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Alzheimer's Disease and Methanol Toxicity (Part 2): Lessons from Four Rhesus Macaques (Macaca mulatta) Chronically Fed Methanol
Abstract and Figures
A recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology has provided a new impetus to investigate the chronic effects of methanol exposure. This paper expands this investigation to the non-human primate, rhesus macaque, through the chronic feeding of young male monkeys with 3% methanol ad libitum. Variable Spatial Delay Response Tasks of the monkeys found that the methanol feeding led to persistent memory decline in the monkeys that lasted 6 months beyond the feeding regimen. This change coincided with increases in tau protein phosphorylation at residues T181 and S396 in cerebrospinal fluid during feeding as well as with increases in tau phosphorylated aggregates and amyloid plaques in four brain regions postmortem: the frontal lobe, parietal lobe, temporal lobe, and the hippocampus. Tau phosphorylation in cerebrospinal fluid was found to be dependent on methanol feeding status, but phosphorylation changes in the brain were found to be persistent 6 months after the methanol feeding stopped. This suggested the methanol feeding caused long-lasting and persistent pathological changes that were related to AD development in the monkey. Most notably, the presence of amyloid plaque formations in the monkeys highlighted a marked difference in animal systems used in AD investigations, suggesting that the innate defenses in mice against methanol toxicity may have limited previous investigations into AD pathology. Nonetheless, these findings support a growing body of evidence that links methanol and its metabolite formaldehyde to AD pathology.
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... There is direct evidence that methanol (a precursor of formaldehyde) can be oxidized to form formaldehyde in rhesus monkey brains [168]. Feeding rhesus monkeys with methanol causes an increase in the formation of SPs and sustained memory impairments [169]. Aβ also interferes with formaldehyde metabolism. ...
... [168]. Feeding rhesus monkeys with methanol causes an increase in the formation of SPs and sustained memory impairments [169]. Aβ also interferes with formaldehyde metabolism. ...
... After feeding them with methanol for 6 months, the levels of tau protein phosphorylation on residues T181 and S396 were increased in the CSF of rhesus monkeys. Meanwhile, NFTs were also widely distributed in the brains [169]. ...
Alzheimer's disease (AD), the most common type of dementia, is characterized by senile plaques composed of amyloid β protein (Aβ) and neurofilament tangles derived from the hyperphosphorylation of tau protein. However, the developed medicines targeting Aβ and tau have not obtained ideal clinical efficacy, which raises a challenge to the hypothesis that AD is Aβ cascade-induced. A critical problem of AD pathogenesis is which endogenous factor induces Aβ aggregation and tau phosphorylation. Recently, age-associated endogenous formaldehyde has been suggested to be a direct trigger for Aβ- and tau-related pathology. Another key issue is whether or not AD drugs are successfully delivered to the damaged neurons. Both the blood-brain barrier (BBB) and extracellular space (ECS) are the barriers for drug delivery. Unexpectedly, Aβ-related SP deposition in ECS slows down or stops interstitial fluid drainage in AD, which is the direct reason for drug delivery failure. Here, we propose a new pathogenesis and perspectives on the direction of AD drug development and drug delivery: (1) aging-related formaldehyde is a direct trigger for Aβ assembly and tau hyperphosphorylation, and the new target for AD therapy is formaldehyde; (2) nano-packaging and physical therapy may be the promising strategy for increasing BBB permeability and accelerating interstitial fluid drainage.
... Importantly, the accumulation sites and spreading routes of Tau are the same as those reported in AD patients, strongly suggesting that monkeys are exceptional animals for modeling late-onset sporadic AD (Arnsten et al., 2021;Paspalas et al., 2018). Investigating the potential contributions of environmental toxic chemicals to AD pathogenesis, Yang et al. (2014) endeavored to induce AD in monkeys by formaldehyde or methanol exposure (Yang et al., 2014;Zhai et al., 2018). Attempts to create AD monkey models also include intracerebral or lateral ventricle injections of patientderived or synthetic Aβ oligomers (AβOs), resulting in early pathological events, such as increased inflammation, reduced spines, and synaptic dysfunction, as well as the development of overt amyloid plaques and NFTs in multiple brain regions (Beckman et al., 2019;Forny-Germano et al., 2014). ...
