Alzheimers Abstracts 10

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Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer's disease: a 1-year, open-label pilot study with an 16-month caregiver extension.
            (Chan et al., 2008)  Download
We examined the efficacy of a vitamin/nutriceutical formulation (folate, vitamin B6, alpha-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine) in a 12-month, open-label trial with 14 community-dwelling individuals with early-stage Alzheimer's disease. Participants improved in the Dementia Rating Scale and Clock-drawing tests (Clox 1 and 2). Family caregivers reported improvement in multiple domains of the Neuropsychiatric Inventory (NPI) and maintenance of performance in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADL). Sustained performance was reported by caregivers for those participants who continued in an 16-month extension. Performance on the NPI was equivalent to published findings at 3 to 6 months for donepezil and exceeded that of galantamine and their historical placebos. Participants demonstrated superior performance for more than 12 months in NPI and ADL versus those receiving naproxen and rofecoxib or their placebo group. This formulation holds promise for treatment of early-stage Alzheimer's disease prior to and/or as a supplement for pharmacological approaches. A larger, placebo-controlled trial is warranted.

Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study.
            (Cotroneo et al., 2013)  Download
BACKGROUND: The studio di intervento nel decadimento vascolare lieve (IDEALE study) was an open multicenter Italian study, the aim of which was to assess the effectiveness and safety of oral citicoline in elderly people with mild vascular cognitive impairment. METHODS: The study was performed in 349 patients. The active or citicoline group was composed of 265 patients and included 122 men and 143 women of mean age 79.9 +/- 7.8 years selected from six Italian regions. Inclusion criteria were age >/= 65 years, Mini-Mental State Examination (MMSE) score >/= 21, subjective memory complaints but no evidence of deficits on MMSE, and evidence of vascular lesions on neuroradiology. Those with probable Alzheimer's disease were excluded. The control group consisted of 84 patients, including 36 men and 48 women of mean age 78.9 +/- 7.01 (range 67-90) years. Patients included in the study underwent brain computed tomography or magnetic resonance imaging, and plasma dosage of vitamin B12, folate, and thyroid hormones. Functional dependence was investigated by scores on the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales, mood was assessed by the Geriatric Depression Scale (GDS), and behavioral disorders using the Neuropsychiatric Inventory scale. Comorbidity was assessed using the Cumulative Illness Rating Scale. An assessment was made at baseline (T0), after 3 months (T1), and after 9 months (T2, ie, 6 months after T1). The main outcomes were an improvement in MMSE, ADL, and IADL scores in the study group compared with the control group. Side effects were also investigated. The study group was administered oral citicoline 500 mg twice a day throughout the study. RESULTS: MMSE scores remained unchanged over time (22.4 +/- 4 at T0; 22.7 +/- 4 at T1; 22.9 +/- 4 at T2), whereas a significant difference was found between the study and control groups, both in T1 and in T2. No differences were found in ADL and IADL scores between the two groups. A slight but not statistically significant difference was found in GDS score between the study and control groups (P = 0.06). No adverse events were recorded. CONCLUSION: In this study, citicoline was effective and well tolerated in patients with mild vascular cognitive impairment. Citicoline activates biosynthesis of phospholipids in neuronal membranes, increases brain metabolism as well as norepinephrine and dopamine levels in the central nervous system, and has neuroprotective effects during hypoxia and ischemia. Therefore, citicoline may be recommended for patients with mild vascular cognitive impairment.

Insulin resistance syndrome and Alzheimer's disease: age- and obesity-related effects on memory, amyloid, and inflammation.
            (Craft, 2005)  Download
Insulin plays an important role in memory and other aspects of brain function. The insulin resistance syndrome, characterized by chronic peripheral insulin elevations, reduced insulin activity, and reduced brain insulin levels, is associated with age-related memory impairment and Alzheimer's disease (AD). Our work has focused on specific mechanisms through which this association is forged, including the effects of peripheral hyperinsulinemia on memory, inflammation, and regulation of the beta-amyloid peptide that plays a key role in AD pathophysiology. Our data suggest that excessive insulin invokes synchronous increases in levels of Abeta and inflammatory agents, effects that are exacerbated by age and obesity. This constellation of events may have deleterious effects on memory. Treatments focused on preventing or correcting insulin abnormalities may be of therapeutic benefit for adults with age-related memory impairment and AD.


