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.     

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.     

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.     

Plasticity in Early Alzheimer's Disease: An Opportunity for Intervention

The scientific evidence of plasticity, or the brain's dynamic ability to alter its organization and activation throughout one's lifetime, has increased significantly over the last decade. This analytic review evaluates selected evidence regarding the persistence of plasticity in people with early-stage Alzheimer's disease (AD). Functional neuroimaging provides persuasive evidence of plasticity throughout aging as well as the early stages of dementia, including the possibility of a heightened response during the prodromal period of AD. Behavioral outcomes research demonstrates the ability of people with early-stage AD to relearn previously forgotten information or otherwise improve cognitive abilities following a cognition-focused intervention. Both of these bodies of evidence support the existence of compensatory processes at work, even in the presence of dementia-related pathology. This retained ability of the brain to adapt to neurodegenerative disease in an attempt to maintain function may provide a valuable opportunity for intervention, particularly in the prodromal or earliest stages of AD.     

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.     

When spacing out brings clarity. Mental lapses serve as diagnostic clue for type of dementia

NEW YORK CITY--Everyone has slow-witted moments: entering a room only to forget why, putting ice cream into the fridge, or blanking out on how to use the microwave. Some clinicians think that periodic mental lapses might help diagnose dementia with Lewy bodies (DLB), a scourge that kills brain cells (see DLB Case Study), although not all experts agree. Now, scientists have found that some cognitive blunders crop up more frequently in patients with DLB than in those with Alzheimer's disease (AD) or in healthy elderly individuals, according to work presented here on 15 January 2004 at an American Medical Association briefing for media.     

Does the prevention of brain ageing constitute anti-ageing medicine? Outline of a new space of representation for Alzheimer's Disease

In this paper we pose the question: Does the prevention of brain ageing constitute anti-ageing medicine? We answer the question by looking at recent changes in the knowledge and organisational structure of dementia research, practice and policy and investigating the boundary relations between this disease-specific field and anti-ageing medicine. Drawing on a qualitative study of the ways in which different clinical and scientific constituencies work to define, organise and negotiate the boundaries between normal and abnormal cognitive aging, we suggest that the field of dementia research, practice and policy has experienced internal diversification forming a ‘new space of representation'. We show how this space is structured by two axes: one that relates to how AD is conceptualised and another that concerns the modes of intervention or actions that will prevent the condition in individuals or populations. We argue that while these changes have blurred the epistemic boundaries between dementia and other fields of research, there are still strong institutional, economic and political factors that glue the field together.     

Neuropathology in Alzheimer's disease: awaking from a hundred-year-old dream

For one hundred years after Alois Alzheimer's first report of Alzheimer's disease (AD) in 1906, the pathological hallmarks of the disease, senile plaques and neurofibrillary tangles (NFTs), have been attractive targets for researchers. Therefore, not surprisingly, efforts to understand disease mechanisms have concentrated on the cell biology of amyloid-beta (Abeta) deposition as senile plaques or on the phosphorylation and aggregation of tau as NFTs. However, it now appears that this focus on pathology as a central contributor to disease may be misguided. Indeed, neurons associated with Abeta and NFTs in AD brain show a decrease in oxidative damage relative to those in vulnerable but morphologically intact areas of the brain, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. That Abeta and tau accumulations indicate an age-related physiological reaction to chronic stress calls into question the rationale of current therapeutic efforts targeted toward lesion removal. Moreover, if this concept holds true for pathology in other neurodegenerative diseases, we may need to restructure our thinking and undergo a paradigm shift before substantial progress can be made in therapeutic intervention.     

Understanding the placebo effect. Part 2: underlying psychological & neurobiological processes

Placebo and nocebo effects are interesting and complex phenomena. In this article, I discuss some findings about the psychological and neurobiological processes that may underlie these effects on the basis of studies of pain, Parkinson's disease, and depression. From a psychological perspective, expectancy and conditioning theories have been used to explain placebo and nocebo effects. These psychological processes may be translated into physiological effects through overlapping brain circuits that are important for cognitive information processing, analgesia, and reward expectations. These brain circuits may represent a fundamentally important common underlying pathway that mediates placebo and nocebo effects in many conditions. Understanding these effects is important for designing clinical treatment studies and interpreting their results and is highly relevant for clinical practices.     

