Alzheimers Abstracts 9

©

Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease
            (Baum et al., 2008) Download
Thirty-four subjects began the 6-month trial. The lack of cognitive decline on placebo in this 6-month trial may have precluded any ability to detect a relative protective effect of curcumin, which presumably would have appeared as a slower decline rather than an improvement in cognition. Although serum A"40 levels did not differ significantly among doses, serum A"40 tended to rise on curcumin, possibly reflecting an ability of curcumin to disaggregate A" deposits in the brain, releasing the A" for circulation and disposal.

CSF d-serine concentrations are similar in Alzheimer's disease, other dementias, and elderly controls.
            (Biemans et al., 2016) Download
Cerebrospinal fluid (CSF) levels of d-serine were recently reported as a potential new biomarker for Alzheimer's disease (AD), showing a perfect distinction between AD patients and healthy controls. In this study, we aimed to confirm these results and extend these previous findings to dementia with Lewy bodies and frontotemporal dementia. d-Serine levels in CSF of 29 AD patients, 8 dementia with Lewy bodies patients, 14 frontotemporal dementia patients, and 28 nondemented controls were measured using ultra-high-performance liquid chromatography-tandem mass spectrometry. In contrast to previous findings, in our study CSF d-serine levels were only slightly increased in AD patients compared with controls. CSF d-serine in AD did not differ from other dementias and was also not correlated to mini-mental state examination-scores. Owing to the large overlap of d-serine levels, we conclude that CSF d-serine is neither a suitable biomarker for AD nor for cognitive decline.


 

Changes in Serine Racemase-Dependent Modulation of NMDA Receptor: Impact on Physiological and Pathological Brain Aging.
            (Billard, 2018) Download
The N-methyl-D-Aspartate glutamate receptors (NMDARs) are pivotal for the functional and morphological plasticity that are required in neuronal networks for efficient brain activities and notably for cognitive-related abilities. Because NMDARs are heterogeneous in subunit composition and associated with multiple functional regulatory sites, their efficacy is under the tonic influence of numerous allosteric modulations, whose dysfunction generally represents the first step generating pathological states. Among the enzymatic candidates, serine racemase (SR) has recently gathered an increasing interest considering that it tightly regulates the production of d-serine, an amino acid now viewed as the main endogenous co-agonist necessary for NMDAR activation. Nowadays, SR deregulation is associated with a wide range of neurological and psychiatric diseases including schizophrenia, amyotrophic lateral sclerosis, and depression. This review aims at compelling the most recent experimental evidences indicating that changes in SR-related modulation of NMDARs also govern opposite functional dysfunctions in physiological and pathological (Alzheimer's disease) aging that finally results in memory disabilities in both cases. It also highlights SR as a relevant alternative target for new pharmacological strategies aimed at preventing functional alterations and cognitive impairments linked to the aging process.

Reversal of cognitive decline: a novel therapeutic program.
            (Bredesen, 2014) Download
This report describes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer's disease, and which involves multiple modalities designed to achieve metabolic enhancement for neurodegeneration (MEND). The first 10 patients who have utilized this program include patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI). Nine of the 10 displayed subjective or objective improvement in cognition beginning within 3-6 months, with the one failure being a patient with very late stage AD. Six of the patients had had to discontinue working or were struggling with their jobs at the time of presentation, and all were able to return to work or continue working with improved performance. Improvements have been sustained, and at this time the longest patient follow-up is two and one-half years from initial treatment, with sustained and marked improvement. These results suggest that a larger, more extensive trial of this therapeutic program is warranted. The results also suggest that, at least early in the course, cognitive decline may be driven in large part by metabolic processes. Furthermore, given the failure of monotherapeutics in AD to date, the results raise the possibility that such a therapeutic system may be useful as a platform on which drugs that would fail as monotherapeutics may succeed as key components of a therapeutic system.

