Neurodegeneration in normal brain aging and disease

Normal "healthy" aging is defined as aging without disease. Many aged people do not exhibit symptoms of disease and lead normal lives, but nonetheless display pathological changes that are characteristic of Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and/or cerebrovascular disease (CVD). These changes are restricted to distinct brain regions and might represent preclinical stages of these disorders. This Perspective discusses arguments in favor of and against the hypothesis that pathological changes related to AD, PD, DLB, and CVD in the brains of nondemented elderly people represent early stages of these diseases rather than healthy aging. We conclude that early pathological disease-related changes do indeed constitute the beginning of AD, PD, DLB, and CVD rather than normal concomitants of aging, even in the absence of any clinical symptoms. Aging is, therefore, a major risk factor for these diseases but does not necessarily lead to age-related diseases.     

Mitochondrial abnormalities and oxidative imbalance in neurodegenerative disease

An increasing body of evidence now suggests the involvement of mitochondrial abnormalities in the etiology of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer disease. In this Perspective, we describe a recent study that shows that treatment of human patients with the antioxidant coenzyme Q(10'), which functions in concert with certain mitochondrial enzymes, reduced the worsening of symptoms associated with PD. These findings are consistent with the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of PD and that treatments that target mitochondrial biochemistry might ameliorate the functional decline observed in patients suffering from PD.     

Amyotrophic lateral sclerosis

In this case study, we describe the symptoms, neurological examination, and pathology of a woman with amyotrophic lateral sclerosis (ALS). ALS is a rare disorder leading to degeneration of the voluntary motor system and death in, on average, 3 to 4 years. The loss of motor neurons in the brain and spinal cord causes the progressive symptoms of muscular weakness, atrophy, fasciculation (muscle twitching), spasticity, and hyperreflexia. Signs of disease in both upper and lower motor neurons are required for a definitive clinical diagnosis. Pathology shows degeneration of the lateral corticospinal tracts, loss of motor neurons and astrogliosis in the brain and brain stem, and neuronal inclusions. This case was marked by the onset of weakness and muscle atrophy in the hand, which spread to involve contiguous muscle segments. Cognition, the extraocular muscles, and the urinary sphincters were spared. Respiratory muscle weakness was a late manifestation.     

Dementia with cerebrovascular disease

In this case study, we review the symptoms, cognitive testing, brain imaging, and brain pathology of a woman with dementia, for whom the neuropathological findings suggest a prominent contribution of cerebrovascular disease. Vascular dementia is the term commonly used for persons with dementia resulting from strokes, either clinically evident or subclinical "silent" events. "Mixed dementia" is the term used when there is an admixture of pathological findings related to Alzheimer's disease (AD) and cerebrovascular disease, as in this situation. In some cases of mixed dementia, the pathological involvement of AD may be the principal contributory cause of the cognitive symptoms, and in others, the vascular changes may give the greater contribution.     

Prevalence of Problem and Pathological Gambling in Parkinson’s Disease

Pathological gambling (PG) has been identified in patients with Parkinson’s disease (PD) treated with dopamine agonists suggesting that dysregulation of brain dopaminergic activity may contribute to the development of gambling problems. The current study was undertaken to further establish the prevalence of problem and PG in patients with PD, identify any clinical correlates, and determine if psychiatric or substance use co-morbidity contributes to the increased prevalence of problem and PG. A cross-sectional survey of 140 serially recruited moderate to severe PD patients was undertaken utilizing the Canadian Problem Gambling Index, Alcohol Use Disorders Identification Test, Drug Abuse Screening Test, Beck Depression Inventory, Beck Anxiety Inventory, and Mini-Mental State Exam augmented by chart review, completed over an 8 month period. The 12 month prevalence of problem and PG in PD was 9.3% compared to 1.6% in the general population within a comparably aged sample. The increased prevalence of problem and PG in the PD group was related to dopamine agonist use and younger age, but not co-morbidity. Most subjects with problem and PG reported their gambling increased after being diagnosed with PD and starting treatment. The results suggest that brain dopaminergic activity is involved in the underlying neurobiology of problem and PG.     

