The free and cued selective reminding test: Validation for mild cognitive impairment and Alzheimer's disease

The International Working Group on Alzheimer's disease (AD) suggested the free and cued selective reminding test (FCSRT) to assess memory, as it showed high sensitivity and specificity in the differentiation of AD from healthy controls and other dementias. The FCSRT involves the use of selective reminding with semantic cueing in memory assessment. This study aims to validate the FCSRT for mild cognitive impairment (MCI) and AD through the analysis of the diagnostic accuracy and the suggestion of cut‐off scores. Patients were classified into two groups according to standard criteria: MCI (n = 100) and AD (n = 70). A matched control group (n = 101) of cognitively healthy subjects was included. The reliability and the validity of the FCSRT were analysed on the immediate (IR) and delayed (DR) recalls. The Cronbach's alpha was 0.915 for the IR and 0.879 for the DR. The total recall measures revealed good areas under the curve for MCI (IR: .818; DR: .828) and excellent for AD (IR: .987; DR: .991). Furthermore, the MCI group was subdivided with respect to a non‐similar/similar AD pattern of impairment, with almost half of the subjects showing an AD‐like decline. This analysis represents a novel contribution regarding the properties of the FCSRT in illustrating the heterogeneity of MCI at baseline. The FCSRT has proved to be a very useful tool in the characterization of the memory impairment of the AD spectrum.     

Alteration of affective Theory of Mind in amnestic mild cognitive impairment

The concept of amnestic mild cognitive impairment (aMCI) concerns a population of older individuals at high risk of developing probable Alzheimer's disease (AD). Impairments of the cognitive component of Theory of Mind (ToM), that is the inference about other people's beliefs, have been well documented in AD; on the contrary, controversial findings have been reported on the affective component of ToM (inference about other's feelings), a process mainly based on medial portions of the prefrontal cortex. The current study aimed at evaluating the affective component of ToM in aMCI subjects. Twenty aMCI subjects and 20 age‐matched healthy controls (HC) underwent a standard neuropsychological assessment and the assessment of affective ToM with the full 36‐item version of reading the mind in the eyes (RME). Although aMCI subjects had formal impaired performances only in memory tasks, HC outperformed aMCI subjects in several cognitive tasks, including also the RME (mean RME scores 21.7 ± 3.0 vs. 17.0 ± 3.8%; 60.3% of correct answers vs. 47.2%). The lower RME performance of aMCI patients provides the first empirical evidence that aMCI may be associated with difficulties in tasks of affective ToM, in accordance with recent findings of early difficulties of aMCI patients in other processes that are mainly dependent on the medial prefrontal cortex, such as reversal learning and decision making under ambiguity. Findings of the current study need further empirical confirmation in larger samples of aMCI patients and also the investigation of other MCI subtypes is needed.     

Effectiveness of follow‐up reminiscence therapy on autobiographical memory in pathological ageing

The objective is to examine the effects of reminiscence therapy (RT) on total, episodic and semantic autobiographical memory in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) groups, testing the effects of RT on different stages of autobiographical memory, and its effectiveness at follow‐up. A sample composed of 43 aMCI (27 treatments, 16 controls) and 30 AD (15 treatments, 15 controls) subjects were evaluated with the Autobiographical Memory Interview (AMI) test. The RT consisted of 10 sessions lasting 60 minutes each. Both groups, aMCI and AD, showed significant effects on overall autobiographical memory; aMCI showed significant main effects on episodic and semantic autobiographical memory in the treatment group, increasing scores in both cases. For AD, significant effects were observed on autobiographical episodic memory, showing an increase in the treatment group from Time 1 to follow‐up; semantic memory showed a decrease in the control group from Time 1 to follow‐up. Results show that RT implementation and follow‐up are effective in increasing autobiographical memory in subjects with aMCI and AD.     