... Importantly, the accumulation sites and spreading routes of Tau are the same as those reported in AD patients, strongly suggesting that monkeys are exceptional animals for modeling late-onset sporadic AD (Arnsten et al., 2021;Paspalas et al., 2018). Investigating the potential contributions of environmental toxic chemicals to AD pathogenesis, Yang et al. (2014) endeavored to induce AD in monkeys by formaldehyde or methanol exposure (Yang et al., 2014;Zhai et al., 2018). Attempts to create AD monkey models also include intracerebral or lateral ventricle injections of patientderived or synthetic Aβ oligomers (AβOs), resulting in early pathological events, such as increased inflammation, reduced spines, and synaptic dysfunction, as well as the development of overt amyloid plaques and NFTs in multiple brain regions (Beckman et al., 2019;Forny-Germano et al., 2014). ...
Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Currently, there are no therapies available that can delay, stop, or reverse the pathological progression of NDs in clinical settings. As the population ages, NDs are imposing a huge burden on public health systems and affected families. Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments. While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms, the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, and vervet monkeys, are phylogenetically, physiologically, biochemically, and behaviorally most relevant to humans. This is particularly evident in the similarity of the structure and function of their central nervous systems, rendering such species uniquely valuable for neuroscience research. Recently, the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms. This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained, as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.
... The phenomena are present in four regions of postmortem brains: the prefrontal cortex (PFC), the parietal cortex, the temporal cortex, and the hippocampus. Subsequently, the researchers fed macaques methanol for 6 months and found persistent changes in phosphorylated tau protein in the brain after consuming methanol, suggesting that methanol feeding leads to long-term pathological changes related to the development of AD in macaques [15]. This result provided a new perspective and means for the prevention and treatment of AD and was also the first rhesus monkey model with the core symptoms of AD. ...
The aging of the population is an increasingly serious issue, and many age-related illnesses are on the rise. These illnesses pose a serious threat to the health and safety of elderly individuals and create a serious economic and social burden. Despite substantial research into the pathogenesis of these diseases, their etiology and pathogenesis remain unclear. In recent decades, rodent models have been used in attempts to elucidate these disorders, but such models fail to simulate the full range of symptoms. Nonhuman primates (NHPs) are the most ideal neuroscientific models for studying the human brain and are more functionally similar to humans because of their high genetic similarities and phenotypic characteristics in comparison with humans. Here, we review the literature examining typical NHP brain disease models, focusing on NHP models of common diseases such as dementia, Parkinson's disease, and epilepsy. We also explore the application of electroencephalography (EEG), magnetic resonance imaging (MRI), and optogenetic study methods on NHPs and neural circuits associated with cognitive impairment.
... The alert to methanol was a surprise but supported by significant literature. As early as 2014, exploration of chronic methanol feeding relationship to AD pathology was explored [194] with feeding to monkeys producing tau phosphorylation and amyloid plaques [195] similar to AD. Increased methanol concentration is known in old age [42]. Interestingly, investigation on APOE-4 and ethanol consumption [81] may be consistent with an important role for methanol in AD pathology. ...
This is an alternative analysis of a simple differential abundance measure between control and AD brains from one recent publication [111]. The differential abundances suggest loss of beneficial organisms maybe acquired at conception. The title derives from literature on some of these organisms being symbionts with plants. As soon as I can figure out how to download the Bioproject data I hope to look at sequence level analysis. This may be another case of the mixed taxonomy getting in the way of seeing what is really there. A good database on metabolism may be helpful too. If nothing else, compare the list here to those most abundant in the endometrium [189]. Also repeats warnings on static measures of all kinds :) This is just released in current form due to hitting a time constraint. It seems to motivate important speculation with acceptable editing issues for now. This is a draft and has not been peer reviewed or completely proof read but released in some state where it seems worthwhile given time or other constraints. Typographical errors are quite likely particularly in manually entered numbers. This work may include output from software which has not been fully debugged. For information only, not for use for any particular purpose see fuller disclaimers in the text. Caveat Emptor. I am not a veterinarian or a doctor or health care professional and this is not particular advice for any given situation. Read the disclaimers in the appendicies or text, take them seriously and take prudent steps to evaluate this information. This work addresses a controversial topic and likely advances one or more viewspoints that are not well accepted in an attempt to resolve confusion. The reader is assumed familiar with the related literature and controversial issues and in any case should seek additional input from sources the reader trusts likely with differing opinions. For information and thought only not intended for any particular purpose. Caveat Emptor
... The Variable Spatial Delayed Response Task (VSDRT) has been widely used to measure the capacity of visuospatial working memory of the brain (25)(26)(27)(28), a function that is severely impaired in AD patients (29). During the test, the monkey was placed in a Wisconsin General Test Apparatus (WGTA) situated in a sound-attenuated room, and was always tested at the same time of the day immediately prior to feeding (30). ...