Folic Acid Supplementation Mitigates Alzheimer's Disease by Reducing Inflammation: A Randomized Controlled Trial.
            (Chen et al., 2016) Download
Background/Aims. Low serum folate levels can alter inflammatory reactions. Both phenomena have been linked to Alzheimer's disease (AD), but the effect of folic acid on AD itself is unclear. We quantified folate supplementation's effect on inflammation and cognitive function in patients with AD over the course of 6 months. Methods. Patients newly diagnosed with AD (age > 60 years; n = 121; mild to severe; international criteria) and being treated with donepezil were randomly assigned into two groups with (intervention group) or without (control group) supplemental treatment with folic acid (1.25 mg/d) for 6 months. The Mini-Mental State Examination (MMSE) was administered to all patients at baseline and follow-up, and blood samples were taken before and after treatment. We quantified serum folate, amyloid beta (Aβ), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), plasma homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and the mRNA levels of presenilin (PS), IL-6, and TNFα in leukocytes. Data were analyzed using a repeated-measures mixed model. Results. The mean MMSE was slightly increased in the intervention group compared to that in the control group (P < 0.05). Posttreatment, plasma SAM and SAM/SAH levels were significantly higher (P < 0.05), while Aβ 40, PS1-mRNA, and TNFα-mRNA levels were lower in the intervention group than in the control group (P < 0.05). The Aβ 42/Aβ 40 ratio was also higher in the intervention group (P < 0.05). Conclusions. Folic acid is beneficial in patients with AD. Inflammation may play an important role in the interaction between folic acid and AD. This trial is registered with clinical trial registration number ChiCTR-TRC-13003246.

Traditional Food Items in Ogimi, Okinawa: l-Serine Content and the Potential for Neuroprotection.
            (Cox and Metcalf, 2017) Download
PURPOSE OF REVIEW:  Ogimi village is renowned for its aging population. We sought to determine if the l-serine content of their diet could account for their neurological health. RECENT FINDINGS:  The most frequently consumed food items, including tofu and seaweeds, are rich in the dietary amino acid l-serine. l-serine content of the Ogimi diet >8 grams/day for Ogimi women significantly exceeds the average American dietary intake of 2.5 grams/day for women >70 years old. Our hypothesis that the high l-serine content of the Ogimi diet is related to the paucity of tangle diseases among villagers is buttressed by in vivo results with non-human primates where dietary l-serine slowed development of neurofibrillary tangles and β-amyloid plaques by up to 85% and a human clinical trial finding that l-serine at 15 grams/day twice daily slows functional decline in ALS patients. Analysis of the Ogimi diet suggests that l-serine should be evaluated for therapeutic potential as a neuroprotective agent.

Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment.
            (Douaud et al., 2013) Download
Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer's disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 micromol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.
            (Dysken et al., 2014) Download
IMPORTANCE: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. OBJECTIVE: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. INTERVENTIONS: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). MAIN OUTCOMES AND MEASURES: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. RESULTS: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). CONCLUSIONS AND RELEVANCE: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235716.

Association of Antioxidant Supplement Use and Dementia in the Prevention of Alzheimer's Disease by Vitamin E and Selenium Trial (PREADViSE).
            (Kryscio et al., 2017) Download
Importance:  Oxidative stress is an established dementia pathway, but it is unknown if the use of antioxidant supplements can prevent dementia. Objective:  To determine if antioxidant supplements (vitamin E or selenium) used alone or in combination can prevent dementia in asymptomatic older men. Design, Setting, and Participants:  The Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADViSE) trial began as a double-blind randomized clinical trial in May 2002, which transformed into a cohort study from September 2009 to May 2015. The PREADViSE trial was ancillary to the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized clinical trial of the same antioxidant supplements for preventing prostate cancer, which closed in 2009 owing to findings from a futility analysis. The PREADViSE trial recruited 7540 men, of whom 3786 continued into the cohort study. Participants were at least 60 years old at study entry and were enrolled at 130 SELECT sites, and Cox proportional hazards models were used in a modified intent-to-treat analysis to compare hazard rates among the study arms. Interventions:  Participants were randomized to vitamin E, selenium, vitamin E and selenium, or placebo. While taking study supplements, enrolled men visited their SELECT site and were evaluated for dementia using a 2-stage screen. During the cohort study, men were contacted by telephone and assessed using an enhanced 2-stage cognitive screen. In both phases, men were encouraged to visit their physician if the screen results indicated possible cognitive impairment. Main Outcomes and Measures:  Dementia case ascertainment relied on a consensus review of the cognitive screens and medical records for men with suspected dementia who visited their physician for an evaluation or by review of all available information, including a functional assessment screen. Results:  The mean (SD) baseline age of the 7540 participants was 67.5 (5.3) years, with 3936 (52.2%) reporting a college education or better, 754 (10.0%) reporting black race, and 505 (6.7%) reporting Hispanic ethnicity. Dementia incidence (325 of 7338 men [4.4%]) was not different among the 4 study arms. A Cox model, which adjusted incidence for participant demographic information and baseline self-reported comorbidities, yielded hazard ratios of 0.88 (95% CI, 0.64-1.20) for vitamin E, 0.83 (0.60-1.13) for selenium, and 1.00 (0.75-1.35) for the combination compared with placebo. Conclusions and Relevance:  Neither supplement prevented dementia. To our knowledge, this is the first study to investigate the long-term association of antioxidant supplement use and dementia incidence among asymptomatic men.