The assessment of recognition memory using the Remember/Know procedure in amnestic mild cognitive impairment and probable Alzheimer’s disease

This study used the Remember/Know (R/K) procedure combined with signal detection analyses to assess recognition memory in 20 elders with amnestic mild cognitive impairment (aMCI), 10 patients with probable Alzheimer’s disease (AD) as well as matched healthy older adults. Signal detection analyses first indicated that aMCI and control participants were comparable on general recognition performance. As regards AD patients, they were impaired relative to both aMCI and healthy elders. When assessing Remember and Know responses the aMCI group showed diminished sensitivity for Remember responses but intact Know responses compared to healthy elders. In contrast, AD patients showed decreased sensitivity for both Remember and Know responses compared to control and aMCI participants. The response bias index revealed that AD patients were more liberal than aMCI and control participants when providing Know responses. On the other measures, response bias was comparable between the groups. Overall, this study indicates that the R/K procedure can characterize different aspects of recognition memory performance in persons with aMCI or AD.     

Lexical and semantic fluency discrepancy scores in aMCI and early Alzheimer's disease

Episodic memory is compromised in amnestic mild cognitive impairment (aMCI), but lesser deficits in other cognitive domains are also commonly observed and may be helpful in identifying this group. The relative difference in performance on lexical and semantic fluency tasks may be a sensitive and specific measure in aMCI and early Alzheimer's disease (AD). We compared four groups of participants, 35 early AD, 47 aMCI, 24 healthy controls, and 18 depressive out‐patient controls, on semantic and lexical fluency as well as other neuropsychological tests. Early AD and aMCI patients showed a distinct pattern of semantic impairment in the two fluency measures compared with the healthy and depressive controls. The findings implicate early failure of the semantic memory system in aMCI and AD and suggest that consideration of the discrepancy in performance on semantic and lexical fluency measures may help in the early identification of AD.     

Insights into spared memory capacity in amnestic MCI and Alzheimer's Disease via minimal interference

Impairment on standard tests of delayed recall is often already maximal in the aMCI stage of Alzheimer's Disease. Neuropathological work shows that the neural substrates of memory function continue to deteriorate throughout the progression of the disease, hinting that further changes in memory performance could be tracked by a more sensitive test of delayed recall. Recent work shows that retention in aMCI patients can be raised well above floor when the delay period is devoid of further material - 'Minimal Interference'. This memory enhancement is thought to be the result of improved memory consolidation. Here we used the minimal interference/interference paradigm (word list retention following 10 min of quiet resting vs. picture naming) in a group of 17 AD patients, 25 aMCI patients and 25 controls. We found (1) that retention can be improved significantly by minimal interference in patients with aMCI and patients with mild to moderate AD; (2) that the minimal interference paradigm is sensitive to decline in memory function with disease severity, even when performance on standard tests has reached floor; and (3) that this paradigm can differentiate well (80% sensitivity and 100% specificity) between aMCI patients who progress and do not progress to AD within 2 years. Our findings support the notion that the early memory dysfunction in AD is associated with an increased susceptibility to memory interference and are suggestive of a gradual decline in consolidation capacity with disease progression.     

Movements execution in amnestic mild cognitive impairment and Alzheimer's disease

We evaluated the relationship between motor and neuropsychological deficits in subjects affected by amnestic Mild Cognitive Impairment (aMCI) and early Alzheimer's Disease (AD). Kinematics of goal-directed movement of aMCI and AD subjects were compared to those of age-matched control subjects. AD showed a slowing down of motor performance compared to aMCI and controls. No relationships were found between motor and cognitive performances in both AD and aMCI. Our results suggest that the different motor behaviour between AD and aMCI cannot be related to memory deficits, probably reflecting the initial degeneration of parietal-frontal circuits for movement planning. The onset of motor dysfunction in early AD could represent the transition from aMCI to AD.     