Alzheimer’s disease (AD) is the most common neurodegenerative disease. To date, its cause is unclear and there are no effective treatments or preventive measures. Despite there are accumulating evidences for the existence of AD pathological hallmarks in the brain of aging rhesus monkeys, it remains a mainstream notion that monkeys do not develop AD naturally. This is an important issue because it will determine how we use monkeys in AD studies. To settle down this issue, a group (n=10) of aged rhesus monkeys 26 years old or above went through a systematic AD screening procedure in this study. Three of these monkeys showed severe memory impairments (SMI) after evaluated with a classic working memory test. Further behavioral testing revealed that the SMI monkeys also exhibited apathy-like behavior, which is another core AD clinical symptom. In addition to the cognitive deficits, two of the three SMI monkeys developed all of the three AD pathological hallmarks, including neurofibrillary tangles, senile plaques and neuronal loss. According to the diagnostic criteria of human AD, the two SMI monkeys were clearly naturally occurring AD monkeys. These results suggest that AD is not a uniquely human disease and monkeys have great potential for the development of much needed etiological AD models, which are vital for better understanding of developmental process of AD and the base of identification of early diagnostic biomarkers and effective therapeutic targets of AD.
... Recent investigations have found that primates can naturally develop amyloid plaques and NFTs in old age [74][75][76] . Importantly, the Tau pathology initiates and is spread in the same manner as that in AD patients, strongly suggesting that monkeys possess unparalleled physical context for the occurrence of late-onset sporadic AD [75,77] . Since toxic chemicals in the environment may contribute to AD pathogenesis, Yang et al. performed methanol administration to induce an AD monkey model [78,79] . ...
Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are pathologically characterized by progressive loss of selective populations of neurons in the affected brain regions and clinically manifested by cognitive, motor, and psychological dysfunctions. Since aging is the major risk factor for NDs and the elderly population is expected to expand considerably in the coming decades, the prevalence of NDs will significantly increase, leading to a greater medical burden to society and affected families. Despite extensive research on NDs, no effective therapy is available for NDs, largely due to a lack of complete understanding of the pathogenesis of NDs. Although research on small animal and rodent models has provided tremendous knowledge of molecular mechanisms of disease pathogenesis, few translational successes have been reported in clinical trials. In particular, most genetically modified rodent models are unable to recapitulate striking and overt neurodegeneration seen in the patient brains. Non-human primates (NHPs) are the most relevant laboratory animals to humans, and recent studies using NHP neurodegeneration models have uncovered important pathological features of NDs. Here, we review the unique features of NHPs for modeling NDs and new insights into AD, PD, and ALS gained from animal models, highlight the contribution of gene editing techniques to establishing NHP models, and discuss the challenges of investigating NHP models.
... It has been demonstrated that aggregation of Aβ plaques which is similar in sequence to humans were naturally found in aged animals accompanied by declining cognitive function (Geula et al., 2002;Sani et al., 2003;Oikawa et al., 2010). In NHPs, some AD models have already been published including rhesus monkeys, cynomolgus monkeys, vervet monkeys, and marmosets (Geula et al., 1998(Geula et al., , 2002Lemere et al., 2004;Forny-Germano et al., 2014;Yang et al., 2014;Melamed et al., 2017;Seita et al., 2020). Details of each model were described elsewhere but it is noteworthy that recent technological advances have made it possible to generate genetically engineered animal models in NHPs (Sasaki et al., 2009;De Felice and Munoz, 2016;Li et al., 2019;Seita et al., 2020). ...