d-serine levels in Alzheimer's disease: implications for novel biomarker development.
            (Madeira et al., 2015) Download
Alzheimer's disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.


L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential.
            (Metcalf et al., 2018) Download
In human neuroblastoma cell cultures, non-human primates and human beings, L-serine is neuroprotective, acting through a variety of biochemical and molecular mechanisms. Although L-serine is generally classified as a non-essential amino acid, it is probably more appropriate to term it as a "conditional non-essential amino acid" since, under certain circumstances, vertebrates cannot synthesize it in sufficient quantities to meet necessary cellular demands. L-serine is biosynthesized in the mammalian central nervous system from 3-phosphoglycerate and serves as a precursor for the synthesis of the amino acids glycine and cysteine. Physiologically, it has a variety of roles, perhaps most importantly as a phosphorylation site in proteins. Mutations in the metabolic enzymes that synthesize L-serine have been implicated in various human diseases. Dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine support the FDA's determination that L-serine is generally regarded as safe (GRAS); it also appears to be neuroprotective. We here consider the role of L-serine in neurological disorders and its potential as a therapeutic agent.

Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease.
            (Nunes et al., 2013) Download
A lower incidence of dementia in bipolar patients treated with lithium has been described. This metal inhibits the phosphorylation of glycogen-synthase-kinase 3-α and β, which are related to amyloid precursor protein processing and tau hyperphosphorylation in pathological conditions, respectively. Following the same rationale, a group just found that lithium has disease-modifying properties in amnestic mild cognitive impairment with potential clinical implications for the prevention of Alzheimer's Disease (AD) when a dose ranging from 150 to 600 mg is used. As lithium is highly toxic in regular doses, our group evaluated the effect of a microdose of 300 μg, administered once daily on AD patients for 15 months. In the evaluation phase, the treated group showed no decreased performance in the mini-mental state examination test, in opposition to the lower scores observed for the control group during the treatment, with significant differences starting three months after the beginning of the treatment, and increasing progressively. This data suggests the efficacy of a microdose lithium treatment in preventing cognitive loss, reinforcing its therapeutic potential to treat AD using very low doses.


 

Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer's Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open-Label Study.
            (Remington et al., 2016) Download
Nutritional interventions have shown varied efficacy on cognitive performance during Alzheimer's disease (AD). Twenty-four individuals diagnosed with AD received a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) under open-label conditions (ClinicalTrials.gov NCT01320527). Primary outcome was cognitive performance. Secondary outcomes were behavioral and psychological symptoms of dementia (BPSD) and activities of daily living. Participants maintained their baseline cognitive performance and BPSD over 12 months. These findings are consistent with improvement in cognitive performance and BPSD in prior placebo-controlled studies with NF, and contrast with the routine decline for participants receiving placebo.

