Clinicopathological overlap of neurodegenerative diseases: A comprehensive review

Clinical and neuropathological overlap of two or more neurodegenerative diseases (ND) is not an uncommon occurrence yet is still underdiagnosed in clinical neurological and neuropathological. The authors present a clinicopathological overview of the current understanding of overlapping ND’s with the hope that this review will encourage further studies that are required to investigate the effect of such overlaps on clinical presentations and how often clinical presentations raise the suspicion of multiple ND’s. The authors suggest that as more patients with overlapping ND’s come to light, traditional classification system of ND’s may need to be modified.     

Neural basis of interpersonal traits in neurodegenerative diseases

Several functional and structural imaging studies have investigated the neural basis of personality in healthy adults, but human lesions studies are scarce. Personality changes are a common symptom in patients with neurodegenerative diseases like frontotemporal dementia (FTD) and semantic dementia (SD), allowing a unique window into the neural basis of personality. In this study, we used the Interpersonal Adjective Scales to investigate the structural basis of eight interpersonal traits (dominance, arrogance, coldness, introversion, submissiveness, ingenuousness, warmth, and extraversion) in 257 subjects: 214 patients with neurodegenerative diseases such as FTD, SD, progressive nonfluent aphasia, Alzheimer's disease, amnestic mild cognitive impairment, corticobasal degeneration, and progressive supranuclear palsy and 43 healthy elderly people. Measures of interpersonal traits were correlated with regional atrophy pattern using voxel-based morphometry (VBM) analysis of structural MR images. Interpersonal traits mapped onto distinct brain regions depending on the degree to which they involved agency and affiliation. Interpersonal traits high in agency related to left dorsolateral prefrontal and left lateral frontopolar regions, whereas interpersonal traits high in affiliation related to right ventromedial prefrontal and right anteromedial temporal regions. Consistent with the existing literature on neural networks underlying social cognition, these results indicate that brain regions related to externally focused, executive control-related processes underlie agentic interpersonal traits such as dominance, whereas brain regions related to internally focused, emotion- and reward-related processes underlie affiliative interpersonal traits such as warmth. In addition, these findings indicate that interpersonal traits are subserved by complex neural networks rather than discrete anatomic areas.     

Developmental neuroplasticity and the origin of neurodegenerative diseases

Objectives. Neurodegenerative diseases like Alzheimer's and Parkinson's Disease, marked by characteristic protein aggregations, are more and more accepted to be synaptic disorders and to arise from a combination of genetic and environmental factors. In this review we propose our concept that neuroplasticity might constitute a link between early life challenges and neurodegeneration. Methods. After introducing the general principles of neuroplasticity, we show how adverse environmental stimuli during development impact adult neuroplasticity and might lead to neurodegenerative processes. Results. There are significant overlaps between neurodevelopmental and neurodegenerative processes. Proteins that represent hallmarks of neurodegeneration are involved in plastic processes under physiological conditions. Brain regions – particularly the hippocampus – that retain life-long plastic capacities are the key targets of neurodegeneration. Neuroplasticity is highest in young age making the brain more susceptible to external influences than later in life. Impacts during critical periods have life-long consequences on neuroplasticity and structural self-organization and are known to be common risk factors for neurodegenerative diseases. Conclusions. Several lines of evidence support a link between developmental neuroplasticity and neurodegenerative processes later in life. A deeper insight into these processes is necessary to design strategies to mitigate or even prevent neurodegenerative pathologies.     

Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases

Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considerable amounts in the skin of grapes, raspberries, mulberries, pistachios and peanuts, and by at least 72 medicinal and edible plant species in response to stress conditions. It was isolated in 1940 and did not maintain much interest for around five decades until its role in treatment of cardiovascular diseases was suggested. To date, resveratrol has been identified as an agent that may be useful to treat cancer, pain, inflammation, tissue injury, and other diseases. However, currently the attention is being focused in analyzing its properties against neurodegenerative diseases and as antiaging compound. It has been reported that resveratrol shows effects in in vitro models of epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and nerve injury. However, evidences in vivo as well as in human beings are still lacking. Thus, further investigations on the pharmacological effects of resveratrol in vivo are necessary before any conclusions on its effects on neurodegenerative diseases can be obtained.     