 

Alzheimer's disease is type 3 diabetes-evidence reviewed
            (de la Monte and Wands, 2008)  Download
Alzheimer's disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-beta (APP-Abeta) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term "type 3 diabetes" accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.

Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms.
            (Epperly et al., 2017)  Download
Alzheimer disease comprises a syndrome of progressive cognitive and functional decline. Treatments should target cognitive and functional symptoms. Cholinesterase inhibitors, memantine, and a combination of a cholinesterase inhibitor and memantine have produced statistically significant but clinically small delays in various domains of cognitive and functional decline in select patients with Alzheimer disease. Vitamin E has been shown to delay functional decline in patients with mild to moderate Alzheimer disease, especially when taken in combination with a cholinesterase inhibitor. Structured programs of physical exercise improve physical function and reduce rates of neuropsychiatric symptoms in patients with mild to severe Alzheimer disease. Cognitive stimulation programs show benefit in maintenance of cognitive function and improved self-reported quality of life in patients with mild to moderate Alzheimer disease.

Sodium butyrate improves memory function in an Alzheimer's disease mouse model when administered at an advanced stage of disease progression.
            (Govindarajan et al., 2011)  Download
Dysregulation of histone acetylation has been implicated in the onset of age-associated memory impairment and the pathogenesis of neurodegenerative diseases. Elevation of histone acetylation via administration of histone deacetylase (HDAC) inhibitors is currently being pursued as a novel therapeutic avenue to treat memory impairment linked to Alzheimer's disease (AD). Here we show that severe amyloid pathology correlates with a pronounced dysregulation of histone acetylation in the forebrain of APPPS1-21 mice. Importantly, prolonged treatment with the pan-HDAC inhibitor sodium butyrate improved associative memory in APPPS1-21 mice even when administered at a very advanced stage of pathology. The recovery of memory function correlated with elevated hippocampal histone acetylation and increased expression of genes implicated in associative learning. These data advance our understanding of the potential applicability of HDAC inhibitors for the treatment of AD and suggest that HDAC inhibitors may have beneficial effects even when administered long after the onset of disease-associated symptoms.

A multinational, randomised, 12-week study comparing the effects of donepezil and galantamine in patients with mild to moderate Alzheimer's disease.
            (Jones et al., 2004)  Download
OBJECTIVES:  To compare directly, in the same patient cohort, the ease of use and tolerability of donepezil and galantamine in the treatment of Alzheimer's disease (AD), and investigate the effects of both treatments on cognition and activities of daily living (ADL). METHODS:  Patients with mild to moderate AD from 14 European centres were randomised to receive open-label donepezil (up to 10 mg once daily) or galantamine (up to 12 mg twice daily) for 12 weeks, according to the approved product labelling. Physicians and caregivers completed questionnaires rating satisfaction with treatment/ease of use in daily practice. Secondary assessments were the ADAS-cog, the MMSE, and the DAD scale to assess ADL. Tolerability was evaluated by reporting adverse events (AEs). RESULTS:  Both physicians and caregivers reported significantly greater overall satisfaction/ease of use for donepezil (n = 64) compared with galantamine (n = 56) at weeks 4, 12, and endpoint (week 12 LOCF; all p-values <0.05). Significantly greater improvements in cognition were also observed for donepezil versus galantamine on the ADAS-cog at Week 12 and endpoint (p-values <0.05). ADL improved significantly in the donepezil group compared with the galantamine group at weeks 4, 12, and endpoint (p-values <0.05). Most AEs were mild to moderate, however, 46% galantamine-treated patients reported gastrointestinal AEs vs 25% donepezil patients. CONCLUSIONS:  Physician and caregiver ease of use/satisfaction scores, and assessments of cognition and ADL, showed significant benefits for donepezil compared with galantamine in this direct comparative trial. Both treatments were well tolerated, with more gastrointestinal AEs reported for galantamine vs donepezil.

Herpes simplex virus infections and Alzheimer's disease. Implications for drug treatment and immunotherapy.
            (Leissring et al., 1998)  Download
Interest in the possible role of herpes simplex virus type 1 (HSV1) as a cofactor in the pathogenesis of Alzheimer's disease (AD) has re-emerged following the detection of viral DNA sequences in the central nervous system (CNS). Evidence from 2 independent laboratories indicates that HSV1 may interact with a host-specific factor, the apolipoprotein E epsilon 4 allele, to further augment the risk for AD. In this review, we consider the arguments implicating HSV1 in the pathogenesis of AD. Although further studies are required to confirm a role for HSV1 in AD and to elucidate its underlying molecular basis, implicating a virus in the pathogenesis of this insidious disease clearly offers novel potential treatments.

