Beta-Amyloid Deposition and the Aging Brain

A central issue in cognitive neuroscience of aging research is pinpointing precise neural mechanisms that determine cognitive outcome in late adulthood as well as identifying early markers of less successful cognitive aging. One promising biomarker is beta amyloid (Aβ) deposition. Several new radiotracers have been developed that bind to fibrillar Aβ providing sensitive estimates of amyloid deposition in various brain regions. Aβ imaging has been primarily used to study patients with Alzheimer’s Disease (AD) and individuals with Mild Cognitive Impairment (MCI); however, there is now building data on Aβ deposition in healthy controls that suggest at least 20% and perhaps as much as a third of healthy older adults show significant deposition. Considerable evidence suggests amyloid deposition precedes declines in cognition and may be the initiator in a cascade of events that indirectly leads to age-related cognitive decline. We review studies of Aβ deposition imaging in AD, MCI, and normal adults, its cognitive consequences, and the role of genetic risk and cognitive reserve.     

Le vieillissement cognitif et l’hypothèse de l’exercice mental révisée

Although intuitively plausible, the evidence relevant to the mental exercise hypothesis is currently mixed. One of the main controversial issues concerning the investigation of this hypothesis has to do with how cognitive stimulation is assessed. The mental exercise hypothesis was here tested with a subjective and self-reported measure of cognitive stimulation. Overall, results have supported that a greater engagement in cognitively stimulating activities was associated with higher levels of cognitive functioning. However, the rate of cognitive decline with advancing age was not reduced for people who were more mentally active. Of great interest, the subjective measure of cognitive engagement have supported that cognitive demands assessed by participants on activities varied as a function of participants’ cognitive resources: lower cognitive resources were associated with lower perceived cognitive demands.     

Influence of education on the pattern of cognitive deterioration in AD patients: the cognitive reserve hypothesis

The cognitive reserve hypothesis proposes that a high educational level could delay the clinical expression of Alzheimer's disease (AD) although neuropathologic changes develop in the brain. Therefore, some studies have reported that when the clinical signs of the disease emerge, high-educated patients may decline more rapidly than low-educated patients because the neuropathology is more advanced. However, these studies have only investigated the decline of global cognition or an isolated cognitive process. To study the differential deterioration pattern of several cognitive processes according to education, the performance of 20 AD patients with a high educational level and a low educational level were compared with the performance of 20 control subjects on a neuropsychological battery. The results showed that cognitive deterioration of AD patients is different according to education, although the global performance was similar in AD patients. The high-educated patients exhibited greater impairment of abstract thinking whereas the low-educated patients showed greater impairment of memory and attentional function. This confirms that some cognitive processes, such as abstract thinking, decline more rapidly in high-educated patients whereas others seem to evolve more slowly if compared to low-educated patients. In this latter case, high-educated patients may still benefit from cognitive reserve after the diagnosis of the dementia.     

Neuropsychological Characteristics of Dementia with Lewy Bodies and Parkinson’s Disease with Dementia: Differentiation, Early Detection, and Implications for “Mild Cognitive Impairment” and Biomarkers

Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are neurodegenerative conditions sharing a disorder of α-synuclein metabolism. Temporal differences in the emergence of symptoms and clinical features warrant the continued clinical distinction between DLB and PDD. While DLB and PDD groups’ neuropsychological profiles often differ from those in Alzheimer’s disease (AD), the diagnostic sensitivity, specificity, and predictive values of these profiles remain largely unknown. PDD and DLB neuropsychological profiles share sufficient similarity to resist accurate and reliable differentiation. Although heterogeneous cognitive changes (predominantly in memory and executive function) may manifest earlier and more frequently than previously appreciated in Parkinson’s disease (PD), and executive deficits may be harbingers of dementia, the enthusiasm to uncritically extend the concept of mild cognitive impairment (MCI) to PD should be tempered. Instead, future research might strive to identify the precise neuropsychological characteristics of the prodromal stages of PD, PDD, and DLB which, in conjunction with other potential biomarkers, facilitate early and accurate diagnosis, and the definition of neuroprotective, neurorestorative, and symptomatic treatment endpoints.     

Lifespan brain activity, β-amyloid, and Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of progressive cognitive decline and dementia in adults. While the amyloid cascade hypothesis of AD posits an initiating role for the β-amyloid (Aβ) protein, there is limited understanding of why Aβ is deposited. A growing body of evidence based on in vitro, animal studies and human imaging work suggests that synaptic activity increases Aβ, which is deposited preferentially in multimodal brain regions that show continuous levels of heightened activation and plasticity across the lifespan. Imaging studies of people with genetic predispositions to AD are consistent with these findings, suggesting a mechanism whereby neural efficiency or cognitive reserve may diminish Aβ deposition. The aggregated findings unify observations from cellular and molecular studies with human cognitive neuroscience to reveal potential mechanisms of AD development.     

