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.     

Cognitive Functioning in Aging and Dementia: The Kungsholmen Project

The Kungsholmen Project (KP) is a community-based longitudinal study of aging and dementia targeting the 75+ population. In this article, we review empirical studies with a cognitive focus from the KP. The main findings indicate that (a) there is an age-related decline for some cognitive domains (e.g., episodic memory, verbal fluency, visuoconstructive skill, psychomotor speed), but not for others (e.g., primary memory, visuoperceptive skill, motor-hand coordination), (b) multiple individual-difference variables within demographic (e.g., sex, education) life-style (e.g., activity levels), genetic (e.g., apolipoprotein E genotype), and health-related (e.g., vitamin B deficiency, depression, diabetes) domains are related to late-life cognitive functioning, (c) a potential for improving cognitive performance – a reserve capacity – is present also among very old adults, (d) the 2 most common dementia diseases, Alzheimer’s disease (AD) and vascular dementia (VaD), affect cognition in a strikingly similar manner, (e) the role of individual-difference variables in cognitive functioning is markedly reduced in dementia – the pathogenesis itself may overshadow the influence of other variables, and (f) there is a long preclinical period in dementia during which cognitive deficits are detectable. As is true with the other projects represented in this issue, the KP portrays a rather diversified picture of cognitive aging, although systematic patterns are evident with regard to the variability of late-life cognitive functioning.     

Action‐semantic and syntactic deficits in subjects at risk for Huntington's disease

Frontostriatal networks play critical roles in grounding action semantics and syntactic skills. Indeed, their atrophy distinctively disrupts both domains, as observed in patients with Huntington's disease (HD) and Parkinson's disease, even during early disease stages. However, frontostriatal degeneration in these conditions may begin up to 15 years before the onset of clinical symptoms, opening avenues for pre‐clinical detection via sensitive tasks. Such a mission is particularly critical in HD, given that patients’ children have 50% chances of inheriting the disease. Against this background, we assessed whether deficits in the above‐mentioned domains emerge in subjects at risk to develop HD. We administered tasks tapping action semantics, object semantics, and two forms of syntactic processing to 18 patients with HD, 19 asymptomatic first‐degree relatives, and sociodemographically matched controls for each group. The patients evinced significant deficits in all tasks, but only those in the two target domains were independent of overall cognitive state. More crucially, relative to controls, the asymptomatic relatives were selectively impaired in action semantics and in the more complex syntactic task, with both patterns emerging irrespective of the subjects’ overall cognitive state. Our findings highlight the relevance of these dysfunctions as potential prodromal biomarkers of HD. Moreover, they offer theoretical insights into the differential contributions of frontostriatal hubs to both domains while paving the way for innovations in diagnostic procedures.     

Person-specific paths of cognitive decline in Alzheimer's disease and their relation to age

Change in global and specific measures of cognitive function was studied in a cohort of 410 persons with Alzheimer's disease. Persons completed up to 5 annual evaluations; follow-up participation among survivors exceeded 90%. Average annual decline was 0.57 standard score units (95% confidence interval [CI]: -0.51 to -0.62) on a composite measure based on 17 individual tests and 3.26 points (95% CI: -3.06 to 3.46) on the Mini-Mental State Examination, but substantial heterogeneity was apparent. On both global and specific measures, rate of cognitive decline was reduced in older persons compared with younger persons. A similar effect was observed for estimated age of disease onset. The effect of age was approximately linear and was not attributable to education, sex, race, other conditions that impair cognition, or mortality. The results indicate that person-specific paths of cognitive decline in Alzheimer's disease vary substantially and suggest that in clinical settings some of this variability is related to age.     

Productive syntax abilities in Huntington's and Parkinson's diseases

This study examined syntactic changes in the spoken discourse of patients with Huntington's (HD) or Parkinson's disease (PD) and explored possible relationships between their syntactic changes and concomitant cognitive and motoric symptoms. Patient and control groups participated in a conversational discourse activity and completed a battery of standardized speech and cognitive tests. The HD group used shorter and fewer grammatically complete utterances than their healthy, age-matched peers, whereas there were no significant syntactic differences between PD patients and their healthy, age-matched peers or between PD and HD patients. Productive syntax abilities in HD and PD were meaningfully related to both neuropsychological and motor speech changes. These findings indicate that patients with subcortical disease, at least those with HD, may present with language production deficits and that these deficits are most likely the product of not only motor speech limitations (i.e., dysarthria) but also underlying cognitive impairments.     

