Multidimensional measures of person knowledge and spatial associative learning: can these be applied to the differentiation of Alzheimer's disease from frontotemporal and vascular dementia?

Patients with early stage Alzheimer's disease (AD) show deficits in person knowledge and spatial associative memory. The current investigation examined the ability of impairment in these domains to differentiate AD from other overlapping conditions. In experiment 1, 14 AD patients, 21 vascular dementia (VaD) patients, 11 frontal variant frontotemporal dementia (fvFTD) patients and 41 controls were administered a graded faces test. VaD patients demonstrated a level of impairment comparable to the AD group on both the naming and person identification elements of the task. A mild naming deficit was revealed in the fvFTD group. In experiment 2, 22 AD patients, 23 patients with mild cognitive impairment (MCI), 11 fvFTD patients, 13 semantic dementia (SD) patients, and 23 elderly controls were administered the face-place test, a newly developed task that combines naming of famous faces, item recognition and spatial location. The naming component of the face-place test clearly differentiated SD patients from all dementia groups. All patient groups, except those with fvFTD, showed substantial deficits in the item recognition and spatial components. Consistency analyses indicated a fairly robust association between the two episodic components (item recognition and placing), but not between semantic and episodic elements of the FPT. Person knowledge deficits are, therefore, not specific to AD and the employment of face stimuli may influence the performance of SD patients on tasks of episodic memory.     

Naming of objects, faces and buildings in mild cognitive impairment

Accruing evidence suggests that the cognitive deficits in very early Alzheimer's Disease (AD) are not confined to episodic memory, with a number of studies documenting semantic memory deficits, especially for knowledge of people. To investigate whether this difficulty in naming famous people extends to other proper names based information, three naming tasks – the Graded Naming Test (GNT), which uses objects and animals, the Graded Faces Test (GFT) and the newly designed Graded Buildings Test (GBT) – were administered to 69 participants (32 patients in the early prodromal stage of AD, so-called Mild Cognitive Impairment (MCI), and 37 normal control participants). Patients were found to be impaired on all three tests compared to controls, although naming of objects was significantly better than naming of faces and buildings. Discriminant analysis successfully predicted group membership for 100% controls and 78.1% of patients. The results suggest that even in cases that do not yet fulfil criteria for AD naming of famous people and buildings is impaired, and that both these semantic domains show greater vulnerability than general semantic knowledge. A semantic deficit together with the hallmark episodic deficit may be common in MCI, and that the use of graded tasks tapping semantic memory may be useful for the early identification of patients with MCI.     

Learning and forgetting new names and objects in MCI and AD

We studied how subjects with mild cognitive impairment (MCI), early Alzheimer's disease (AD) and age-matched controls learned and maintained the names of unfamiliar objects that were trained with or without semantic support (object definitions). Naming performance, phonological cueing, incidental learning of the definitions and recognition of the objects were tested during follow-up. We found that word learning was significantly impaired in MCI and AD patients, whereas forgetting patterns were similar across groups. Semantic support showed a beneficial effect on object name retrieval in the MCI group 8 weeks after training, suggesting that the MCI patients’ preserved semantic memory can compensate for impaired episodic memory. The MCI group performed equally well as the controls in the tasks measuring incidental learning and recognition memory, whereas the AD group showed impairment in this respect. Both the MCI and the AD group benefited less from phonological cueing than the controls. Our findings indicate that word learning is compromised in both MCI and AD, whereas long-term retention of newly learned words is not affected to the same extent. Incidental learning and recognition memory seem to be well preserved in MCI.     

The nature of lexico-semantic processing deficits in mild cognitive impairment

Lexico-semantic impairments in Alzheimer disease (AD) have been attributed to abnormalities in both intentional and automatic access to semantic memory. However, the order in which these impairments appear during the course of the disease is unclear. We sought to answer this question by documenting lexico-semantic impairments in 61 subjects with mild cognitive impairment (MCI), a pre-AD stage, and by comparing them to those of 39 AD and 60 normal elderly (NE) subjects. All subjects were tested with intentional access tasks (picture naming and semantic probes), automatic access tasks (lexical decision and priming), and executive function tasks (Stroop and Stroop-Picture naming). Results indicated that the MCI group was only impaired on tasks of intentional access relative to the AD group who was impaired on both types of tasks. Because most MCI subjects eventually develop AD, these results suggest that intentional access to semantic memory is impaired before automatic access. Further, impairments on the Stroop-Picture naming task but not on the Stroop task, suggest that lexico-semantic impairments in the MCI group may be related to inhibition deficits during semantic search. Findings are discussed in light of executive dysfunctions within the framework of semantic memory theories.     