Continually emerging data indicate that sub-clinical, non-convulsive epileptiform activity is not only prevalent in Alzheimer’s disease (AD) but is detectable early in the course of the disease and predicts cognitive decline in both humans and animal models. Epileptiform activity and other electroencephalographic (EEG) measures may hold powerful, untapped potential to improve the translational validity of AD-related biomarkers in model animals ranging from mice, to rats, and non-human primates. In this review, we will focus on studies of epileptiform activity, EEG slowing, and theta-gamma coupling in preclinical models, with particular focus on its role in cognitive decline and relevance to AD. Here, each biomarker is described in the context of the contemporary literature and recent findings in AD relevant animal models are discussed.
Formaldehyde (FA) has been found to induce major Alzheimer’s disease (AD)-like features including cognitive impairment, Aβ deposition, and Tau hyperphosphorylation, suggesting that it may play a significant role in the initiation and progression of AD. Therefore, elucidating the mechanism underlying FA-induced neurotoxicity is crucial for exploring more comprehensive approaches to delay or prevent the development of AD. Mangiferin (MGF) is a natural C-glucosyl-xanthone with promising neuroprotective effects, and is considered to have potential in the treatment of AD. The present study was designed to characterize the effects and mechanisms by which MGF protects against FA-induced neurotoxicity. The results in murine hippocampal cells (HT22) revealed that co-treatment with MGF significantly decreased FA-induced cytotoxicity and inhibited Tau hyperphosphorylation in a dose-dependent manner. It was further found that these protective effects were achieved by attenuating FA-induced endoplasmic reticulum stress (ERS), as indicated by the inhibition of the ERS markers, GRP78 and CHOP, and downstream Tau-associated kinases (GSK-3β and CaMKII) expression. In addition, MGF markedly inhibited FA-induced oxidative damage, including Ca2+ overload, ROS generation, and mitochondrial dysfunction, all of which are associated with ERS. Further studies showed that the intragastric administration of 40 mg/kg/day MGF for 6 weeks significantly improved spatial learning ability and long-term memory in C57/BL6 mice with FA-induced cognitive impairment by reducing Tau hyperphosphorylation and the expression of GRP78, GSK-3β, and CaMKII in the brains. Taken together, these findings provide the first evidence that MGF exerts a significant neuroprotective effect against FA-induced damage and ameliorates mice cognitive impairment, the possible underlying mechanisms of which are expected to provide a novel basis for the treatment of AD and diseases caused by FA pollution.
Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer's disease (AD) have been made and multifarious novel therapeutic approaches have been developed, AD remains an incurable disease. Evidence shows that AD neuropathology occurs decades before clinical presentation. AD is divided into three stages: preclinical stage, mild cognitive impairment (MCI), and AD dementia. In the natural world, some animals, such as non-human primates (NHPs) and canines, can develop spontaneous AD-like dementia. However, most animals do not develop AD. With the development of transgenic techniques, both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods. Most AD research focuses on early-onset familial AD (FAD) because FAD is associated with specific genetic mutations. However, there are no well-established late-onset sporadic AD (SAD) animal models because SAD is not directly linked to any genetic mutation, and multiple environmental factors are involved. Moreover, the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages. This review summarizes the common models used to study AD, from yeast to NHP models, and discusses the different applications, evaluation methods, and challenges related to AD animal models, as well as prospects for the evolution of future studies.