A stop-signal task for sheep: introduction and validation of a direct measure for the stop-signal reaction time

Huntington’s disease (HD) patients show reduced flexibility in inhibiting an already-started response. This can be quantified by the stop-signal task. The aim of this study was to develop and validate a sheep version of the stop-signal task that would be suitable for monitoring the progression of cognitive decline in a transgenic sheep model of HD. Using a semi-automated operant system, sheep were trained to perform in a two-choice discrimination task. In 22% of the trials, a stop-signal was presented. Upon the stop-signal presentation, the sheep had to inhibit their already-started response. The stopping behaviour was captured using an accelerometer mounted on the back of the sheep. This set-up provided a direct read-out of the individual stop-signal reaction time (SSRT). We also estimated the SSRT using the conventional approach of subtracting the stop-signal delay (i.e., time after which the stop-signal is presented) from the ranked reaction time during a trial without a stop-signal. We found that all sheep could inhibit an already-started response in 91% of the stop-trials. The directly measured SSRT (0.974 ± 0.04 s) was not significantly different from the estimated SSRT (0.938 ± 0.04 s). The sheep version of the stop-signal task adds to the repertoire of tests suitable for investigating both cognitive dysfunction and efficacy of therapeutic agents in sheep models of neurodegenerative disease such as HD, as well as neurological conditions such as attention deficit hyperactivity disorder.     

Movement abnormalities and the progression of prodromal symptomatology in adolescents at risk for psychotic disorders

The link between movement abnormalities and psychotic disorders is presumed to reflect common neural mechanisms that influence both motor functions and vulnerability to psychosis. The prodromal period leading to psychotic disorders represents both a viable point for intervention and a developmental period that, if studied, could shed light on etiology; however, no published studies have examined the temporal progression of this link. A group with high levels of prodromal symptomatology (i.e., adolescents with schizotypal personality disorder [SPD]; n = 42) and both psychiatric controls (with other personality disorders or conduct disorder [OD]; n = 30) and nonpsychiatric controls ([NC]; n = 49) were recruited. Videotapes of structured psychiatric interviews were coded for movement abnormalities by raters blind to participants' diagnostic status, and follow-up assessments were conducted 1 year later. Controlling for psychotropic medications, the authors found that adolescents with SPD exhibited significantly more motor abnormalities in the face and upper body than did OD and NC controls. At baseline, movement abnormalities were positively correlated with the severity of positive, negative, and total prodromal symptoms. Within the SPD group, baseline movement abnormalities predicted symptom severity 1 year later. Movement abnormalities represent an early risk indicator that may be predictive of later symptom severity and potentially of psychosis onset.     

The Early Presentation of Dementia in People with Down Syndrome: a Systematic Review of Longitudinal Studies

Adults with Down syndrome (DS) are at a very high risk of developing early onset Alzheimer’s disease (AD) due to trisomy of chromosome 21. AD is preceded by a prolonged prodromal “pre-clinical” phase presenting with clinical features that do not fulfil the diagnostic criteria for AD. It is important to clinically characterise this prodromal stage to help early detection of the disease as neuropathology of AD is almost universal by the fifth decade in DS. There is a lack of knowledge of the trajectory of decline associated with the onset of dementia in this population and early signs may be overlooked or misdiagnosed, negatively affecting the quality of life of those affected and the use of early pharmacological or psychosocial interventions. The objective of this systematic review is to evaluate the published literature on longitudinal data in order to identify the cognitive and behavioural changes occurring during the prodromal and early stages of AD in this population. Fifteen peer-reviewed articles met the inclusion criteria, including a total number of 831 participants, with the duration between baseline and follow up varying from 1 year to 47 years. Results suggest that, compared to the general population for which short-term (episodic) memory loss is the most common indicator associated with the onset of AD, in people with DS, executive dysfunction and Behavioural and Psychological Symptoms of Dementia (BPSD) are commonly observed during pre-clinical and early stages and may precede memory loss. The review highlights the importance of using a broad spectrum of assessments in the context of heterogeneity of symptoms. Theoretical and practical implications are discussed, as well as the need for further research.     

How does cognition evolve? Phylogenetic comparative psychology

Now more than ever animal studies have the potential to test hypotheses regarding how cognition evolves. Comparative psychologists have developed new techniques to probe the cognitive mechanisms underlying animal behavior, and they have become increasingly skillful at adapting methodologies to test multiple species. Meanwhile, evolutionary biologists have generated quantitative approaches to investigate the phylogenetic distribution and function of phenotypic traits, including cognition. In particular, phylogenetic methods can quantitatively (1) test whether specific cognitive abilities are correlated with life history (e.g., lifespan), morphology (e.g., brain size), or socio-ecological variables (e.g., social system), (2) measure how strongly phylogenetic relatedness predicts the distribution of cognitive skills across species, and (3) estimate the ancestral state of a given cognitive trait using measures of cognitive performance from extant species. Phylogenetic methods can also be used to guide the selection of species comparisons that offer the strongest tests of a priori predictions of cognitive evolutionary hypotheses (i.e., phylogenetic targeting). Here, we explain how an integration of comparative psychology and evolutionary biology will answer a host of questions regarding the phylogenetic distribution and history of cognitive traits, as well as the evolutionary processes that drove their evolution.     