Hippocampal formation alterations differently contribute to autobiographic memory deficits in mild cognitive impairment and Alzheimer's disease

Autobiographical memory (AM) is part of declarative memory and includes both semantic and episodic aspects. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. Previous MRI studies in AD patients have showed that deficits in semantic and episodic AM are associated with hippocampal alterations. However, the question which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits of AM in individuals with mild cognitive impairment (MCI) and AD patients has not been investigated so far. Hundred and seven participants (38 AD patients, 38 MCI individuals and 31 healthy controls [HC]) underwent MRI at 3 Tesla. AM was assessed with a semi‐structured interview (E‐AGI). FreeSurfer 5.3 was used for hippocampal parcellation. Semantic and episodic AM scores were related to the volume of 5 hippocampal subfields and cortical thickness in the parahippocampal and entorhinal cortex. Both semantic and episodic AM deficits were associated with bilateral hippocampal alterations. These associations referred mainly to CA1, CA2‐3, presubiculum, and subiculum atrophy. Episodic, but not semantic AM loss was associated with cortical thickness reduction of the bilateral parahippocampal and enthorinal cortex. In MCI individuals, episodic, but not semantic AM deficits were associated with alterations of the CA1, presubiculum and subiculum. Our findings support the crucial role of CA1, presubiculum, and subiculum in episodic memory. The present results implicate that in MCI individuals, semantic and episodic AM deficits are subserved by distinct neuronal systems.     

Visual and visuospatial short-term memory in mild cognitive impairment and Alzheimer disease: role of attention

It has been proposed that visual recognition memory and certain attentional mechanisms are impaired early in Alzheimer disease (AD). Little is known about visuospatial recognition memory in AD. The crucial role of the hippocampus on spatial memory and its damage in AD suggest that visuospatial recognition memory may also be impaired early. The aim of the present study was to evaluate which modality, i.e. visual or visuospatial, is more implicated in the early memory impairment in AD. First, to determine onset of memory impairment, we compared the performances of patients with AD to those with amnestic mild cognitive impairment (MCI). Second, to determine the relative contribution of attentional impairment on the performance of MCI and AD patients, we tested the influence of a distractor in the interval between the memory image and recognition tests. Results showed that visuospatial short-term deficits appear earlier than visual short-term ones. In addition to mnemonic deficits, results showed attentional deficiency in both MCI and AD patients. Deficits of performances in visual modality seemed of attentional origin whereas those of visuospatial modality seemed of memory origin. The combination of attentional and mnemonic evaluation is likely to be a promising approach to finding predictive markers that distinguish MCI patients that convert to AD.     

Semantic knowledge in mild cognitive impairment and mild Alzheimer's disease

The aim of this study was to investigate memory in patients with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Ten patients with MCI, 11 with AD and a group of age and education matched healthy control participants were assessed on a comprehensive battery of semantic memory tests, including traditional semantic memory measures and a non-verbal test of knowledge of object use. The MCI group was impaired on tests of category fluency and all three conditions of an object knowledge test (matching to recipient, function and action), plus a difficult object-naming test. The mild AD group showed additional impairments on traditional measures of semantic memory, including naming high frequency items, comprehension and semantic association. Together these findings suggest that semantic memory impairments occur early in the course of AD, more specifically in patients with "amnesic" MCI, and provide further evidence that impaired category fluency reflects semantic breakdown.     

The Semantic Object Retrieval Test (SORT) in amnestic mild cognitive impairment.