Microtubule-associated protein tau gene: a risk factor in human neurodegenerative diseases

Tau is a microtubule-associated protein mainly expressed in neurons of central nervous system, which is crucial in the maintenance of these cells. It has a central role in the polymerization and stabilization of microtubules and in the traffic of organelles along axons and dendrites. Aggregates of hyperphosphorylated forms of tau protein participate in the formation of neurofibrillary tangles, which characterize numerous neurodegenerative disorders named tauopathies. The analysis of tau gene and the study of familial cases of tauopathies have led to the discovery of tau gene mutations that cause inherited dementia designated as Frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17). However, these familial cases remain rare compared to the sporadic tauopathies, the later involving both genetic and environmental etiologic factors. As tau pathology represents a primary pathogenic event in various neurodegenerative diseases, the hypothesis that tau genotype could influence the development of these diseases was tested by several groups. This review summarizes advances in the molecular genetics of the tau gene, as well as recent studies addressing the disease incidence of novel tau polymorphisms in different neurodegenerative diseases. Hopefully, the identification of several genetic defects of the tau gene will be helpful in improving our understanding of the role of tau protein in the pathogenesis of various neurodegenerative diseases.     

经颅超声技术在抑郁症及神经变性疾病伴抑郁中的应用

本文目的是对经颅超声技术(TCS)在抑郁症及神经变性疾病伴抑郁中的应用进行综述,以期为抑郁症及神经变性疾病伴抑郁的临床诊断提供新的方向。TCS在抑郁症患者可表现中缝低回声,在神经变性疾病伴抑郁患者中也出现了特异性表现。本文对TCS在抑郁症及神经变性疾病伴抑郁中的应用进行探讨。     

Final common pathways in neurodegenerative diseases: regulatory role of the glutathione cycle

Attempts to unify diverse mechanisms of neurotoxicity have led to the concept of final common pathways which characterize frequently occurring cellular responses to disruption of homeostasis. The clinical presentation and common patho-biochemistry of reactive oxygen intermediates of Guam's disease have suggested that such pathways may be operative in three major neurodegenerative disorders: Alzheimer's dementia, amyotrophic lateral sclerosis and Parkinson's disease. A candidate-signaling pathway in this regard is characterized by the cascade arachidonic acid/HPETE/^·OH/cGMP followed by activation of cGMP-dependent kinase and phosphorylation of NF-kB proteins and possibly CREB. This sequence may lead to apoptosis as well as long-term potentiation and memory and constitutes a biochemical correlate to excitotoxicity. The predominant control of ^·OH release from HPETE, a checkpoint in this pathway, is exerted by the glutathione cycle, a central biochemical process that is also intimately associated with the synthesis of the neurotransmitters glutamate and GABA and is connected to energy metabolism. Modifications in the activity of the glutathione cycle may provide treatment options.     

Atrophy in two attention networks is associated with performance on a Flanker task in neurodegenerative disease

This study investigated the neurobiological basis of attentional control dysfunction in neurodegenerative disease by determining the effect of regional brain atrophy on Flanker task performance of neurodegenerative patients. We hypothesized that atrophy in DLPFC and ACC would be significantly associated with decreased attentional control performance on the Flanker task. We used voxel-based morphometry (VBM) to measure the relationship between MRI measures of regional grey matter atrophy and performance on a version of the Flanker task, measured by accuracy and response time. Sixty-five subjects participated, including patients with frontotemporal dementia, Alzheimer's disease, mild cognitive impairment, non-fluent progressive aphasia, corticobasal degeneration, progressive supranuclear palsy, semantic dementia, and healthy controls. Accuracy measures of attentional control and response time measures of attentional control were associated with two different patterns of regional atrophy across subjects. First, there was an association between left hemisphere DLPFC and ACC atrophy and poorer attentional control accuracy. Second, right hemisphere temporal-parietal junction (TPJ) and ventrolateral prefrontal cortex (VLPFC) and DLPFC atrophy were associated with slower response times during attentional control on accurate trials, which may reflect emergent involvement due to deficits in the DLPFC-ACC network.     