Frontotemporal dementia

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with frontotemporal dementia (FTD). FTD most often presents with either a change in personality or behavior, such as social withdrawal, increased gregariousness, disinhibition, or obsessive behaviors; or with impairment of language function. Memory difficulties are common, but usually are less prominent than these other symptoms in the early stages of the disease. Frequently, psychiatric diagnoses are initially the primary consideration. Cases may be either familial or sporadic. In this familial case, an autopsy was ultimately performed and revealed findings characteristic of FTD, with grossly evident focal brain degeneration in the frontal and temporal regions, microscopic signs of gliosis, and cellular abnormalities of the intracellular microtubule-associated protein tau.     

Huntington's disease

In this case study, we describe the symptoms, neurological exam, neuropsychological test results, and brain pathology of a man who died with Huntington's disease (HD). HD is a rare neurodegenerative disease. Like other movement disorders involving the basal ganglia, HD affects motor, cognitive, and psychiatric functioning. The disease follows an autosomal dominant pattern of inheritance, with onset of symptoms most commonly occurring in the late 30s or early 40s, as in this patient. HD is caused by an unstable expansion of the trinucleotide CAG, coding for glutamine, on chromosome 4. Despite knowledge of the gene mutation responsible for HD, no definitive treatment is currently available to slow or halt progression of the disease. However, symptomatic treatment can significantly improve the quality of life for patients with HD.     

Monitoring proteins in intact cells

In the past decade, tremendous progress has been made in understanding the molecular mechanisms that underlie many neurodegenerative disorders, and common aspects of the pathological processes that lead to neuronal cell death have emerged. Nearly all of these advances have come from genetic, molecular, and biochemical studies that point to alterations in protein folding or protein-protein interactions as the fundamental mechanism behind these disorders. New microscopy/imaging technologies for detecting protein-protein interactions are now poised to contribute to progress in this field. Here we describe a novel technique based on fluorescence resonance energy transfer, called fluorescence lifetime imaging microscopy (FLIM), which allows monitoring of protein conformation and protein-protein interactions in intact cells. For example, using FLIM, we have studied the interaction of two proteins related to Alzheimer's disease: amyloid precursor protein (APP) and presenilin (PS-1). By measuring the lifetime of a donor fluorophore linked to PS-1, we show, with high subcellular resolution, localization of the PS-1-APP interaction within neurons. This approach may have widespread applicability in studies of neurodegenerative disease mechanisms.     

Cortical basal ganglionic degeneration

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a retired mason's assistant with cortical basal ganglionic degeneration (CBGD). CBGD is an extremely rare neurodegenerative disease that is categorized under both Parkinsonian syndromes and frontal lobe dementias. It affects men and women nearly equally, and the age of onset is usually in the sixth decade of life. CBGD is characterized by Parkinson's-like motor symptoms and by deficits of movement and cognition, indicating focal brain pathology. Neuronal cell loss is ultimately responsible for the neurological symptoms.     

Impact of Drugs and Alcohol on the Brain Through the Life Cycle

Abstract

This article discusses the impact of alcohol and other drugs on the brain during five stages of the life cycle: perinatal (pregnancy-2 years), childhood (2-12 years), adolescence (13-21), adulthood (22-50), and senior (50+). Alcohol and psychotropic drugs act through specific chemicals in the brain called neurotransmitters. Neurotransmitters have two main functions in the brain: mediate electrical transmission (synaptic activity) and promote growth (trophic activity). The trophic activity results in a neuron increasing its size and the complexity of its branches (dendrites). The ability of drugs and alcohol to influence neuronal growth (neuroplasticity) has unique consequences in children, adults, and seniors. Knowledge of such biological principles as developmental critical period, age-related cortical shrinkage and steroid-induced neuronal growth is presented in the context of alcohol and other drug abuse. A few suggestions are made for developing new treatment strategies based on the inherent dynamics of the brain during the life cycle.     