BACKGROUND: Between 10% and 15% of patients with the amnestic variety of Mild Cognitive Impairment (MCI) convert to Alzheimer disease (AD) per year. OBJECTIVE: Characterize cognitive markers that may herald conversion from MCI to AD and directly assess semantic memory in patients meeting criteria for amnestic MCI. DESIGN: Thirty-five amnestic MCI patients and 121 healthy aging controls enrolled at an Alzheimer Disease Center received a battery of standard neuropsychologic tests, and the Semantic Object Retrieval Test (SORT), a test that we have developed for the assessment of semantic memory and subsequent name production, and that has been shown to be able to differentiate between normals and patients with AD. RESULTS: On the basis of normative data from the SORT, the MCI subjects could be divided into 2 groups: 10 patients (29%) with a significant semantic impairment (SI+) and 25 without a semantic memory deficit (SI-). There was a significant correlation between all SORT variables and performance on the Boston Naming Test. In this MCI population, significantly impaired SORT performance was associated with a relative decrease in performance on tests of frontal lobe functions, although disruption of thalamic-related processes cannot be excluded as an etiology for semantic memory impairment. CONCLUSIONS: The SORT is a specific test of semantic memory, and is a sensitive measure of semantic memory deficits in patients who otherwise meet criteria for amnestic MCI. Using this specific assessment tool, a significant number of MCI patients were found to have semantic memory deficits. As these patients may be early in the course of possible progression toward dementia, the SORT or other tests of semantic memory may provide important diagnostic or prognostic information in patients with MCI.     

Probable Alzheimer's disease patients presenting as "focal temporal lobe dysfunction" show a slow rate of cognitive decline

Several authors have recently shown that anterograde amnesia is often associated with semantic memory impairment in amnesic MCI patients. Similarly, after the MCI condition, some patients who convert to Alzheimer's disease (AD) show the classic onset (cAD) characterized by the impairment of memory and executive functions, whereas other AD patients show isolated defects of episodic and semantic memory without deficits in other cognitive domains. The latter have been considered an AD variant characterized by 'focal Temporal Lobe Dysfunction' (TLD). The aim of the present study was to assess the differences in disease progression between cAD and TLD. For this purpose a continuous series of newly diagnosed probable AD patients presenting as cAD (n = 30) and TLD (n = 25), matched for severity, and 65 healthy controls underwent a comprehensive neuropsychological evaluation at baseline; TLD and cAD were re-evaluated at a 24-month follow-up. At follow-up, TLD patients showed no significant worsening of cognitive functions, whereas cAD subjects displayed a significant worsening in all explored cognitive domains. In conclusion, our results confirm that probable AD presenting as TLD represents a specific onset of AD characterized by a slower rate of progression.     

Different mechanisms of episodic memory failure in mild cognitive impairment

Mild cognitive impairment (MCI), defined as episodic memory impairment beyond what is expected in normal aging, is often associated with hippocampal atrophy (HA) and may represent incipient Alzheimer's disease. However, recent studies suggest that MCI is very heterogeneous and multiple etiologies likely exist. One possibility is small vessel cerebrovascular disease (CVD). Specifically, we hypothesized that white matter hyperintensities (WMH), an MRI marker for CVD, would lead to impairments in executive control processes critical for working memory that may, in turn, result in episodic memory impairment. To test this hypothesis, we examined a group of subjects clinically diagnosed with MCI and used MRI to further subcategorize individuals as either MCI with severe white matter hyperintensities (MCI-WMH) or MCI with severe hippocampal atrophy (MCI-HA). MCI-WMH, MCI-HA, and matched control subjects each performed a battery of working memory and episodic memory tasks. Results showed that MCI-HA and MCI-WMH were equally impaired on the episodic memory task relative to controls, but MCI-WMH were additionally impaired on tests tapping verbal and spatial working memory abilities and attentional control processes. These results suggest that CVD and hippocampal dysfunction are associated with distinct neuropsychological profiles. Although both syndromes are associated with episodic memory deficits, CVD is additionally associated with working memory and executive control deficits.     