Variability in fundamental frequency during speech in prodromal and incipient Parkinson's disease: a longitudinal case study

Nearly two centuries ago, first observed that a particular pattern of speech changes occur in patients with idiopathic Parkinson's disease (PD). Numerous studies have documented these changes using a wide variety of acoustic measures, and yet few studies have attempted to quantify any such changes longitudinally, through the early course of the disease. Moreover, no attempt has been made to determine if speech changes are evident during the prodromal period, prior to the onset of clinically noticeable symptoms. This case-control pilot study is a first attempt to determine if changes in fundamental frequency variability during speech, an acoustic measure known to be affected later in the course of the disease, are evident during the prodromal period. A retrospective analysis of videotape footage recorded and made available by a leading national television news service. Videotape samples were obtained for a single individual (and a well-matched control subject) over an 11-year period of this individual's life (7 years prior to diagnosis of PD, and 3 years post-diagnosis). Results suggest that changes in F0 variability can be detected as early as 5 years prior to diagnosis (consistent with findings from other laboratories that have relied on cross-sectional study approaches). This pilot study supports the utility of such a design approach, and these results warrant continued effort to better understand the onset of PD and sensitivity of measurement of voice acoustical changes during the prodromal period.     

Age-related declines in general cognitive abilities of Balb/C mice are associated with disparities in working memory, body weight, and general activity

A defining characteristic of age-related cognitive decline is a deficit in general cognitive performance. Here we use a testing and analysis regimen that allows us to characterize the general learning abilities of young (3-5 mo old) and aged (19-21 mo old) male and female Balb/C mice. Animals' performance was assessed on a battery of seven diverse learning tasks. Aged animals exhibited deficits in five of the seven tasks and ranked significantly lower than their young counterparts in general learning abilities (aggregate performance across the battery of tasks). Aging added variability to common core performance (i.e., general learning ability), which translated into increased variability on the individual cognitive tasks. Relatedly, general learning abilities did not differ between the two ages among the best quartile of learners (i.e., cognitive abilities were spared in a subsample of the aged animals). Additionally, working memory capacity (resistance to interference) and duration (resistance to decay) accounted for significantly more of the variability in general learning abilities in aged relative to young animals. Tests of 15 noncognitive performance variables indicated that an increase in body weight (and an associated decrease in general activity) was characteristic of those aged animals which exhibited deficient general learning abilities. These results suggest the possibility that general cognitive deficits in aged animals reflect a failure of specific components of the working memory system, and may be related to variations in body weight and an associated decrease in activity.     

Family expressed emotion prior to onset of psychosis

This study compared components of expressed emotion (EE; rejection, warmth, protectiveness, and fusion) across three samples: two in which the subjects had an established schizophrenic or mood disorder, and a third in which the subjects were at high risk for an initial psychosis. METHODS: Family members rated themselves on the Social Adjustment Scale-III and, in the prodromal sample, estimated the duration of the prodrome. RESULTS: Scores were all but identical in the two established-disorder samples but were markedly higher than scores in the prodromal sample on all four factors. In mothers, warmth (decreasing), rejection, protectiveness, and fusion (increasing) were significantly correlated with duration of prodrome, whereas for fathers, warmth and protectiveness were similarly correlated. CONCLUSION: These data suggest that expressed emotion is largely reactive to deterioration manifested by the young person developing a psychotic disorder, rather than a trait of family members.     

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.     

Interactive Effects of Chronic Health Conditions And Financial Hardship On Episodic Memory Among Older Blacks: Findings From The Health And Retirement Study

Previous research links chronic health conditions and financial hardship to cognitive outcomes among older Blacks. However, few studies have explored the moderating effect of financial hardship on chronic disease burden and specific cognitive domains. This study examined whether financial hardship (as measured by difficulty paying monthly bills) modifies the impact of self-reported chronic health conditions (e.g., diabetes, stroke) on episodic memory among 871 older Blacks (50+ years) in the 2006 Health and Retirement Study . Financial hardship modified the association between chronic disease burden and episodic memory performance such that individuals who reported very little difficulty paying their monthly bills had significantly lower memory scores at high levels of disease burden compared to those reporting high financial difficulty after controlling for age, gender and education (F 2, 49 = 5.03, p = .010). This cross-sectional study suggests that both financial and physical wellbeing may have joint effects on cognitive health in older Blacks.     