A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer's disease.
            (Shinto et al., 2014) Download
Oxidative stress, inflammation, and increased cholesterol levels are all mechanisms that have been associated with Alzheimer's disease (AD) pathology. Several epidemiologic studies have reported a decreased risk of AD with fish consumption. This pilot study was designed to evaluate the effects of supplementation with omega-3 fatty acids alone (omega-3) or omega-3 plus alpha lipoic acid (omega-3 + LA) compared to placebo on oxidative stress biomarkers in AD. The primary outcome measure was peripheral F2-isoprostane levels (oxidative stress measure). Secondary outcome measures included performance on: Mini-Mental State Examination (MMSE), Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL), and Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Thirty-nine AD subjects were randomized to one of three groups: 1) placebo, 2) omega-3, or 3) omega-3 + LA for a treatment duration of 12 months. Eighty seven percent (34/39) of the subjects completed the 12-month intervention. There was no difference between groups at 12 months in peripheral F2-isoprostane levels (p = 0.83). The omega-3 + LA and omega-3 were not significantly different than the placebo group in ADAS-cog (p = 0.98, p = 0.86) and in ADL (p = 0.15, p = 0.82). Compared to placebo, the omega-3 + LA showed less decline in MMSE (p < 0.01) and IADL (p = 0.01) and the omega-3 group showed less decline in IADL (p < 0.01). The combination of omega-3 + LA slowed cognitive and functional decline in AD over 12 months. Because the results were generated from a small sample size, further evaluation of the combination of omega-3 fatty acids plus alpha-lipoic acid as a potential treatment in AD is warranted.


 

Chronic d-serine supplementation impairs insulin secretion.
            (Suwandhi et al., 2018) Download
OBJECTIVE:  The metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis. METHODS:  We apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals. RESULTS:  We show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans. CONCLUSION:  Thus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.

 


References

Baum, L., et al. (2008), ‘Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease’, J Clin Psychopharmacol, 28 (1), 110-13. PubMed: 18204357
Biemans, EA, et al. (2016), ‘CSF d-serine concentrations are similar in Alzheimer’s disease, other dementias, and elderly controls.’, Neurobiol Aging, 42 213-16. PubMed: 27143438
Billard, JM (2018), ‘Changes in Serine Racemase-Dependent Modulation of NMDA Receptor: Impact on Physiological and Pathological Brain Aging.’, Front Mol Biosci, 5 106. PubMed: 30555832
Bredesen, DE (2014), ‘Reversal of cognitive decline: a novel therapeutic program.’, Aging (Albany NY), 6 (9), 707-17. PubMed: 25324467
Chen, H, et al. (2016), ‘Folic Acid Supplementation Mitigates Alzheimer’s Disease by Reducing Inflammation: A Randomized Controlled Trial.’, Mediators Inflamm, 2016 5912146. PubMed: 27340344
Cox, PA and JS Metcalf (2017), ‘Traditional Food Items in Ogimi, Okinawa: l-Serine Content and the Potential for Neuroprotection.’, Curr Nutr Rep, 6 (1), 24-31. PubMed: 28331770
Douaud, G, et al. (2013), ‘Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment.’, Proc Natl Acad Sci U S A, 110 (23), 9523-28. PubMed: 23690582
Dysken, MW, et al. (2014), ‘Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.’, JAMA, 311 (1), 33-44. PubMed: 24381967
Kryscio, RJ, et al. (2017), ‘Association of Antioxidant Supplement Use and Dementia in the Prevention of Alzheimer’s Disease by Vitamin E and Selenium Trial (PREADViSE).’, JAMA Neurol, 74 (5), 567-73. PubMed: 28319243
Madeira, C, et al. (2015), ‘d-serine levels in Alzheimer’s disease: implications for novel biomarker development.’, Transl Psychiatry, 5 e561. PubMed: 25942042
Metcalf, JS, et al. (2018), ‘L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential.’, Neurotox Res, 33 (1), 213-21. PubMed: 28929385
Nunes, MA, TA Viel, and HS Buck (2013), ‘Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease.’, Curr Alzheimer Res, 10 (1), 104-7. PubMed: 22746245
Remington, R, et al. (2016), ‘Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer’s Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open-Label Study.’, J Alzheimers Dis, 51 (4), 991-95. PubMed: 26967219
Shinto, L, et al. (2014), ‘A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease.’, J Alzheimers Dis, 38 (1), 111-20. PubMed: 24077434
Suwandhi, L, et al. (2018), ‘Chronic d-serine supplementation impairs insulin secretion.’, Mol Metab, 16 191-202. PubMed: 30093356