Topographical recognition memory sensitive to amnestic mild cognitive impairment but not to depression

OBJECTIVE: Amnestic mild cognitive impairment (aMCI) involves episodic memory. The person who presents aMCI has a high risk of developing Alzheimer's disease (AD). However, prediction of deterioration to dementia in cases of aMCI can be confounded with depression due to lack of specificity on selective memory tests. Finding a test sensitive to aMCI but not to depression would be potentially most useful to subsequent longitudinal studies researching the neuropsychological markers of preclinical AD. We hypothesized that the performance on a topographical memory task would be sensitive to the aMCI condition, while depression would not influence such a performance. PARTICIPANTS AND METHODS: A group of 137 community-dwelling French-speaking subjects between 55 and 70 years old was administered a topographical recognition memory task. Based on aMCI and depression criteria, 45 subjects were selected and divided into four groups: 11 patients with aMCI without depression, nine depressive patients with aMCI, ten depressive patients without cognitive impairment and 15 control subjects. The remaining non-selected participants did not belong to any of the previous interest groups. RESULTS: The 'aMCI' factor had a significant effect on the topographical recognition memory task scores, while the 'depression' factor did not. The aMCI patients performed worse than the non-aMCI. CONCLUSION: Although these results were found with relatively small groups, deficits in topographical recognition memory were observed in aMCI patients and did not seem to be sensitive to depression. Further longitudinal studies are needed to examine whether deficits in topographical recognition memory are a neuropsychological marker of preclinical AD.     

Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease

Neuropsychological deficits, such as poor episodic memory, are consistent features of mild cognitive impairment and also that of early stage of dementia. The aim of the present study was to detect cognitive dysfunction among patients with Alzheimer's disease or with mild cognitive impairment (MCI), which refers to a transitional state between the cognition of normal aeging and mild dementia regarded as a high-risk condition for the development of clinically probable Alzheimer's disease (AD). Computerized tests of memory, attention and executive functions were studied in groups of AD subjects (n=15) and MCI subjects (n=25). On all measures, the performance of the AD group was significantly weaker compared to healthy individuals or to the MCI group. The performance of both the AD and MCI patients in the Paired Associate Learning test was significantly impaired, which may suggest that MCI patients are already in the early stages of the disease.     

The influence of semantic encoding on recognition memory in Alzheimer''s disease

Within the framework of the distinction between episodic and semantic memory, it has been argued that these two memory systems are organised in a hierarchical way. The hierarchical hypothesis assumes that episodic memory is a specific subsystem of semantic memory and therefore implies that episodic memory cannot exist without semantic memory. If this hypothesis is correct, it should be expected that patients with impaired semantic memory also have impaired episodic memory. In the present study, two experiments investigated the influence of semantic encoding on recognition memory performance in a population of 20 patients with Alzheimer's disease and 18 normal controls. Both experiments assessed recognition memory for semantically-related items. In Experiment 2, but not in Experiment 1, subjects were explicitly instructed to make a semantic association between the items. Alzheimer's disease patients were impaired, compared to the normal controls, on the recognition memory performance of both experiments. The ability to make a semantic association between two items was significantly and positively correlated with the subjects' performance on the recognition tasks. A further analysis showed that patients who were impaired on the semantic association task did significantly worse on the recognition task of Experiment 2 than normal controls and patients who were unimpaired on the semantic association task. These findings are discussed in the context of memory deficits in Alzheimer's disease, and are interpreted as supporting the view that episodic memory for an item is affected by the level of semantic awareness of that same item.     