Biomarkers for Alzheimer's Disease Diagnosis.
            (Mantzavinos and Alexiou, 2017)  Download
OBJECTIVE:  The dramatic increase in the population with dementia expected in the next decades is accompanied by the establishment of novel and innovated methods that will offer accurate and efficient detection of the disease in its early stages. While Alzheimer's disease is the most common cause of dementia, by the time it is typically diagnosed, substantial neuronal loss and neuropathological lesions can damage many brain regions. The aim of this study is to investigate the main risk factors that affect and increase Alzheimer's disease progression over time even in cases with no significant memory impairment present. Several potential markers are discussed such as oxidative stress, metal ions, vascular disorders, protein dysfunctions and alterations in the mitochondrial populations. CONCLUSION:  A multiparametric model of Alzheimer's biomarkers is presented according to the latest classification of the disease.


 

A Phase II Randomized Clinical Trial of a Nutritional Formulation for Cognition and Mood in Alzheimer's Disease.
            (Remington et al., 2015)  Download
BACKGROUND:  Increasing evidence points toward the efficacy of nutritional modifications in delaying cognitive decline and mood/behavioral difficulties in Alzheimer's disease (AD). Nutritional supplementation with individual agents has shown varied results suggesting the need for combinatorial intervention. OBJECTIVE:  We set out to determine whether nutritional intervention could positively impact cognitive performance and behavioral difficulties for individuals diagnosed with AD. METHODS:  A double-blind, multi-site, phase II study (ClinicalTrials.gov NCT01320527; Alzheimer's Association Trialmatch) was conducted in which 106 individuals with AD were randomized to a nutraceutical formulation (NF; folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or placebo for 3 or 6 months, followed by an open-label extension where participants received NF for 6 additional months. RESULTS:  The NF cohort improved versus the placebo cohort within 3 months (Clox-1 p = 0.0083, 95%CI [0.4481, 2.9343]; Dementia Rating Scale p = 0.0266, 95%CI [0.1722, 2.7171]). Caregivers reported non-significant improvements in Neuropsychiatric Inventory. Both cohorts improved or maintained baseline performance during open-label extensions. Activities of Daily Living did not change for either cohort. CONCLUSIONS:  These findings extend phase I studies where NF maintained or improved cognitive performance and mood/behavior.

Tolerability and pharmacokinetics of oxaloacetate 100 mg capsules in Alzheimer's subjects.
            (Swerdlow et al., 2016)  Download
Bioenergetics and bioenergetic-related functions are altered in Alzheimer's disease (AD) subjects. These alterations represent therapeutic targets and provide an underlying rationale for modifying brain bioenergetics in AD-affected persons. Preclinical studies in cultured cells and mice found that administering oxaloacetate (OAA), a Krebs cycle and gluconeogenesis intermediate, enhanced bioenergetic fluxes and upregulated some brain bioenergetic infrastructure-related parameters. We therefore conducted a study to provide initial data on the tolerability and pharmacokinetics of OAA in AD subjects. Six AD subjects received OAA 100 mg capsules twice a day for one month. The intervention was well-tolerated. Blood level measurements following ingestion of a 100 mg OAA capsule showed modest increases in OAA concentrations, but pharmacokinetic analyses were complicated by relatively high amounts of endogenous OAA. We conclude that OAA 100 mg capsules twice per day for one month are safe in AD subjects but do not result in a consistent and clear increase in the OAA blood level, thus necessitating future clinical studies to evaluate higher doses.


 

Biomarkers for preclinical Alzheimer's disease.
            (Tan et al., 2014)  Download
Currently, there is a pressing need to shift the focus to accurate detection of the earliest phase of increasingly preclinical Alzheimer's disease (AD). Meanwhile, the growing recognition that the pathophysiological process of AD begins many years prior to clinically obvious symptoms and the concept of a presymptomatic or preclinical stage of AD are becoming more widely accepted. Advances in clinical identification of new measurements will be critical not only in the discovery of sensitive, specific, and reliable biomarkers of preclinical AD but also in the development of tests that will aid in the early detection and differential diagnosis of dementia and in monitoring disease progression. The goal of this review is to provide an overview of biomarkers for preclinical AD, with emphasis on neuroimaging and neurochemical biomarkers. We conclude with a discussion of emergent directions for AD biomarker research.