Dementia with lewy bodies

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with dementia with Lewy bodies. Dementia with Lewy bodies might be the second most common form of degenerative dementia in the elderly. Progressive cognitive decline, well-formed visual hallucinations, and parkinsonism are core features of this disease. This case was marked by preserved verbal expression despite impairment in memory, visuospatial skills, and attention span. Development of visual symptoms and parkinsonism occurred very early in the course of the disease.     

Cyclin-dependent kinase 5--a neuronal killer?

In dividing cells, cyclin-dependent kinases (Cdks) are cell cycle-associated protein kinases that regulate proliferation, differentiation, senescence, and apoptosis. In neurons that no longer divide, deregulation of Cdks, especially Cdk5, occurs in many neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Cdk5 is a unique member of the Cdk family because it does not play a critical role in cell cycle progression, and it is not activated by a cyclin. Instead, Cdk5 normally is activated by the regulatory protein p35. This Cdk5/p35 activity has emerged as an important regulator of proper development of the mammalian central nervous system. In vitro studies suggest that aberrant activation of Cdk5 by an endogenous truncated version (p25) of p35 might be a key event in the process of neurodegeneration. One enzyme responsible for cleavage of p35 to form p25 is calpain, a calcium-activated protease that has been shown to be involved in neuronal cell death. Recent studies provided important in vivo evidence that hyperactivation and redistribution of Cdk5 by p25 plays an essential role in the phosphorylation of "pathological" substrates (such as tau) and the cell death of neurons in experimental models of AD and PD. Because amyloid beta peptide, the primary neurotoxic component of amyloid plaques in AD, has been shown to increase the conversion of p35 to p25, aberrant activation of Cdk5 by p25 might be a pathway connecting amyloid beta toxicity to tau hyperphosphorylation in AD.     

Targeting the role of the endosome in the pathophysiology of Alzheimer's disease: a strategy for treatment

Membrane-bound endosomal vesicles play an integral role in multiple cellular events, including protein processing and turnover, and often critically regulate the cell-surface availability of receptors and other plasma membrane proteins in many different cell types. Neurons are no exception, being dependent on endosomal function for housekeeping and synaptic events. Growing evidence suggests a link between neuronal endosomal function and Alzheimer's disease (AD) pathophysiology. Endosomal abnormalities invariably occur within neurons in AD brains, and endocytic compartments are one likely site for the production of the pathogenic beta-amyloid peptide (Abeta), which accumulates within the brain during the disease and is generated by proteolytic processing of the amyloid precursor protein (APP). The enzymes and events involved in APP processing are appealing targets for therapeutic agents aimed at slowing or reversing the pathogenesis of AD. The neuronal endosome may well prove to be the intracellular site of action for inhibitors of beta-amyloidogenic APP processing. We present here the view that knowledge of the endosomal system in the disease can guide drug discovery of AD therapeutic agents.     

A children, teachers and designers as evaluators of usability of educational software

This article sets out to discuss the results of evaluations of usability made by children, teachers and designers through methods targeted on their profiles and contexts of use. Based on a survey of methods for evaluating usability, a field study was conducted in which such users--stakeholders--explored the educational software called "Mundo da Crian?a" ("Child's World"). The focus of this study was the analysis of this system and principally of the appropriateness of methods as to the avenues they suggest such users and contexts might explore.     

Alzheimer's disease

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with Alzheimer's disease (AD). AD commonly presents with impairment of memory and language function. In this case, language difficulties were noted more prominently than was memory impairment. Throughout the limbic system and neocortex of the patient were large numbers of senile plaques and neurofibrillary tangles, the pathological hallmarks of AD.     

