with nilotinib significantly reduces collagen and DDR1 gene expression (upregulated in AD brain), in association with inhibition of CSF DDR1. Pro-inflammatory cytokines, including interleukins and chemokines are reduced along with caspase-3 gene expression. Specific genes that indicate vascular fibrosis, e.g., collagen, Transforming Growth Factors (TGFs) and Tissue Inhibitors of Metalloproteases (TIMPs) are altered by DDR1 inhibition with nilotinib. Specific changes in vesicular transport, including the neurotransmitters dopamine and acetylcholine, and autophagy genes, including ATGs, indicate facilitation of autophagic flux and cellular trafficking. Inhibition of DDR1 with nilotinib may be a safe and effective adjunct treatment strategy involving an oral drug that enters the CNS and adequately engages its target. DDR1 inhibition with nilotinib exhibits multi-modal effects not only on amyloid and tau clearance but also on anti-inflammatory markers that may reduce cerebrovascular fibrosis.

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice.

The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power, a neuronal population activity which is important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power, while attenuation of ECM can instead enhance this endpoint. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice. Importantly, as compared to APOE4/wild-type heterozygotes, APOE4/CCR5 knockout heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.

Safety, target engagement, and biomarker effects of bosutinib in dementia with Lewy bodies.

Introduction: Bosutinib, a dual Abelson/Src inhibitor, was investigated in individuals with dementia with Lewy bodies (DLB). Methods: A single site, randomized, double-blind, placebo-controlled study of the effects of oral bosutinib, 100 mg once daily for 12 weeks on primary safety and pharmacokinetics and secondary biomarker outcomes. Results: Twenty-six participants were randomized and included male and female (12:1) in the bosutinib arm and all male (13) in the placebo arm. The average age was 72.9 ± 8.1 (year ± standard deviation). There were no serious adverse events and no dropouts. Bosutinib was measured in the cerebrospinal fluid (CSF) and inhibited Abelson. Bosutinib reduced CSF alpha-synuclein and dopamine catabolism. Discussion: Bosutinib is safe and well tolerated and penetrates the blood-brain barrier to inhibit Abelson and reduce CSF alpha-synuclein and dopamine catabolism, suggesting that bosutinib (100 mg) may be at or near the lowest effective dose in DLB. These results will guide adequately powered studies to determine the efficacy of a dose range of bosutinib and longer treatment in DLB. Highlights: Bosutinib is a dual Abl/Src inhibitor that penetrates the blood brain barrierBosutinib is safe and tolerated in individuals with dementia with Lewy bodiesBosutinib engages its target via inhibition of Abl and SrcBosutinib reduces CSF alpha-synuclein and attenuates breakdown of dopamineBosutinib improves activities of daily living in dementia with Lewy bodies.

Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer's Disease.

Second-generation anti-amyloid monoclonal antibodies are emerging as a viable therapeutic option for individuals with prodromal and mild dementia due to Alzheimer's disease (AD). Passive immunotherapy with aducanumab (Aduhelm), lecanemab, donanemab, and gantenerumab all lower CNS amyloid (Aß) burden but come with a significant risk of amyloid-related imaging abnormality (ARIA)-the most common side effect of this class of drugs. While usually asymptomatic and detected only on brain MRI, ARIA may lead to new signs and symptoms including headache, worsening confusion, dizziness, visual disturbances, nausea, and seizures. In addition, one fatality related to ARIA-E (edema) with aducanumab and one fatality due to ARIA-H (hemorrhage) with donanemab are reported to date. ARIA-E may be associated with excessive neuroinflammation and saturation of perivascular clearance pathways, while ARIA-H may be related to vascular amyloid clearance with weakening and rupture of small blood vessels. The risk of ARIA-E is higher at treatment initiation, in ApoE4 carriers, with higher dosage, and with >4 of microhemorrhages on a baseline MRI. The risk of ARIA-H increases with age and cerebrovascular disease. Dose titration mitigates the risk of ARIA, and contraindications include individuals with >4 microhemorrhages and those prescribed anti-platelet or anti-coagulant drugs. A brain MRI is required before aducanumab is initiated, before each scheduled dose escalation, and with any new neurologic sign or symptom. Management of ARIA ranges from continued antibody treatment with monthly MRI monitoring for asymptomatic individuals to temporary or permanent suspension for symptomatic individuals or those with moderate to severe ARIA on MRI. Controlled studies regarding prevention and treatment of ARIA are lacking, but anecdotal evidence suggests that a pulse of intravenous corticosteroids may be of benefit, as well as a course of anticonvulsant for seizures.

Acceptability of collecting speech samples from the elderly via the telephone.