The Effects of Healthy Aging,Amnestic Mild Cognitive Impairment,and Alzheimer’s Disease on Recollection and Familiarity: A Meta-Analytic Review

It is well established that healthy aging, amnestic Mild Cognitive Impairment (aMCI), and Alzheimer’s Disease (AD) are associated with substantial declines in episodic memory. However, there is still debate as to how two forms of episodic memory – recollection and familiarity – are affected by healthy and pathological aging. To address this issue we conducted a meta-analytic review of the effect sizes reported in studies using remember/know (RK), receiver operating characteristic (ROC) and process dissociation (PD) methods to examine recollection and familiarity in healthy aging (25 published reports), aMCI (9 published reports), and AD (5 published reports). The results from the meta-analysis revealed that healthy aging is associated with moderate-to-large recollection impairments. Familiarity was not impaired in studies using ROC or PD methods but was impaired in studies that used the RK procedure. aMCI was associated with large decreases in recollection whereas familiarity only tended to show a decrease in studies with a patient sample comprised of both single-domain and multiple-domain aMCI patients. Lastly, AD was associated with large decreases in both recollection and familiarity. The results are consistent with neuroimaging evidence suggesting that the hippocampus is critical for recollection whereas familiarity is dependent on the integrity of the surrounding perirhinal cortex. Moreover, the results highlight the relevance of method selection when examining aging, and suggest that familiarity deficits might be a useful behavioral marker for identifying individuals that will develop dementia.     

Visual associations cued recall A Paradigm for Measuring Episodic Memory Decline in Alzheimer’s Disease

Repeated measurements of episodic memory are needed for monitoring amnestic mild cognitive impairment (aMCI) and mild Alzheimer’s disease (AD). Most episodic memory tests may pose a challenge to patients, even when they are in the milder stages of the disease. This cross-sectional study compared floor effects of the Visual Association Test (VAT) and the Rey Auditory Verbal Learning Test (RAVLT) in healthy elderly controls and in patients with aMCI or AD (N = 125). A hierarchical multiple regression analysis was used to examine whether linear or quadratic trends best fitted the data of cognitive test performance across global cognitive impairment. Results showed that VAT total scores decreased linearly across the range of global cognitive impairment, whereas RAVLT total scores showed a quadratic trend, with total scores levelling off for 90% of aMCI patients and 94% of AD patients. We conclude that the VAT shows few if any floor effects in patients with aMCI and mild AD and is therefore a potentially promising cognitive test for monitoring episodic memory impairment.     

Inhibitory Control Deficits in Individuals with Amnestic Mild Cognitive Impairment: a Meta-Analysis

Neuropsychology Review - Amnestic mild cognitive impairment (aMCI) is a prodromal stage of Alzheimer’s disease that is characterized by impairments in episodic memory. Recent evidence has...     

Increased sensitivity to proactive interference in amnestic mild cognitive impairment is independent of associative and semantic impairment

Episodic memory deficit is the hallmark of amnestic mild cognitive impairment (aMCI). There is, however, an overlap in performance among patients with aMCI and elderly controls (EC). The memory deficit in aMCI therefore needs to be better characterized. Studies have shown that associative memory is selectively impaired in aMCI, and recent work suggested that aMCI may be hypersensitive to semantic proactive interference (PI). It is not known whether this increased PI is related to associative or semantic impairment. EC (n = 44) and patients with aMCI (n = 30) performed two tasks presenting a gradually increasing PI effect across four lists. One task used semantic cueing, the other phonological cueing. We controlled for associative memory by introducing it as a covariate and by matching our subjects for it. Patients with aMCI had a greater PI effect than EC matched for associative memory, regardless of the type of cueing. The increased PI effect in patients with aMCI is independent of their associative and semantic impairment.     

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.     

Hippocampal metabolites and memory performances in patients with amnestic mild cognitive impairment and Alzheimer's disease

In patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD), previous studies have reported the decrease of N-acetylaspartate (NAA) concentration and the increase of myo-inositol (MI) concentration using proton magnetic resonance spectroscopy (1H-MRS). However, it remains to be investigated what aspects of cognition these metabolite changes reflect. In this study we evaluated the correlations between the subtests of Wechsler Memory Scale-Revised (WMS-R) and the concentrations of NAA and MI. The study group was composed of 42 patients with aMCI and 67 patients with AD. 1H-MR spectra with a single voxel-point resolved spectroscopy (PRESS) at a short echo time were acquired from the bilateral hippocampi and posterior cingulate gyrus. Positive correlations were shown between the NAA concentration in the left hippocampus and verbal memory, visual memory, general memory, attention and delayed recall; and furthermore, between the NAA concentration in the right hippocampus and verbal memory and general memory. Negative correlations were shown between the MI concentration in the left hippocampus and verbal memory, general memory, and delayed recall, and between the MI concentration in the right hippocampus and verbal memory. There was no significant correlation between any subtest of WMS-R and these two metabolite concentrations in the posterior cingulate gyrus. These findings suggest that bilateral, especially left hippocampal NAA and MI concentrations are associated with memory dysfunction observed in patients with aMCI and AD. In contrast, NAA and MI concentrations in the posterior cingulate gyrus may be less related to memory function than those in the hippocampus.     