The relationship between Big-5 personality traits and cognitive ability in older adults – a review

It is well established that fundamental aspects of cognition such as memory and speed of processing tend to decline with age; however, there is substantial between-individual variability in levels of cognitive performance in older adulthood and in rates of change in cognitive abilities over time. Recent years have seen an increasing number of studies concerned with examining personality characteristics as possible predictors of some of this variability in cognitive aging. The purpose of this article is to review the literature, and identify patterns of findings regarding the relationships between personality (focusing on the Big-5) and cognitive ability across nonclinical populations of older adults. Possible mechanisms underlying associations of personality characteristics with cognition are reviewed, and assessed in the context of the current literature. Some relatively consistent relationships are identified, including positive associations between openness and cognitive ability, and associations of conscientiousness with slower rates of cognitive decline. However, the relationships between several personality traits and cognitive abilities in older adults remain unclear. We suggest some approaches to research design and analysis that may help increase our understanding of how personality differences may contribute to cognitive aging.     

Fonctions exécutives,vieillissement cognitif et variations stratégiques

Aging is characterized by a decrease of cognitive performance in most of cognitive domains. One of the most fundamental issues is then to know what are the underlying mechanisms of these age-related changes in human cognition. Recent research suggests that in addition to speed of processing and working memory capacities, age-related impairment in executive functioning plays an important role in the cognitive decline associated to aging. Above and beyond performance, current research shows that the mediating role of executive function in age-related changes in cognitive performance occurs via changes in strategies variations (i.e., repertoire, distribution, execution, and selection of the strategies used to accomplish a cognitive task). In this article, we illustrate both strategic variations and underlying executive control mechanisms in two important cognitive domains : episodic memory and problem solving.     

Bilingualism: consequences for mind and brain

Building on earlier evidence showing a beneficial effect of bilingualism on children's cognitive development, we review recent studies using both behavioral and neuroimaging methods to examine the effects of bilingualism on cognition in adulthood and explore possible mechanisms for these effects. This research shows that bilingualism has a somewhat muted effect in adulthood but a larger role in older age, protecting against cognitive decline, a concept known as 'cognitive reserve'. We discuss recent evidence that bilingualism is associated with a delay in the onset of symptoms of dementia. Cognitive reserve is a crucial research area in the context of an aging population; the possibility that bilingualism contributes to cognitive reserve is therefore of growing importance as populations become increasingly diverse.     

Juvenile onset Huntington's disease--clinical and research perspectives

Huntington's disease (HD) is an inherited neurodegenerative disorder. The mutation which causes the disease is an expansion in the number of repetitions of three nucleotides, C, A, and G in exon 1 of the huntingtin gene. The gene normally has 15 to 30 repeats and an expansion to 40 or more is associated with HD. HD usually has a mid-life onset, but a juvenile form, defined by onset of symptoms before the age of 21 years, is present in about 7% of HD cases. Juvenile HD is characterized by (1) transmission from an HD affected father, (2) an unusually large repeat size, usually of 60 or more units, and (3) unique clinical features, including rigidity and seizure disorder. Although juvenile onset is associated with a more severe neuropathological involvement, the neuropathological characteristics of juvenile HD are similar to those seen in the adult form in that the striatum bears the brunt of the illness. Clumps of protein, termed inclusion bodies, which stain positive for huntingtin and ubiquitin, are found primarily in the nucleus but also in the cytoplasm and axons in HD neurons. Research suggests that these inclusion bodies sequester a deleterious protein fragment and prolong cell life during the degenerative process of the disease.     

Prospective memory training in older adults and its relevance for successful aging

In research on cognitive plasticity, two training approaches have been established: (1) training of strategies to improve performance in a given task (e.g., encoding strategies to improve episodic memory performance) and (2) training of basic cognitive processes (e.g., working memory, inhibition) that underlie a range of more complex cognitive tasks (e.g., planning) to improve both the training target and the complex transfer tasks. Strategy training aims to compensate or circumvent limitations in underlying processes, while process training attempts to augment or to restore these processes. Although research on both approaches has produced some promising findings, results are still heterogeneous and the impact of most training regimes for everyday life is unknown. We, therefore, discuss recent proposals of training regimes aiming to improve prospective memory (i.e., forming and realizing delayed intentions) as this type of complex cognition is highly relevant for independent living. Furthermore, prospective memory is associated with working memory and executive functions and age-related decline is widely reported. We review initial evidence suggesting that both training regimes (i.e., strategy and/or process training) can successfully be applied to improve prospective memory. Conceptual and methodological implications of the findings for research on age-related prospective memory and for training research in general are discussed.