Although methanol toxicity is well known for acute neurological sequelae leading to blindness or death, there is a new impetus to investigate the chronic effects of methanol exposure. These include a recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology. In the present study, mice were fed with methanol to revisit the chronic effects of methanol toxicity, especially as it pertains to AD progression. Three groups of mice (n = 9) were given either water as a control or a methanol solution (concentrations of 2% or 3.8%) over a 6-week period. The methanol-fed mice were found to have impaired spatial recognition and olfactory memory in Y-maze and olfactory memory paradigms. Immunohistochemical analysis of the mouse brains found increased neuronal tau phosphorylation in the hippocampus and an increased cellular apoptotic marker in hippocampal CA1 neurons (~10% of neurons displayed chromatin condensation) in the methanol-fed groups. Two additional in vitro experiments in mouse embryonic cerebral cortex neurons and mouse neuroblastoma N2a cells found that formaldehyde, but not methanol or the methanol end product formic acid, induced microtubule disintegration and tau protein hyperphosphorylation. The findings of the behavioral tests and immunohistochemical analysis suggested that the methanol-fed mice presented with partial AD-like symptoms. The in vitro experiments suggested that formaldehyde was most likely the detrimental component of methanol toxicity related to hippocampal tau phosphorylation and the subsequent impaired memory in the mice. These findings add to a growing body of evidence that links formaldehyde to AD pathology.
Formaldehyde is directly toxic to cells and its intermediate metabolite formic acid leads to acidosis in microenvironment in vivo. According to recent literatures, endogenous formaldehyde production is related to several metabolic pathways such as amine oxidation (catalyzed by semicarbazide-sensitive amine oxidase, SSAO), methylation and demethylation. Under oxidation stress and energy metabolic imbalance, formaldehyde markedly increases in human circulation. Here, the authors found that formaldehyde is released from the reaction of malondialdehyde with a protein (BSA) in which protein side chains such as amino groups are chemically modified. Moreover, formaldehyde is also produced from the sphingomyelin solution in the presence of hydrogen peroxide as the myelin peroxidation occurs. Formaldehyde at low concentration induces neuronal Tau aggregation, resulting in formation of globular like aggregates which are toxic to SH-SY5Y cells, HEK-293 cells and hippocampus neurons in the primary culture. According to Chen et al. (2006), endogenous aldehydes are related to beta-amyloid misfolding, oligomerization and fibrillogenesis. Furthermore, formaldehyde is able to react with some neurotransmitters and thus impairs their structures and functions. Under physiological conditions, the human blood formaldehyde is dynamically kept approximately (0.087±0.004) mmol/L. Notably, this concentration is close to the half-lethal dose of formaldehyde (0.10-0.12 mmol/L) to neural cells in the in vitro cell culture such as SH-SY5Y cells. Furthermore, cell growth can be partially affected and inhibited in the presence of formaldehyde at (0.087 ± 0.004) mmol/L during the in vitro culture. This suggests that human body needs a strong degradation system to remove endogenous formaldehyde. As shown in clinical trials, the formaldehyde level in urine of Alzheimer's patients was markedly higher than the control subjects. The urine formaldehyde level was shown to be related to the cognitive impairment. Therefore, the level of blood (brain) formaldehyde is supposed to be changeable and increased under aging, leading to a higher risk chance to impair human brain, especially under stressing. The formaldehyde chronic damage to neural cells (grey mater) and neural fibers (white mater) may be one of the most important pathological mechanisms for sporadic neurodegeneration for instance Alzheimer's disease, because hypofunction in scavengering endogenous formaldehyde occurs as aging.