OBJECTIVE: There is a critical need to develop rapid, inexpensive and easily accessible screening tools for mild cognitive impairment (MCI) and Alzheimer's disease (AD). We report on the efficacy of collecting speech via the telephone to subsequently develop sensitive metrics that may be used as potential biomarkers by leveraging natural language processing methods. METHODS: Ninety-one older individuals who were cognitively unimpaired or diagnosed with MCI or AD participated from home in an audio-recorded telephone interview, which included a standard cognitive screening tool, and the collection of speech samples. In this paper we address six questions of interest: (1) Will elderly people agree to participate in a recorded telephone interview? (2) Will they complete it? (3) Will they judge it an acceptable approach? (4) Will the speech that is collected over the telephone be of a good quality? (5) Will the speech be intelligible to human raters? (6) Will transcriptions produced by automated speech recognition accurately reflect the speech produced? RESULTS: Participants readily agreed to participate in the telephone interview, completed it in its entirety, and rated the approach as acceptable. Good quality speech was produced for further analyses to be applied, and almost all recorded words were intelligible for human transcription. Not surprisingly, human transcription outperformed off the shelf automated speech recognition software, but further investigation into automated speech recognition shows promise for its usability in future work. CONCLUSION: Our findings demonstrate that collecting speech samples from elderly individuals via the telephone is well tolerated, practical, and inexpensive, and produces good quality data for uses such as natural language processing.

Nilotinib Improves Bioenergetic Profiling in Brain Astroglia in the 3xTg Mouse Model of Alzheimer's Disease.

Current treatments targeting amyloid beta in Alzheimer's disease (AD) have minimal efficacy, which results in a huge unmet medical need worldwide. Accumulating data suggest that brain mitochondrial dysfunction play a critical role in AD pathogenesis. Targeting cellular mechanisms associated with mitochondrial dysfunction in AD create a novel approach for drug development. This study investigated the effects of nilotinib, as a selective tyrosine kinase inhibitor, in astroglia derived from 3xTg-AD mice versus their C57BL/6-controls. Parameters included oxygen consumption rates (OCR), ATP, cytochrome c oxidase (COX), citrate synthase (CS) activity, alterations in oxidative phosphorylation (OXPHOS), nuclear factor kappa B (NF-κB), key regulators of mitochondrial dynamics (mitofusin (Mfn1), dynamin-related protein 1 (Drp1)), and mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1α), calcium/calmodulin-dependent protein kinase II (CaMKII), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)). Nilotinib increased OCR, ATP, COX, Mfn1, and OXPHOS levels in 3xTg astroglia. No significant differences were detected in levels of Drp1 protein and CS activity. Nilotinib enhanced mitochondrial numbers, potentially through a CaMKII-PGC1α-Nrf2 pathway in 3xTg astroglia. Additionally, nilotinib-induced OCR increases were reduced in the presence of the NF-κB inhibitor, Bay11-7082. The data suggest that NF-κB signaling is intimately involved in nilotinib-induced changes in bioenergetics in 3xTg brain astroglia. Nilotinib increased translocation of the NF-κB p50 subunit into the nucleus of 3xTg astroglia that correlates with an increased expression and activation of NF-κB. The current findings support a role for nilotinib in improving mitochondrial function and suggest that astroglia may be a key therapeutic target in treating AD.

Research Attitudes Questionnaire scores predict Alzheimer's disease clinical trial dropout.

BACKGROUND: Missing data are a notable problem in Alzheimer's disease clinical trials. One cause of missing data is participant dropout. The Research Attitudes Questionnaire is a 7-item instrument that measures an individual's attitudes toward biomedical research, with higher scores indicating more favorable attitudes. The objective of this study was to describe the performance of the Research Attitudes Questionnaire over time and to examine whether Research Attitudes Questionnaire scores predict study dropout and other participant behaviors that affect trial integrity. METHODS: The Research Attitudes Questionnaire was collected at baseline and weeks 26 and 52 from each member of 119 participant/study partner dyads enrolled in a Phase 2, randomized, double-blind, placebo-controlled mild-to-moderate Alzheimer's disease clinical trial. Within-subject longitudinal analyses examined change in Research Attitudes Questionnaire scores over time in each population. Logistic regression analyses that controlled for trial arm and clustering in trial sites were used to assess whether baseline Research Attitudes Questionnaire scores predicted trial completion, study medication compliance, and enrollment in optional substudies. RESULTS: Participants and study partners endorsed statistically similar ratings on the Research Attitudes Questionnaire that were stable over time. Participants with baseline Research Attitudes Questionnaire scores above 28.5 were 4.7 (95% confidence interval = 1.01 to 21.95) times as likely to complete the trial compared to those with lower scores. Applying the same cutoff, baseline study partner Research Attitudes Questionnaire scores were similarly able to predict study completion (odds ratio = 4.2, 95% confidence interval = 1.71 to 10.32). Using a score cutoff of 27.5, higher participant Research Attitudes Questionnaire scores predicted study medication compliance (odds ratio = 5.85, 95% confidence interval = 1.34 to 25.54). No relationship was observed between Research Attitudes Questionnaire score and participation in optional substudies. CONCLUSION: This brief instrument that measures research attitudes may identify participants at risk for behaviors that cause missing data.