Zinc in Alzheimer's Disease: A Meta-Analysis of Serum, Plasma, and Cerebrospinal Fluid Studies.
            (Ventriglia et al., 2015)  Download
To evaluate whether zinc levels in serum, plasma, and cerebrospinal fluid are altered in Alzheimer's disease (AD), we performed meta-analyses of 27 studies on the topic published from 1983 to 2014. The subjects' sample obtained by merging studies was a pooled total of 777 AD subjects and 1,728 controls for serum zinc studies, 287 AD subjects and 166 controls for plasma zinc, and of 292 AD subjects and 179 controls for CSF zinc. The main result of this meta-analysis is the very high heterogeneity among the studies either in demographic terms or in methodological approaches. Although we considered these effects in our analyses, the heterogeneity persisted and it has to be taken into account in the interpretation of the results. Our meta-analysis indicated that serum zinc appears significantly decreased in AD patients compared with healthy controls, and this result is confirmed when serum and plasma studies were analyzed together. If we considered the age-matched studies, the meta-analysis carried out on only six studies showed no significant difference in zinc levels between AD and healthy controls (SMD =-0.55, 95% CI (-1.18; 0.09); p = 0.094; I2 = 91%). In the light of these findings, we speculated about the possibility that the decreases observed could indicate a possible dietary zinc deficiency and we suggested that the possible involvement of zinc alterations in AD may have an interplay with copper metabolism.


 

Alzheimer's disease: Only prevention makes sense.
            (Viña and Sanz-Ros, 2018)  Download
Alzheimer's disease therapeutics is one of the most important endeavours in today's clinical investigation. Over more than 30 years of research, no disease-modifying treatment has been approved by either the FDA or the EMA to treat Alzheimer's disease. Recently, the evidence of pathological alterations in the brain tissue has been gathered showing that the signs of brain damage appear more than 20 years before the onset of Alzheimer's dementia. The major aim of this review is to underpin the idea that in Alzheimer's therapeutics, only prevention makes sense. It is difficult to visualise that would-be patients may be treated with endovenous administration of antibodies for several years to delay the onset of dementia. Rather, changes in lifestyle that should be specific, stratified and personalised are a likely alternative to delay the transition from asymptomatic Alzheimer's to minimal cognitive impairment and from there to dementia. These efforts are of the utmost importance. If we could delay the onset of full-blown dementia by 5 years, the number of demented patients would be almost halved. Thus, emphasis on preventive measures that can be implemented for decades must be supported. This approach, where even mild changes in cognition are of the greatest importance, cannot be underestimated in terms of both the individual and society's viewpoints.

Insulin effects on CSF norepinephrine and cognition in Alzheimer's disease.
            (Watson et al., 2006)  Download
We assessed the effects of induced hyperinsulinemia on plasma and cerebrospinal fluid (CSF) levels of norepinephrine (NE) and on cognition for patients with Alzheimer's disease (AD) and normal older adults. For normal adults, insulin increased plasma and CSF NE levels; also, recall for paraphrased details of a story improved as CSF NE levels increased. Mental control was positively correlated with CSF levels of NE for patients. These findings demonstrate that raising peripheral insulin levels can modulate CNS NE levels and suggest that insulin-stimulated increases in NE may modulate cognitive functions.


 

Metabolic syndrome: a potential culprit for Alzheimer's disease?
            (Wu et al., 2008)  Download
The etiology of Alzheimer’s disease has been mysterious for more than a century, clearly Alzhei- mer’s disease falls into the incomprehensible class. Recently, emerging evidence suggests that components (including hyperglycemia, hypertriglyceridemia, and a low HDL cholesterol con- centration) of the Metabolic syndrome (MS) either in isolation or in aggregate may impact the onset or severity of neurodegenerative pro- cesses, including those physiologic changes that lead to Alzheimer’s disease (AD).