Early Detection of Memory Impairment in Alzheimer’s Disease: A Neurocognitive Perspective on Assessment

We propose that the earliest neuropsychological detection of Alzheimer’s disease (AD) can be informed by current views about the neuropathogenesis of AD and cognitive models of memory and its neurobiological substrates. The primary impairment in early AD is encoding/consolidation, resulting from medial temporal lobe (MTL) pathology. On theoretical and empirical grounds, paired associate learning (PAL) appears to be the ideal paradigm for detecting MTL dysfunction in early AD. It has not been embraced as a test of choice, however, and this critical review discusses why the paradigm may have not fulfilled its potential. We suggest that a new PAL variant, ‘associate-recognition’, may prove to be clinically efficacious.     

Review of Interventions to Improve Family Engagement and Retention in Parent and Child Mental Health Programs

Engaging and retaining families in mental health prevention and intervention programs is critically important to insure maximum public health impact. We evaluated randomized-controlled trials testing methods to improve family engagement and retention in child mental health programs published since 1980 (N = 17). Brief, intensive engagement interventions in which providers explicitly addressed families’ practical (e.g. schedules, transportation) and psychological (e.g. family members’ resistance, beliefs about the treatment process) barriers as they entered treatment were effective in improving engagement in early sessions. The few interventions found to produce long-term impact on engagement and retention integrated motivational interviewing, family systems, and enhanced family stress and coping support strategies at multiple points throughout treatment. Few interventions have been tested in the context of prevention programs. There are promising approaches to increasing engagement and retention; they should be replicated and used as a foundation for future research in this area.     

Multiple combinations of co-factors produce variants of age-related cognitive decline: a theory.

A theory concerning the etiology of age-related cognitive decline, like Alzheimer's disease (AD), is presented. The view utilizes the idea that this form of dementia is a etiologically complex and heterogeneous brain disorder that is caused by various co-factors. A particular patient with AD would have some combination of these co-factors present but the exact type and combinations might be different from another patient. This theory could also be used to explain other forms of dementia and age-related cognitive decline and the differences in severity of memory impairments associated with each. The co-factors in the present model include genes, neurotransmitter changes, vascular abnormalities, stress hormones, circadian rhythms, head trauma, and seizures.     

Community Engagement to Facilitate,Legitimize and Accelerate the Advancement of Nanotechnologies in Australia

There are increasing calls internationally for the development of regulation and policies related to the rapidly growing nanotechnologies sector. As part of the process of policy formation, it is widely accepted that deliberative community engagement processes should be included, enabling publics to have a say about nanotechnologies, expressing their hopes and fears, issues and concerns, and that these will be considered as part of the policy process. The Australian Federal and State governments have demonstrated a commitment to these ideals, undertaking a number of public engagement activities in recent years. However, despite promises that these community engagement activities will enable policy makers to identify complex and contested community attitudes, and that these will be included as part of the policy making process, a closer look at Australia’s engagement activities reveals something quite different. Through an analysis of a number of Australia’s nano-engagement activities, this paper demonstrates the limits of public engagement related to the development of nanotechnology related policies and regulation in Australia. Our analysis reveals the extent to which industry interests have captured policy makers and regulators, dissenting voices have been excluded from engagement processes, and engagement processes have not connected with actual policy making activities. Reflecting on these limits, this paper concludes with recommendations for improving public engagement processes related to nanotechnologies in Australia.     

Eyeblink classical conditioning differentiates normal aging from Alzheimer’s disease

Eyeblink classical conditioning is a useful paradigm for the study of the neurobiology of learning, memory, and aging, which also has application in the differential diagnosis of neurodegenerative diseases expressed in advancing age. Converging evidence from studies of eyeblink conditioning in neurological patients and brain imaging in normal adults document parallels in the neural substrates of this form of associative learning in humans and non-human mammals. Age differences in the short-delay procedure (400 ms CS-US interval) appear in middle age in humans and may be caused at least in part by cerebellar cortical changes such as loss of Purkinje cells. Whereas the hippocampus is not essential for conditioning in the delay procedure, disruption of hippocampal cholinergic neurotransmission impairs acquisition and slows the rate of learning. Alzheimer’s disease (AD) profoundly disrupts the hippocampal cholinergic system, and patients with AD consistently perform poorly in eyeblink conditioning. We hypothesize that disruption of hippocampal cholinergic pathways in AD in addition to age-associated Purkinje cell loss results in severely impaired eyeblink conditioning. The earliest pathology in AD occurs in entorhinal cortical input to hippocampus, and eyeblink conditioning may detect this early disruption before declarative learning and memory circuits become impaired. A case study is presented in which eyeblink conditioning detected impending dementia six years before changes on other screening tests indicated impairment. Because eyeblink conditioning is simple, non-threatening, and non-invasive, it may become a useful addition to test batteries designed to differentiate normal aging from mild cognitive impairment that progresses to AD and AD from other types of dementia.     