The neuroprotective effects of caffeine in neurodegenerative diseases

Caffeine is the most widely used psychostimulant in Western countries, with antioxidant, anti‐inflammatory and anti‐apoptotic properties. In Alzheimer's disease (AD), caffeine is beneficial in both men and women, in humans and animals. Similar effects of caffeine were observed in men with Parkinson's disease (PD); however, the effect of caffeine in female PD patients is controversial due to caffeine's competition with estrogen for the estrogen‐metabolizing enzyme, CYP1A2. Studies conducted in animal models of amyotrophic lateral sclerosis (ALS) showed protective effects of A_2AR antagonism. A study found caffeine to be associated with earlier age of onset of Huntington's disease (HD) at intakes >190 mg/d, but studies in animal models have found equivocal results. Caffeine is protective in AD and PD at dosages equivalent to 3‐5 mg/kg. However, further research is needed to investigate the effects of caffeine on PD in women. As well, the effects of caffeine in ALS, HD and Machado‐Joseph disease need to be further investigated. Caffeine's most salient mechanisms of action relevant to neurodegenerative diseases need to be further explored.     

Cerebral peduncle angle: Unreliable in differentiating progressive supranuclear palsy from other neurodegenerative diseases

IntroductionThe significant symptom overlap between progressive supranuclear palsy (PSP) and other parkinsonian neurodegenerative diseases frequently results in misdiagnosis. However, neuroimaging can be used to quantify disease-related morphological changes and specific markers. The cerebral peduncle angle (CPA) has been shown to differentiate clinically diagnosed PSP from other parkinsonian diseases but this result has yet to be confirmed in autopsy-proven disease.MethodsMagnetic resonance imaging (MRI) scans were obtained for 168 patients representing 69 medical facilities. Following randomization, the images were divided into two groups (Type 1 and Type 2) based upon midbrain morphological differences. Two readers were blinded and independently measured the CPA of 146 patients with autopsy-proven progressive supranuclear palsy (PSP; n = 54), corticobasal degeneration (n = 16), multiple system atrophy (MSA; n = 11) and Lewy body disease (n = 65).ResultsApplying two separate measurement techniques revealed no statistically significant differences in CPA measurements among any study groups regardless of classification measurement approach. The interobserver agreement showed significant differences in measurements using the Type 2 approach.ConclusionMeasuring the CPA on MRI is not a reliable way of differentiating among patients with PSP, corticobasal degeneration, MSA, or Lewy body disease.     

快速眼动睡眠期行为障碍与神经变性病发病机制研究进展

快速眼动睡眠期行为障碍系指快速眼动睡眠期肌肉失弛缓,并出现梦境(通常是暴力梦境)相关肢体运动(梦境演绎行为)。其人群发病率为0.38%~2.01%,在神经变性病尤其是α-突触核蛋白病患者中的发病率明显增加。快速眼动睡眠期行为障碍可早于α-突触核蛋白病数十年出现,因此可以作为预测神经变性病的早期标记。本文拟就近年来关于快速眼动睡眠期行为障碍发病机制及其与神经变性病之间的关系进行简要综述。     

Sodium cyanate alters glutathione homeostasis in rodent brain: relationship to neurodegenerative diseases in protein-deficient malnourished populations in Africa