Amyloid imaging studies of presymptomatic familial Alzheimer's disease have revealed the striatum and thalamus to be the earliest sites of amyloid deposition. This study aimed to investigate whether there are associated volume and diffusivity changes in these subcortical structures during the presymptomatic and symptomatic stages of familial Alzheimer's disease. As the thalamus and striatum are involved in neural networks subserving complex cognitive and behavioural functions, we also examined the diffusion characteristics in connecting white matter tracts. A cohort of 20 presenilin 1 mutation carriers underwent volumetric and diffusion tensor magnetic resonance imaging, neuropsychological and clinical assessments; 10 were symptomatic, 10 were presymptomatic and on average 5.6 years younger than their expected age at onset; 20 healthy control subjects were also studied. We conducted region of interest analyses of volume and diffusivity changes in the thalamus, caudate, putamen and hippocampus and examined diffusion behaviour in the white matter tracts of interest (fornix, cingulum and corpus callosum). Voxel-based morphometry and tract-based spatial statistics were also used to provide unbiased whole-brain analyses of group differences in volume and diffusion indices, respectively. We found that reduced volumes of the left thalamus and bilateral caudate were evident at a presymptomatic stage, together with increased fractional anisotropy of bilateral thalamus and left caudate. Although no significant hippocampal volume loss was evident presymptomatically, reduced mean diffusivity was observed in the right hippocampus and reduced mean and axial diffusivity in the right cingulum. In contrast, symptomatic mutation carriers showed increased mean, axial and in particular radial diffusivity, with reduced fractional anisotropy, in all of the white matter tracts of interest. The symptomatic group also showed atrophy and increased mean diffusivity in all of the subcortical grey matter regions of interest, with increased fractional anisotropy in bilateral putamen. We propose that axonal injury may be an early event in presymptomatic Alzheimer's disease, causing an initial fall in axial and mean diffusivity, which then increases with loss of axonal density. The selective degeneration of long-coursing white matter tracts, with relative preservation of short interneurons, may account for the increase in fractional anisotropy that is seen in the thalamus and caudate presymptomatically. It may be owing to their dense connectivity that imaging changes are seen first in the thalamus and striatum, which then progress to involve other regions in a vulnerable neuronal network.
Hyperphosphorylation of Tau protein and related neuron death is one of the most important characteristics of Alzheimer's disease. Our laboratory has shown that Tau protein is able to bind and protect DNA. It is still unknown whether phosphorylation affects the binding of Tau to DNA. Therefore, it is of importance to investigate the effect of phosphorylation on the interaction of Tau with DNA in cells. In this work, we treated N2a cells with formaldehyde and found that Tau protein was hyperphosphorylated in the cells under the experimental conditions. Phosphorylation was remarkably observed at both T181 and S396 of Tau protein in the cells in the presence of formaldehyde compared with those in the absence of formaldehyde. Cytoimmunofluorescence hardly showed that most of the nuclear phosphorylated Tau protein was co-localized with DNA, while Tau protein was partially co-localized with DNA in the absence of formaldehyde as control. Electrophoretic mobility shift assay (EMSA) showed that phosphorylated Tau catalyzed by GSK-3 beta reduced the interaction between Tau protein and DNA in vitro. These findings reveal that hyperphosphorylation declines Tau protein to protect DNA, and may thereafter lead to damage of DNA and even cell death, giving a novel viewpoint to the pathology of Alzheimer's disease.
Opiates and dopamine (DA) play key roles in learning and memory in humans and animals. Although interactions between these neurotransmitters have been found, their functional roles remain to be fully elucidated, and their dysfunction may contribute to human diseases and addiction. Here we investigated the interactions of morphine and dopaminergic neurotransmitter systems with respect to learning and memory in rhesus monkeys by using the Wisconsin General Test Apparatus (WGTA) delayed-response task. Morphine and DA agonists (SKF-38393, apomorphine and bromocriptine) or DA antagonists (SKF-83566, haloperidol and sulpiride) were co-administered to the monkeys 30 min prior to the task. We found that dose-patterned co-administration of morphine with D1 or D2 antagonists or agonists reversed the impaired spatial working memory induced by morphine or the compounds alone. For example, morphine at 0.01 mg/kg impaired spatial working memory, while morphine (0.01 mg/kg) and apomorphine (0.01 or 0.06 mg/kg) co-treatment ameliorated this effect. Our findings suggest that the interactions between morphine and dopaminergic compounds influence spatial working memory in rhesus monkeys. A better understanding of these interactive relationships may provide insights into human addiction.
Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and dimethylarginine metabolism (plasma and CSF asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, L-arginine) as well as CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis.