Effectiveness of water-based exercise in people living with Parkinson’s disease: a systematic review

This systematic review summarizes the relatively scant literature concerning the effectiveness of water-based exercise (WBE) interventions in people with Parkinson’s disease (PD). Databases MEDLINE, EMBASE, PEDro, Scopus, and SportDiscus were searched from the earliest available date to December 2011. Studies had to meet the following selection criteria: (1) the target population was patients with PD; (2) the effects of a WBE intervention (as the primary intervention) were tested; (3) the abstract of the research was available in English. Selected studies were subject to unmasked quality assessment by applying a methodological scoring with a possible maximum score of 15 points. Twelve studies met the inclusion criteria, although only three of them achieved a methodological quality score above 10 points. Collectively, the data showed that WBE has some beneficial short-term effects on the impact that PD has on the patients (mainly on their motor symptoms and on their functional mobility), as well as on their quality of life. This review provides evidence that WBE is safe for patients with PD, but there is a lack of hard evidence regarding its beneficial effects. Further randomized and controlled trials with larger sample sizes are required.     

Innate immunity, local inflammation, and degenerative disease

The brain lesions associated with Alzheimer's disease (AD), which are referred to as neurofibrillary tangles and senile plaques, are characterized by the presence of a broad spectrum of inflammatory mediators. Surprisingly, these mediators, which include complement proteins, inflammatory cytokines, prostaglandins, and acute phase reactants such as C-reactive protein and amyloid P, are produced by resident brain cells, including neurons. Although secondary to the fundamental pathology caused by the presence of tangles and plaques, there is strong evidence that inflammation exacerbates the neuronal loss. In particular, AD lesions show evidence of self-attack by the complement system--a part of the immune system that normally functions to rid the body of invading pathogens. However, the lesions are devoid of significant T cell infiltration, a hallmark of an inflammatory immune response, and antibodies. We define this phenomenon as autotoxicity to distinguish it from classical autoimmunity, in which the body raises antibodies to normal endogenous macromolecules. Locally produced inflammatory mediators have also been identified in atherosclerotic plaques, along with evidence of complement self-attack. As was previously shown for heart attacks, epidemiological evidence indicates that extended use of nonsteroidal anti-inflammatory drugs (NSAIDs) results in a reduced risk of AD. NSAIDs inhibit the production of prostaglandin inflammatory mediators, but powerful new therapeutic agents might be developed by targeting more critical inflammatory mechanisms, especially the complement system.     

Management of Parkinson's disease in older women

Elderly women with Parkinson's disease (PD) represent a specific patient population that may benefit from individualized treatment strategies. PD has been shown to occur approximately twice as often in men than in women, resulting in theories regarding estrogen being protective against the disease and as a potential treatment strategy. Given women's longer life expectancy, they are more likely to reach an age where antiparkinsonian medications are associated with side-effects. This paper will review medical and surgical treatments as well as the relationship of gender and age with respect to the management of PD.     

Neural transplants for parkinson’s disease: what are the issues?

Parkinson’s disease (PD) is a common neurodegenerative disorder of the nervous system that affects about 1 in 800 people and for which we have symptomatic but not curative therapies. At the core of the disease is the loss of a specific population of dopaminergic neurons within the brain, and replacement of dopamine through drug therapies has provided clinically significant benefit for many patients. However this therapy only ever offers a temporary amelioration of symptoms and with time this symptomatic therapy becomes less efficacious and produces its own unique side-effects. As a result more effective curative therapies have been sought, including the use of cell based therapies to replace the lost dopaminergic neurons. In this review I am going to discuss PD and its possible repair using neural transplants. In particular I am going to discuss which type of cells are best considered as a reparative therapy, where they should be transplanted in the brain, when in the disease course and in which type of patient. By considering these issues, I hope to be able to make some recommendations as to the future use of this approach in PD.