Potential New Approaches for Diagnosis of Alzheimer's Disease and Related Dementias.

Dementia is an umbrella term-caused by a large number of specific diagnoses, including several neurodegenerative disorders. Alzheimer's disease (AD) is now the most common cause of dementia in advanced countries, while dementia due to neurosyphilis was the leading cause a century ago. Many challenges remain for diagnosing dementia definitively. Some of these include variability of early symptoms and overlap with similar disorders, as well as the possibility of combined, or mixed, etiologies in some cases. Newer technologies, including the incorporation of PET neuroimaging and other biomarkers (genomics and proteomics), are being incorporated into revised diagnostic criteria. However, the application of novel diagnostic methods at clinical sites is plagued by many caveats including availability and access. This review surveys new diagnostic methods as well as remaining challenges-for clinical care and clinical research.

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial.

IMPORTANCE: Oligomeric amyloid-ß peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. OBJECTIVE: To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. DESIGN, SETTING, AND PARTICIPANTS: This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-ß peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. INTERVENTIONS: AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. MAIN OUTCOMES AND MEASURES: Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. RESULTS: Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. CONCLUSIONS AND RELEVANCE: Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02167256.

Long-Term maintenance of anomia treatment effects in primary progressive aphasia.

This study examined the maintenance of anomia treatment effects in primary progressive aphasia (PPA). Following baseline testing, a phonological treatment and an orthographic treatment were administered over the course of six months. The treatment stimuli consisted of nouns that were consistently named correctly at baseline (Prophylaxis items) and/or nouns that were consistently named incorrectly at baseline (Remediation items). Naming accuracy was measured at baseline, and it was measured at 1 month, 8 months, and 15 months post-treatment. The change in naming accuracy from baseline to each post-treatment evaluation was calculated within each treatment condition, and within a matched untrained condition. The change in naming accuracy was then compared between the three conditions. The results of these analyses indicate that phonological and orthographic treatments are both effective in the Prophylaxis and Remediation of anomia in all three variants of PPA. For Prophylaxis items, some of the effects of each treatment can persist for as long as 15 months post-treatment. These long-term treatment effects were more robust in the orthographic treatment condition and for participants with the semantic variant of PPA.

Resveratrol for Alzheimer's disease.

The amyloid hypothesis suggests that the progressive accumulation and deposition of central nervous system (CNS) amyloid with aging is the proximate cause of Alzheimer's disease (AD). Thus, targeting molecular mechanisms of aging may be a viable treatment approach. Caloric restriction prevents diseases of aging, including AD, in animal models, perhaps by activation of sirtuins. The sirtuins (e.g., mammalian SIRT1) are deacetylases that link energy balance (NAD+ /NADH) to regulation of gene transcription. Resveratrol is a potent activator of SIRT1, and thus may mimic caloric restriction to prevent diseases of aging. We conducted a randomized, double-blind, placebo-controlled, phase II trial of resveratrol for individuals with mild-to-moderate AD. Resveratrol (1) is detectable in cerebrospinal fluid (at low nanomolar levels), (2) is safe and well tolerated, (3) alters AD biomarker trajectories, (4) preserves blood-brain barrier integrity, and (5) modulates the CNS immune response. Further studies are needed to determine the safety and efficacy of resveratrol and the validity of this approach in the treatment and prevention of AD and other diseases of aging.

Polo-like kinase 2 phosphorylation of amyloid precursor protein regulates activity-dependent amyloidogenic processing.

Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits. Amyloidogenic processing of amyloid precursor protein (APP) produces amyloid ß (Aß), the major component of hallmark AD plaques. Synaptic activity stimulates APP cleavage, whereas APP promotes excitatory synaptic transmission, suggesting APP participates in neuronal homeostasis. However, mechanisms linking synaptic activity to APP processing are unclear. Here we show that Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic plasticity, directly binds and phosphorylates threonine-668 and serine-675 of APP in vitro and associates with APP in vivo. Plk2 accelerates APP amyloidogenic cleavage by ß-secretase at synapses and is required for neuronal overactivity-stimulated Aß secretion. These findings implicate Plk2 as a novel mediator of activity-dependent APP amyloidogenic processing.

Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease.

BACKGROUND: Treatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aß40 levels and activities of daily living (ADL) scores. METHODS: For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aß42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples. RESULTS: Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aß42 levels during the 52-week trial, but did not alter tau levels. CONCLUSIONS: Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT01504854.