Neuropsychological predictors of conversion to probable Alzheimer disease in elderly with mild cognitive impairment

In the field of neuropsychology, it is essential to determine which neuropsychological tests predict Alzheimer's disease (AD) in people with mild cognitive impairment (MCI) and which cut‐off points should be used to identify people at greater risk for converting to dementia. The aim of the present study was to analyse the predictive value of the cognitive tests included in a neuropsychological battery for conversion to AD among MCI participants and to analyse the influence of some sociodemographic variables – sex, age, schooling – and others, such as follow‐up time and emotional state. A total of 105 participants were assessed with a neuropsychological battery at baseline and during a 3‐year follow‐up period. For the present study, the data were analysed at baseline. During the follow‐up period, 24 participants (22.85%) converted to dementia (2.79 ± 1.14 years) and 81 (77.14%) remained as MCI. The logistic regression analysis determined that the long delay cued recall and the performance time of the Rey figure test were the best predictive tests of conversion to dementia after an MCI diagnosis. Concerning the sociodemographic factors, sex had the highest predictive power. The results reveal the relevance of the neuropsychological data obtained in the first assessment. Specifically, the data obtained in the episodic verbal memory tests and tests that assess visuospatial and executive components may help to identify people with MCI who may develop AD in an interval not longer than 4 years, with the masculine gender being an added risk factor.     

Social cognition and social functioning in patients with amnestic mild cognitive impairment or Alzheimer’s dementia

The aim of the present study was to examine social cognition and social functioning in a group of amnestic mild cognitive impairment (aMCI) and Alzheimer’s dementia (AD) patients. Thirty one people with aMCI, 29 individuals with AD, and 45 healthy older adults participated in the study. Facial expressions of happiness, anger, fear, disgust, and surprise presented in different intensities had to be labelled. Mentalizing was assessed using first-order belief theory of mind (ToM) stories and everyday social functioning by the Inventory of Interpersonal Situations (IIS), completed by an informant. aMCI patients were impaired in recognizing the emotions anger, disgust, and fear, while AD patients were impaired in recognizing the emotions anger, disgust, and surprise. More importantly, no significant differences between aMCI and AD patients were found on overall emotion recognition. Both the aMCI and AD patients were impaired on the ToM task, but no differences between the aMCI and AD patients were found. On everyday social functioning, only the AD patients showed impairments. No associations between the IIS and ToM were found, but the IIS and emotion perception were significantly correlated. Regression analysis taking all potentially confounding variables into account showed that only mood, but not the social-cognitive task performance or any other cognitive variable, predicted social functioning. aMCI and AD patients demonstrated impairments in mentalizing and facial emotion perception, and showed decrements in everyday social functioning. Informing caregivers about these deficits may help them to understand deficits in social cognition that may be present already in the MCI stage of Alzheimer’s disease.     

Alterations in working memory networks in amnestic mild cognitive impairment

Patients with amnestic mild cognitive impairment (aMCI) show preserved or mildly impaired working memory, despite their deficits in episodic memory. We aimed to identify performance and/or neural differences between aMCI patients and matched controls on a standard working memory fMRI task. Neuropsychological assessment demonstrated aMCI impairments in verbal and visual episodic long-term memory, with intact IQ and executive function. Participants completed a standard three-level N-back task where patients were unimpaired. Functional activations in the control group were found in expected areas, including the inferior parietal lobule and dorsolateral prefrontal cortex. Group differences were found in the insula and lingual gyrus and, in a region of interest analysis, in the hippocampus. In all cases, these were caused by an absence of task-related deactivations in the aMCI group. The results are consistent with reports of failure in task-related deacivations in aMCI and could be early indications of pathology.     