Androgens, apoE, and Alzheimer's disease

Increasing evidence indicates that there are reductions in estrogen and androgen levels in aged men and women. These hormonal reductions might be risk factors for cognitive impairments and the development of Alzheimer's disease (AD). Aged people show improved cognition after treatments with sex steroids. Therefore, ongoing clinical AD trials have been designed to evaluate the potential benefits of estrogen therapy in women and testosterone therapy in men. Apolipoprotein E (apoE) plays an important role in the metabolism and redistribution of lipoproteins and cholesterol. The three major human apoE isoforms, apoE2, apoE3, and apoE4, differ in their effects on AD risk and pathology. Here I review various mechanisms proposed to mediate the differential effects of apoE isoforms on brain function and highlight the potential contribution of detrimental isoform-dependent effects of apoE on androgen- and androgen receptor (AR)-mediated pathways. I also discuss potential interactions of androgens with other AD-related factors.     

Cognitive impairment and effects on upper body strength of adults with dementia

The purpose of this investigation was to examine the association between cognitive ability and upper body muscle strength. Two sources of existing data were pooled for this examination. Thirty-eight older participants diagnosed with Alzheimer's disease or dementia (25 women, 13 men; age = 83.2 +/- 5.6 years, MMSE score = 16.75 +/- 7.04, M +/- SD) underwent an assessment of grip strength via handheld dynamometry. Multiple-regression analysis indicated that cognitive status was a significant predictor of strength and, when combined in a model with age and sex, explained 57% of the between-individuals variance in handgrip strength. The findings from this exploratory investigation suggest that dementia is associated with strength loss, a key contributor to functional disability; this further justifies efforts to investigate mechanisms responsible for this decay and to preserve muscle integrity by integrating physical activity interventions, notably, muscle strengthening, into the lifestyle of adults with dementia.     

Brain tumor-associated dementia

In this case study, we describe a patient with a dementia due to a brain tumor. This unusual cause of dementia illustrates the importance of a thorough evaluation of anyone who experiences relatively sudden changes in cognitive functions. The disorder had features common to other dementias but also had some unusual attributes that made a diagnosis of neurodegenerative disease less likely. Common features included intellectual decline involving difficulties in word-finding, the occurrence of paraphasia, poor concentration, disorientation in familiar environments, problems performing routine complex tasks, and elements of social withdrawal. Unlike more common degenerative dementias, however, there was no marked memory involvement. In addition, the onset of illness was rapid and associated with headaches, incontinence, and some gait and motor dysfunction.     

An integrated dementia intervention for Korean older adults

Called dotage in Korea, dementia is primarily characterized by cognitive impairments. Secondary manifestations include mental-emotional problems, including depression. This study was designed to examine the effects of an integrated dementia intervention for Korean older adults. The intervention is composed of cognitive stimulation training, exercise, music, art, and horticultural therapy. Participants included 38 older adults with mild dementia. Twenty were assigned to the experimental group and 18 to the control group. Participants in the experimental group attended 18 program sessions. Significant differences were found postintervention between the two groups in measures of cognitive function, depression levels, and mental-emotional health. The findings indicate that this integrated dementia intervention can be applied to help older adults with mild dementia.     

Asian Americans and Alzheimer's disease: Assimilation,culture, and beliefs

Because most successful interventions for Alzheimer's disease (AD) rely upon early diagnosis and implementation, it is important to understand the factors influencing dementia treatment-seeking behaviors. These include perceptions, beliefs, values, and feelings relating to AD, which may vary among and within ethnic groups according to the strength of culturally-based explanatory models and individual group members' ages and experiences. This study used ten focus groups drawn from Asian American communities representing different national origins (Chinese, Japanese, and Korean) to examine the factors shaping attitudes toward AD in general, and treatment-seeking in particular, that may constitute barriers to timely diagnosis and treatment of AD among Asian Americans of various ages and cultural backgrounds. The results suggest that, while these communities share a keen awareness of AD, beliefs regarding the disorder may be influenced at least as strongly by folk wisdom and culturally acceptable partial truths as by scientific information.     

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.     

Cognitive,social, and neural determinants of diminished decision-making and financial exploitation risk in aging and dementia: A review and new model

ABSTRACT

In this article we will briefly review how changes in brain and in cognitive and social functioning, across the spectrum from normal to pathological aging, can lead to decision-making impairments that increase abuse risk in many life domains (e.g., health care, social engagement, financial management). The review will specifically focus on emerging research identifying neural, cognitive, and social markers of declining financial decision-making capacity in older adults. We will highlight how these findings are opening avenues for early detection and new interventions to reduce exploitation risk.     