The duality principle: irreducibility of sub-threshold psychophysical computation to neuronal brain activation

A key working hypothesis in neuroscience is ‘materialistic reductionism’, i.e., the assumption whereby all physiological, behavioral or cognitive phenomena is produced by localized neurochemical brain activation (but not vice versa). However, analysis of sub-threshold Weber’s psychophysical stimulation indicates its computational irreducibility to the direct interaction between psychophysical stimulation and any neuron/s. This is because the materialistic-reductionistic working hypothesis assumes that the determination of the existence or non-existence of any psychophysical stimulation [s] may only be determined through its direct interaction [di1] with a given neuron/s [N] that together forms the ‘neural registry’ computational level [NR/di1]. But, this implies that in cases of (initial) sub-threshold (sensory-specific) psychophysical stimulation which is increased above the sensory-specific threshold but below Weber’s psychophysical ‘dv’—the psychophysical computational processing [PCP] produces an apparently ‘computationally indeterminate’ output. This is because materialistic reductionism asserts the contingency of PCP upon the existence of a direct interaction between ‘s’ and ‘N’ within the NR/di1 level, but in the special case of Weber’s sub-threshold psychophysical stimulation the same PCP/di1 also asserts the non-existence of ‘s’ (as demanded by Weber’s psychophysical law). However, given robust empirical evidence indicating the capability of PCP to determine whether (or not) ‘s’ exists, we must conclude that PCP may not be carried out from within NR’s direct interaction between a particular psychophysical stimulation and any set of neuron/s in the brain. Hence, the Duality Principle asserts the conceptual irreducibility of sub-threshold psychophysical stimulation to any direct NR/di1: s-N interaction, thereby challenging the current materialistic-reductionistic assumption.     

Youth belonging and cognitive engagement in organized activities: A large-scale field study

Numerous studies of organized activities have found that participation is associated with a range of positive outcomes; however, findings from recent randomized trials have been more mixed. Understanding youth's psychological experiences of program involvement – their cognitive and emotional reaction to and participation in activities – may be key to understanding the influence of organized activities. Hierarchical linear modeling was used to investigate correlates of youth belonging and cognitive engagement in a sample of 1160 youth in 123 program offerings in 66 sites. Results revealed that intensity (frequency) of exposure positively predicted belonging and cognitive engagement; however, duration was negatively associated with cognitive engagement. The staff practice of providing a welcoming atmosphere predicted belonging; whereas provision of active skill-building predicted cognitive engagement. These relations were found to vary across content type.     

Category Cued Recall Following Controlled Encoding as a Neuropsychological Tool in the Diagnosis of Alzheimer’s Disease: A Review of the Evidence

Aim of the present review paper was to evaluate the hypothesis (included in the proposal of new research criteria for Alzheimer’s disease; Dubois et al., Lancet Neurology, 6, 734–746, 2007) that a neuropsychological tool which provides support for the semantic encoding of memorandum at the time of study and supplies category cues at the time of retrieval (i.e. the Grober-Buschke paradigm) is more effective than traditional measures of free recall in 1) differentiating patients affected by the amnestic form of Mild Cognitive Impairment (MCI) or by mild to moderate forms of Alzheimer’s disease (AD) from healthy matches, 2) predicting the conversion of individuals with MCI to AD, and 3) differentiating AD patients from individuals affected by other forms of dementia. Results of the review are controversial regarding the superiority of the Grober-Buschke procedure in differentiating individuals affected by AD or MCI from healthy individuals. The only study that evaluated this issue directly found that the Grober-Buschke procedure was more sensitive and specific than more traditional memory tests in predicting the conversion of MCI patients to AD. Finally, two studies reported that patients affected by AD or other forms of dementia showed different performance patterns in the free and cued recall tasks of the Grober-Buschke procedure. In conclusion, although encouraging results are reported in the few studies that investigated the ability of this procedure to predict the evolution of individuals with amnestic MCI and to differentiate AD patients from patients with other forms of cortical and subcortical dementia, more experimental work is needed to confirm these positive findings.     

Issues Involving Informed Consent for Research Participants with Alzheimer’s Disease

Alzheimer’s disease is the most common form of dementia which is estimated to impact 350,000 people over 65 years of age in Canada. The lack of effective treatment and the growing number of people who are expected to be diagnosed with Alzheimer’s disease in the near future are compelling reasons why continued research is in this area is necessary. With additional research, there needs to be greater recognition of the complexity of seeking ongoing informed consent from those with Alzheimer’s disease. This complexity is because the impairment of memory and cognitive ability does not diminish in a linear manner, but rather fluctuates between periods of impairment and relatively normal cognitive lucidness. There is limited discussion in the guidelines of those progressing from early stages of Alzheimer’s disease who have intermittent cognitive function. Guidelines to research and Research Ethics Boards require further development to facilitate researcher including those with Alzheimer’s disease while protecting this growing pool of potential participants.     