Estrogen associated gene polymorphisms and their interactions in the progress of Alzheimer's disease.
            (Xing et al., 2013)  Download
The extensive neuroprotective effects of estrogen against Alzheimer's disease (AD) have been proven in numerous laboratory studies. However, in clinical studies, the exact role of estrogen in AD is still ambiguous. Some evidences even suggested the high levels of estrogen or estrogen replacement treatment increased the risk of AD. Thus, there must be other factors affecting the neuroprotective effects of estrogen. Multiple enzymes and receptor proteins are involved in the biosynthesis, metabolism and signaling pathways of estrogen, and mediate the beneficial effects of estrogen on AD. Previous studies have suggested some polymorphisms of genes encoding these enzymes and proteins are associated with the risk of AD. In addition to the genes associated with estrogen biosynthesis and metabolism and the genes encoding estrogen receptor proteins, some other genes also modulate the effects of estrogen on AD, or interact with other estrogen-associated genes on the progress of AD. The gene-hormone and gene-gene interactions may be key to unraveling the conflicting results regarding the effect of estrogen on AD. In this paper, we will review and discuss the associations between polymorphisms of these genes and their interactions and the susceptibility to AD. A better understanding of these estrogen-associated genes is significant to explore the pathogenesis of AD.

 


References

Chan, A, et al. (2008), ‘Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer’s disease: a 1-year, open-label pilot study with an 16-month caregiver extension.’, Am J Alzheimers Dis Other Demen, 23 (6), 571-85. PubMed: 19047474
Cotroneo, AM, et al. (2013), ‘Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study.’, Clin Interv Aging, 8 131-37. PubMed: 23403474
Craft, S (2005), ‘Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation.’, Neurobiol Aging, 26 Suppl 1 65-69. PubMed: 16266773
de la Monte, S. M. and J. R. Wands (2008), ‘Alzheimer’s disease is type 3 diabetes-evidence reviewed’, J Diabetes Sci Technol, 2 (6), 1101-13. PubMed: 19885299
Epperly, T, MA Dunay, and JL Boice (2017), ‘Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms.’, Am Fam Physician, 95 (12), 771-78. PubMed: 28671413
Govindarajan, N, et al. (2011), ‘Sodium butyrate improves memory function in an Alzheimer’s disease mouse model when administered at an advanced stage of disease progression.’, J Alzheimers Dis, 26 (1), 187-97. PubMed: 21593570
Jones, RW, et al. (2004), ‘A multinational, randomised, 12-week study comparing the effects of donepezil and galantamine in patients with mild to moderate Alzheimer’s disease.’, Int J Geriatr Psychiatry, 19 (1), 58-67. PubMed: 14716700
Leissring, MA, MC Sugarman, and FM LaFerla (1998), ‘Herpes simplex virus infections and Alzheimer’s disease. Implications for drug treatment and immunotherapy.’, Drugs Aging, 13 (3), 193-98. PubMed: 9789723
Mantzavinos, V and A Alexiou (2017), ‘Biomarkers for Alzheimer’s Disease Diagnosis.’, Curr Alzheimer Res, 14 (11), 1149-54. PubMed: 28164766
Remington, R, et al. (2015), ‘A Phase II Randomized Clinical Trial of a Nutritional Formulation for Cognition and Mood in Alzheimer’s Disease.’, J Alzheimers Dis, 45 (2), 395-405. PubMed: 25589719
Swerdlow, RH, et al. (2016), ‘Tolerability and pharmacokinetics of oxaloacetate 100 mg capsules in Alzheimer’s subjects.’, BBA Clin, 5 120-23. PubMed: 27051598
Tan, CC, JT Yu, and L Tan (2014), ‘Biomarkers for preclinical Alzheimer’s disease.’, J Alzheimers Dis, 42 (4), 1051-69. PubMed: 25024325
Ventriglia, M, et al. (2015), ‘Zinc in Alzheimer’s Disease: A Meta-Analysis of Serum, Plasma, and Cerebrospinal Fluid Studies.’, J Alzheimers Dis, 46 (1), 75-87. PubMed: 25697706
Viña, J and J Sanz-Ros (2018), ‘Alzheimer’s disease: Only prevention makes sense.’, Eur J Clin Invest, 48 (10), e13005. PubMed: 30028503
Watson, GS, et al. (2006), ‘Insulin effects on CSF norepinephrine and cognition in Alzheimer’s disease.’, Neurobiol Aging, 27 (1), 38-41. PubMed: 16298239
Wu, G. C., et al. (2008), ‘Metabolic syndrome: a potential culprit for Alzheimer’s disease?’, Med Hypotheses, 71 (4), 620-21. PubMed: 18562130
Xing, Y, et al. (2013), ‘Estrogen associated gene polymorphisms and their interactions in the progress of Alzheimer’s disease.’, Prog Neurobiol, 111 53-74. PubMed: 24096044