Loss in insight is a major feature of frontotemporal dementia (FTD) but has been investigated relatively little. More importantly, the neural basis of insight loss is still poorly understood. The current study investigated insight deficit profiles across a large cohort of neurodegenerative patients (n ¼ 81), including FTD and Alzheimer's disease (AD) patients. We employed a novel insight questionnaire, which tapped into changes across different domains: social interaction, emotion, diagnosis/treatment, language, and motivation. FTD subtypes varied considerably for insight loss, with the behavioral variant worst and the progressive non-fluent variant least affected. All other subtypes and AD showed milder but consistent insight loss. Voxel-based morphometry analysis revealed that overall insight loss correlated with ventromedial and frontopolar prefrontal atrophy, with exception of social interaction and emotion insight loss, which additionally correlated with lateral temporal and amygdala atrophy, respectively. Our results show that patients with neurodegener-ative conditions show variable loss of insight, with ventromedial and frontopolar cortex regions appearing to be particularly important for insight. Hum Brain Mapp 35:616–626,
Background:
Elevated total plasma homocysteine (tHcy) levels are considered a risk factor for cerebrovascular disease and may also play an important role in the pathogenesis of Alzheimer's disease (AD). High values of plasma tHcy and low levels of vitamin B(12) and folate are frequently present in AD patients. Moreover, the homozygous mutation (C677T) of the methylene tetrahydrofolate reductase (MTHFR) gene, related to a thermolabile type of the encoded enzyme, causes hyperhomocysteinemia by reducing the 5-methyltetrahydrofolate availability.
Objective:
The aim of the study was to investigate plasma levels of folate, vitamin B(12) and tHcy in patients with AD. These values were also related to the severity and the duration of the disease and to the possible role of the MTHFR genotype (C677T).
Method:
Plasma tHcy levels, homozygosity for the C677T mutation of the MTHFR gene, and folate and vitamin B(12) plasma levels were evaluated in 74 patients with AD (45 men, 29 women, mean age 68 years) and in 74 healthy matched controls (42 men, 32 women, mean age 68 years).
Results:
AD patients had higher mean (+/- SD) plasma levels of tHcy (20.9 +/- 15 micromol/l compared to 11.8 +/- 5 micromol/l, p < 0.001) and lower mean plasma folate (5.7 +/- 2.1 ng/ml compared to 8.5 +/- 3.2 ng/ml, p < 0.001) and vitamin B(12) (491 +/- 144 pmol/l compared to 780 +/- 211 pmol/l, p < 0.001) concentrations. Homozygosity for the C677T mutation of the MTHFR gene had a similar prevalence among controls (18%) and AD patients (20%). Homozygous AD patients (n = 15) had higher plasma tHcy values than nonhomozygotes, in spite of similar mean plasma folate and vitamin B(12) levels. This difference in plasma tHcy levels was not observed in controls. Patients with levels of plasma tHcy above and of plasma folate below the normal limits were more frequent in the homozygous AD group. The duration of the disease correlated with plasma levels of tHcy (r = +0.832, p < 0.001), plasma folate (r = -0.580, p < 0.05), and vitamin B(12) (r = -0.460, p < 0.05). However, when all the data were corrected for age, serum creatinine levels, and duration of the disease, mean plasma tHcy, folate, and vitamin B(12) levels were not statistically different between controls and AD patients.
Conclusions:
Our data suggest that rather than a risk factor for AD, hyperhomocysteinemia is related to its progression and increasing severity. This might be particularly relevant in homozygotes for the C677T mutation of the MTHFR gene and supports the possible need for continuous supplements in this setting.
Alzheimer's disease (AD) is a major cause of functional dependence, poor quality of life, institutionalization, and mortality among elderly people. As a multifactorial disorder, AD has been frequently linked to vascular risk factors (e.g., smoking, hypertension, obesity, diabetes, hyperlipidemia, and inflammation) in numerous prospective cohort studies of the general population. Systematic reviews and meta-analyses of prospective studies have from the life-course perspective revealed an age-dependent association with the risk of AD for several vascular risk factors such as high blood pressure, obesity, and high total cholesterol, such that possessing these factors in mid-life, but not necessarily in late-life, is associated with an increased risk of AD. The biological plausibility for vascular risk factors to be involved in the pathogenesis and clinical manifestation of Alzheimer syndrome is partly supported by population-based neuroimaging and neuropathological studies. However, randomized controlled trials that target those major cardiovascular risk factors (e.g., antihypertensive, cholesterol-lowering, and anti-inflammatory therapies) have generally failed to prove as efficacious preventative approaches for AD. To bridge the gap, the multifactorial nature of AD and the proper time-window for intervention should be taken into account in the future when designing preventative interventions against the devastating disorder.