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Zusammenfassung Morbus Parkinson (MP) ist eine verbreitete neurodegenerative Erkrankung des Nervensystems, die etwa einen unter 800 Menschen befällt und für die nur symptomatische, aber keine heilenden Therapien bekannt sind. Den Kern der Krankheit bildet der Verlust einer spezifischen Population dopaminerger Neuronen innerhalb des Gehirns. Dopaminersatz durch Medikationen hat daher bei vielen Patienten klinisch signifikanten Nutzen gezeigt. Solche Therapie bietet jedoch nur vorübergehende Linderung von Symptomen, und mit der Zeit verliert diese symptomatische Therapie immer mehr an Wirksamkeit und ruft ihre eigenen spezifischen Nebenwirkungen hervor. Folglich sucht man nach effektiveren kurativen Therapien, darunter auch Zelltherapien, zur Ersetzung der verlorenen dopaminergen Neuronen. In diesem Übersichtsartikel werden MP und seine mögliche Behebung mittels neuraler Transplantate diskutiert. Insbesondere wird darauf eingegangen, welche Zelltypen am besten als reparative Therapiezellen in Betracht gezogen werden sollten, wo im Gehirn sie zu transplantieren wären, in welcher Phase der Krankheit und bei welchem Patiententyp. Ziel dieser Betrachtungen ist die mögliche Formulierung von Empfehlungen hinsichtlich der zukünftigen Nutzung dieses Therapieansatzes für MP.

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Résumé La maladie de Parkinson (MP) est une affection neurodégénérative très répandue du système nerveux, qui touche environ une personne sur 800 et pour laquelle existent des traitements symptomatiques, mais pas de traitements curatifs. Au cœur de la maladie, il y a la disparition d’une population spécifique de neurones dopaminergiques dans le cerveau. Le remplacement médicamenteux de la dopamine s’est par conséquent avéré très bénéfique du point de vue clinique pour de nombreux patients. De telles thérapies n’apportent toutefois qu’un apaisement passager des symptômes, et la thérapie symptomatique perd de plus en plus de son efficacité avec le temps, et finit par ne plus provoquer que ses propres effets secondaires. On recherche par conséquent des thérapies curatives plus efficaces, dont des thérapies cellulaires visant à remplacer les neurones dopaminergiques détruits. Cet article récapitulatif se penche sur la MP et les réparations éventuellement possibles au moyen de transplants neuraux. Il s’interroge en particulier sur les types de cellules pouvant être envisagés pour une thérapie cellulaire réparatrice, sur le lieu de transplantation dans le cerveau, sur la phase de la maladie indiquée pour cette intervention et sur le type de patients approprié. Le but de ces observations est de formuler certaines recommandations sur l’utilisation future de cette approche de la MP.

     

Tai Chi-based exercise for older adults with Parkinson's disease: a pilot-program evaluation

The primary objective of this study was to provide preliminary evaluation of the feasibility, safety, and efficacy of a newly developed Tai Chi-based exercise program for older adults with Parkinson's disease (PD). Using a one-group pretest-posttest design, 17 community-dwelling adults (mean age 71.51 years) with mild to moderate idiopathic PD (Stage I, II, or III on the Hoehn and Yahr scale) and stable medication use completed a 5-day, 90-min/day Tai Chi exercise-evaluation program. Outcome measures included face-to-face exit interviews on appropriateness and safety and physical performance (i.e., 50-ft speed walk, up-and-go, functional reach). At the end of this brief intervention, exercise adherence was 100% and the program was shown to be safe. Exit interviews indicated that the program was well received by all participants with respect to program appropriateness, participant satisfaction and enjoyment, and intentions to continue. Furthermore, a significant pretest-to-posttest change was observed at the end of the 5-day program in all three physical-performance measures (p < .05). The results of this pilot evaluation suggest that Tai Chi is an appropriate physical activity for older adults with PD and might also be useful as a therapeutic exercise modality for improving and maintaining physical function. These preliminary findings warrant further investigation.