Semantic Fluency Performance of Patients with Cortical and Subcortical Neurodegenerative Diseases

Previous studies using the Animals Fluency Test have shown that dementia patients with Alzheimer's disease (AD), Huntington's disease (HD), or Parkinson's disease (PD) produce fewer correct words and have smaller semantic cluster sizes than controls or PD patients without dementia (PDND). Although the number of correct words generated by the patients with AD was positively correlated with mental status, cluster size, surprisingly, was not. To increase word output and increase the reliability of estimates of cluster size, semantic fluency was reexamined using the Supermarket Fluency Task. Overall, patients with HD or PD with dementia (PDD) exhibited reduced cluster sizes compared to older controls or PDND patients, but cluster sizes were only marginally reduced for patients with AD. These effects were evident only for female participants, because the cluster sizes for elderly control men were substantially smaller than those of elderly women. For the female patients with AD, cluster size was correlated with mental status, but the relationship was nonlinear. Cluster size was normal for mildly demented patients with AD, but much reduced for moderately or severely demented participants. In contrast to a previous report, in the present study the proportion of category labels generated was increased for patients with HD with dementia but not for patients with AD. This finding questions one line of evidence that semantic memory stores undergo “bottom-up” degradation in AD. Together with previous results, these findings indicate that semantic cluster size reflects efficiency of access to semantic knowledge which is similarly compromised in subcortical and cortical diseases.     

Neuropsychological Contributions to the Early Identification of Alzheimer’s Disease

A wealth of evidence demonstrates that a prodromal period of Alzheimer’s disease (AD) exists for some years prior to the appearance of significant cognitive and functional declines required for the clinical diagnosis. This prodromal period of decline is characterized by a number of different neuropsychological and brain changes, and reliable identification of individuals prior to the development of significant clinical symptoms remains a top priority of research. In this review we provide an overview of those neuropsychological changes. In particular, we examine specific domains of cognition that appear to be negatively affected during the prodromal period of AD, and we review newer analytic strategies designed to examine cognitive asymmetries or discrepancies between higher-order cognitive functions versus fundamental skills. Finally, we provide a critical examination of the clinical concept of Mild Cognitive Impairment and offer suggestions for an increased focus on the impact of cerebrovascular disease (CVD) and CVD risk during the prodromal period of AD.     

常态脑老化认知功能障碍及相关代谢机制研究进展

常态脑老化（NBA ）是老年期痴呆的首要危险因素,与病态性脑老化有相似的病理基础,但并不完全相同。虽然单一的“脑老化”因素并不足以成为导致老年期痴呆的独立原因,但脑老化状态确实使得大脑对外界负性刺激的敏感性增加,进而使老年人更容易发生认知障碍。阿尔茨海默病等老年痴呆症状的治疗方面尚无逆转的方法,而是重在预防。因此,我们将重点放在痴呆发生之前更早的阶段---常态脑老化阶段,就常态脑老化状态下与认知功能障碍的表现、发生机理及代谢相关机制进行综述,旨在为早期寻找措施防止老年期痴呆性认知功能下降提供理论基础。     

活动参与在认知损害中的延缓作用

认知损害有关的病理机制、危险因素研究由来已久,但尚未找到有效治疗认知损害的途径,认知损害的保护性因素研究进而成为研究者们关注的热点。前人的研究显示活动参与对认知损害具有积极的影响,可能是认知损害的重要保护性因素,但活动参与对认知损害的影响机制以及各活动之间存在的交互作用仍不明确。未来的研究可着重探讨不同活动类型及其交互作用同认知损害的关系,并分析活动参与对认知损害起保护作用的公共因子。     

Motor-Skill Learning in Alzheimer’s Disease: A Review with an Eye to the Clinical Practice

Since elderly people suffering from dementia want to go on living independently for as long as possible, they need to be able to maintain familiar and learn new practical skills. Although explicit or declarative learning methods are mostly used to train new skills, it is hypothesized that implicit or procedural techniques may be more effective in this population. The present review discusses 23 experimental studies on implicit motor-skill learning in patients with Alzheimer’s disease (AD). All studies found intact implicit motor-learning capacities. Subsequently, it is elaborated how these intact learning abilities can be exploited in the patients’ rehabilitation with respect to the variables ‘practice’ and ‘feedback.’ Recommendations for future research are provided, and it is concluded that if training programs are adjusted to specific needs and abilities, older people with AD are well able to (re)learn practical motor skills, which may enhance their autonomy.