Strategic value-directed learning and memory in Alzheimer's disease and behavioural-variant frontotemporal dementia

In healthy adults, the ability to prioritize learning of highly valued information is supported by executive functions and enhances subsequent memory retrieval for this information. In Alzheimer's disease (AD) and behavioural-variant frontotemporal dementia (bvFTD), marked deficits are evident in learning and memory, presenting in the context of executive dysfunction. It is unclear whether these patients show a typical memory bias for higher valued stimuli. We administered a value-directed word-list learning task to AD (n = 10) and bvFTD (n = 21) patients and age-matched healthy controls (n = 22). Each word was assigned a low, medium or high point value, and participants were instructed to maximize the number of points earned across three learning trials. Participants’ memory for the words was assessed on a delayed recall trial, followed by a recognition test for the words and corresponding point values. Relative to controls, both patient groups showed poorer overall learning, delayed recall and recognition. Despite these impairments, patients with AD preferentially recalled high-value words on learning trials and showed significant value-directed enhancement of recognition memory for the words and points. Conversely, bvFTD patients did not prioritize recall of high-value words during learning trials, and this reduced selectivity was related to inhibitory dysfunction. Nonetheless, bvFTD patients showed value-directed enhancement of recognition memory for the point values, suggesting a mismatch between memory of high-value information and the ability to apply this in a motivationally salient context. Our findings demonstrate that value-directed enhancement of memory may persist to some degree in patients with dementia, despite pronounced deficits in learning and memory.     

Differential Memory Test Sensitivity for Diagnosing Amnestic Mild Cognitive Impairment and Predicting Conversion to Alzheimer's Disease

ABSTRACT

Episodic memory is the first and most severely affected cognitive domain in Alzheimer's disease (AD), and it is also the key early marker in prodromal stages including amnestic mild cognitive impairment (MCI). The relative ability of memory tests to discriminate between MCI and normal aging has not been well characterized. We compared the classification value of widely used verbal memory tests in distinguishing healthy older adults (n = 51) from those with MCI (n = 38). Univariate logistic regression indicated that the total learning score from the California Verbal Learning Test-II (CVLT-II) ranked highest in terms of distinguishing MCI from normal aging (sensitivity = 90.2; specificity = 84.2). Inclusion of the delayed recall condition of a story memory task (i.e., WMS-III Logical Memory, Story A) enhanced the overall accuracy of classification (sensitivity = 92.2; specificity = 94.7). Combining Logical Memory recognition and CVLT-II long delay best predicted progression from MCI to AD over a 4-year period (accurate classification = 87.5%). Learning across multiple trials may provide the most sensitive index for initial diagnosis of MCI, but inclusion of additional variables may enhance overall accuracy and may represent the optimal strategy for identifying individuals most likely to progress to dementia.     

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.     

Gesturing helps memory encoding in aMCI

Encoding in episodic memory is a step often impaired in patients with amnestic Mild Cognitive Impairment (aMCI). However, procedural memory processes are still relatively preserved. In line with previous research on the enactment effect, we investigated the potential benefit of encoding words combined with imitative gestures on episodic memory. Based on the Grober and Buschke’s free/cued recall procedure, we developed the Symbiosis test in which 13 patients with aMCI and 16 healthy elderly participants learned 32 words belonging to 16 different semantic categories either in a verbal encoding (A) or a bimodal (B; verbal and motor imitation) condition, using a blocked ABBA/BAAB procedure. Overall, memory retrieval was better in healthy participants than in patients with aMCI, and better for cued retrieval in the bimodal encoding (gesture cues) than the verbal encoding (category cues) condition, but there was no interaction effect between group and encoding conditions. These results show that performing concomitant gestures can enhance cued episodic memory retrieval in patients with aMCI and in healthy elderly controls. The Symbiosis test broadens the scope of the enactment effect, from action phrases to isolated words learning in patients with aMCI. Future work should investigate how bimodal encoding provides novel perspectives for memory rehabilitation in patients with aMCI.