Sodium cyanate, a neurotoxic chemical in rodents, primates and humans, is implicated in neurodegenerative disorders in protein-deficient populations subsisting in parts of Africa on the cyanogenic plant cassava. The molecular and cellular mechanisms of cyanate neurotoxicity are not understood. This study investigates the effect of sodium cyanate on glutathione (GSH) homeostasis in rodent brain and liver in vitro and in vivo. GSH levels in mouse brain were rapidly, time- and dose-dependently decreased following intraperitoneal administration of 100, 200 or 300 mg/kg sodium cyanate. By contrast, GSH disulfide (GSSG) levels were increased and GSH/GSSG ratios were decreased in a dose-dependent manner in rat brain. Sodium cyanate depleted GSH levels in all regions of mouse brain. Brain glutathione reductase activity was dose-dependently inhibited, while glutathione peroxidase activity was not affected by sodium cyanate. The disruption of GSH homeotasis, as evidenced by reduced tissue GSH/GSSG ratios, likely results from cyanate-induced inhibition of glutathione reductase activity. The results of this study suggest that cyanate neurotoxicity, and perhaps cassava-associated neurodegenerative diseases, are mediated in part by disruption of glutathione homeostasis in neural tissue.     

Zebrafish as a model for investigating developmental lead (Pb) neurotoxicity as a risk factor in adult neurodegenerative disease: A mini-review

Lead (Pb) exposure has long been recognized to cause neurological alterations in both adults and children. While most of the studies in adults are related to higher dose exposure, epidemiological studies indicate cognitive decline and neurobehavioral alterations in children associated with lower dose environmental Pb exposure (a blood Pb level of 10 μg/dL and below). Recent animal studies also now report that an early-life Pb exposure results in pathological hallmarks of Alzheimer's disease later in life. While previous studies evaluating higher Pb exposures in adult animal models and higher occupational Pb exposures in humans have suggested a link between higher dose Pb exposure during adulthood and neurodegenerative disease, these newer studies now indicate a link between an early-life Pb exposure and adult neurodegenerative disease. These studies are supporting the “fetal/developmental origin of adult disease” hypothesis and present a new challenge in our understanding of Pb neurotoxicity. There is a need to expand research in this area and additional model systems are needed. The zebrafish presents as a complementary vertebrate model system with numerous strengths including high genetic homology. Several zebrafish genes orthologous to human genes associated with neurodegenerative diseases including Alzheimer's and Parkinson's diseases are identified and this model is starting to be applied in neurodegenerative disease research. Moreover, the zebrafish is being used in developmental Pb neurotoxicity studies to define genetic mechanisms of toxicity and associated neurobehavioral alterations. While these studies are in their infancy, the genetic and functional conservation of genes associated with neurodegenerative diseases and application in developmental Pb neurotoxicity studies supports the potential for this in vivo model to further investigate the link between developmental Pb exposure and adult neurodegenerative disease pathogenesis. In this review, the major factors influencing the pathogenesis of neurodegenerative diseases, Pb neurotoxicity, the developmental origin of adult disease paradigm, and the zebrafish as a model system to investigate the developmental origin of low-dose Pb-induced neurodegenerative diseases is discussed.     

Chronic peripheral inflammation: a possible contributor to neurodegenerative diseases

The contribution of chronic peripheral inflammation to the pathogenesis of neurodegenerative diseases is an outstanding question. Sustained activation of the peripheral innate and adaptive immune systems occurs in the context of a broad array of disorders ranging from chronic infectious diseases to autoimmune and metabolic diseases. In addition, progressive systemic inflammation is increasingly recognized during aging. Peripheral immune cells could potentially modulate the cellular brain environment via the secretion of soluble molecules. There is an ongoing debate whether peripheral immune cells have the potential to migrate into the brain under certain permissive circumstances. In this perspective, we discuss the possible contribution of chronic peripheral inflammation to the pathogenesis of age-related neurodegenerative diseases with a focus on microglia, the resident immune cells of the brain parenchyma.