Numerical Reasoning Ability and Irrational Beliefs in Problem Gambling

Numerous studies have shown that pathological gamblers are particularly prone to various cognitive biases that may explain why they continue to gamble despite having occurred substantial losses. A common explanation advanced to account for this finding is that pathological gamblers may have poorer numerical or statistical knowledge than other people. Addressing these deficits is therefore seen as one possible way in which to assist pathological gamblers or prevent the development of problematic behaviour within the broader community. The aim of this study was test this assumption by assessing the numerical reasoning skills, objective gambling knowledge and tendency towards biased reasoning in a sample of 90 regular poker-machine gamblers (pathological and non-pathological) and a non-gambling comparison group (n = 45). Analyses based on both group comparisons and regression analyses controlling for differences in educational attainment showed that pathological gamblers scored significantly higher on the cognitive biases measure than other gamblers. However, this difference could not be attributed to poorer knowledge of gambling odds or limited numerical ability among pathological gamblers. The findings suggest that educating pathological gamblers with greater knowledge about the odds of gambling is unlikely to be an effective harm minimisation strategy.     

Alzheimer's disease,neuropeptides, neuropeptidase,and amyloid-beta peptide metabolism

Amyloid-beta peptide (Abeta), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We have focused our attention and effort on elucidating the unresolved aspect of Abeta metabolism: proteolytic degradation. Among a number of Abeta-degrading enzyme candidates, we used a novel in vivo paradigm to identify a member of the neutral endopeptidase family, neprilysin, as the major Abeta catabolic enzyme. Neprilysin deficiency results in defects in the metabolism of endogenous Abeta 40 and 42 in a gene dose-dependent manner. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Abeta accumulation. Moreover, we discuss the fact that an aging-dependent decline of neprilysin activity, which leads to elevation of Abeta concentrations in the brain, is a natural process that precedes AD pathology. In this Perspective, we hypothesize that neprilysin down-regulation has a role in sporadic AD (SAD) pathogenesis, and we propose that this knowledge be used for developing preventive and therapeutic strategies through use of a G protein-coupled receptor (GPCR).     

Effects of motor practice on cognitive disorders in older adults

The demographics of our societies have changed drastically during the past few decades. The general population is aging rapidly as human life spans continue to expand and more adults are set to mature during the next quarter century. This aging process has numerous implications for the way we live and will have particularly important impacts on health and healthcare. In particular, substantial evidence suggests that cognitive–motor function deteriorates considerably as the result of inactive life style, biological aging, and cognitive impairments. The number of individuals with Alzheimer's disease (AD), an aging-related cognitive disorder, is expected to increase significantly during the next 40 years. The development of mild cognitive impairment (MCI) or AD can exaggerate the functional declines observed in cognitive or motor performance. The functional declines affect an array of social, cognitive, mental, physical, and motor activities in our daily lives. However, recent studies suggest that cognitive, physical, motor practice, or skill learning can improve motor speed, smoothness, and accuracy in both MCI and AD patients and their age-matched healthy peers. From theoretical and practical perspectives, this paper addresses several critical aspects of motor deficits and the kinematical characteristics of motor skill development in MCI and AD populations. Empirical data will be presented relative to the sensory–motor functions of MCI and AD, the motor skill acquisition, exercise rehabilitation in older adults with memory loss, as well as the implications for therapies. Finally, this review concludes with thoughts and suggestions for future research in these areas.     

The genetic connections of Alzheimer's disease: An emerging source of caregiver stress

The purpose of this study was to expand and refine current theoretical conceptualization of dementia caregiving by identifying and analyzing new potential sources of stress. A qualitative analysis of unsolicited letters (N=51) written by family caregivers of persons diagnosed with Alzheimer's disease (AD) was conducted. Content analysis of the data confirmed that providing care for persons diagnosed with AD could impart emotional, physiological, and financial stress on caregivers. The data also revealed an emerging source of stress for family caregivers—fears and uncertainties regarding possible genetic connections between family caregivers and relatives suffering from AD. These results strongly suggest that concerns with genetic connections should be included in theoretical models of stress and dementia caregiving. Implications include the need for increased dissemination of information regarding genetic connections and AD, as well as increased support for family members if and when genetic connections are discovered.