轻度认知障碍老年人情节记忆功能的磁共振成像研究

目的 运用核磁共振(MRI)技术探讨轻度认知障碍(MCI)老人与健康老人脑结构和功能的异同.方法 对14例MCI老人(MCI组)和15名健康老人(正常对照组)进行神经心理学检查,并应用基于体素的形态测量方法 ,测定两组的灰质体积,并用事件相关功能MRI技术,测定两组在执行情节记忆提取任务时相关脑区的功能变化.结果 (1)神经心理学:MCI组听觉词语记忆测试[(2.1±1.7)分]和画钟试验[(7.8±1.2)分]成绩差于正常对照组[分别为(9.2±1.3)分和(9.2±0.8)分;P＜0.05].(2)结构影像:MCI组的灰质体积小于正常对照组,主要位于情节记忆相关脑区(P＜0.001).(3)功能影像:MCI组与正常对照组任务正确率和反应时间的差别无统计学意义;MCI组激活降低的脑区主要是海马旁回,而增强激活的脑区主要是前额叶前侧、背外侧、右侧颞上回、右侧颞下回、枕叶皮层(P＜0.005).结论 MCI组内侧颞叶记忆系统结构萎缩、功能下降,在任务难度适当的情节记忆提取任务中,MCI组动员额外脑区激活,以代偿颞叶内侧记忆系统的损害.     

Hippocampal morphology and autobiographic memory in mild cognitive impairment and Alzheimer's disease

Autobiographical memory (AM) comprises memories of one's own past that are characterized by a sense of subjective time and autonoetic awareness. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. However, little is known on the association between cerebral alterations and AM in mild cognitive impairment (MCI) and AD. In the current study, patients with AD or MCI and healthy controls underwent high-resolution magnetic resonance imaging (MRI) and neuropsychological testing including semi-structured assessment of semantic and episodic AM of distinct lifetime periods. In MRI analysis, FSL-FIRST was used to automatically ascertain volume and shape of the hippocampal formation. Episodic, but not semantic AM loss was associated with morphological changes of the hippocampus, primarily involving the left hemisphere. According to shape analyses, these associations referred to regionally specific rather than global atrophy of the hippocampus. Our study demonstrates that loss of episodic AM early in the course of AD is associated with regionally confined hippocampal atrophy, thus supporting the multiple trace theory for the role of the hippocampus in episodic AM. Our findings are not only relevant for the understanding of memory function, but may also contribute to facilitating the early diagnosis of AD.     

Reduced semantic fluency as an additional screening tool for subjects with questionable dementia

BACKGROUND: Subjective memory complaints in subjects with mild cognitive impairment may represent a genuine decline in episodic memory. This paper evaluates the neuropsychological correlates of the semantic fluency test in subjects with questionable dementia (QD). METHODS: A total of 331 Chinese subjects (118 normal controls, NC, 150 with QD and 63 with mild Alzheimer's disease, AD) were assessed with the Category Verbal Fluency Test (CVFT), the AD Assessment Scale-cognitive subscale (ADAS-Cog), and digit and verbal span tests. CVFT performance was evaluated in each Clinical Dementia Rating (CDR) group. The total number of exemplars, the subcategory and the category size generated were evaluated. Neuropsychological correlates of CVFT scores were computed. RESULTS: Significant differences in CVFT performance were found between the different CDR groups. The subjects with QD had intermediate scores compared to the NC and AD subjects (1-way ANOVA, p < 0.001, post-hoc Bonferroni comparisons). In NC the CVFT scores were significantly associated with ADAS-Cog total, and immediate and delayed recall scores (partial correlations controlled for age and education, p < 0.005). In the QD group the CVFT scores were correlated with ADAS-Cog total, and immediate recall and object naming scores (partial correlation controlled for age and education, p < 0.005). Regression analysis revealed that age and delayed recall were significant predictors of CVFT performance in NCs. In the QD group, age, ADAS-Cog immediate recall and object naming scores predicted the CVFT performance. CONCLUSIONS: The CVFT was impaired in the subjects with QD. Apart from episodic memory, semantic memory deficits also occur early in AD. The different cognitive predictors of CVFT scores in the NC and QD groups suggest that the test is associated with specific psychological functions at different stages of cognitive impairment.     

Memory evaluation in mild cognitive impairment using recall and recognition tests

Amnestic mild cognitive impairment (MCI) is a selective episodic memory deficit that often indicates early Alzheimer's disease. Episodic memory function in MCI is typically defined by deficits in free recall, but can also be tested using recognition procedures. To assess both recall and recognition in MCI, MCI (n = 21) and older comparison (n = 30) groups completed the USC-Repeatable Episodic Memory Test. Subjects memorized two verbally presented 15-item lists. One list was used for three free recall trials, immediately followed by yes/no recognition. The second list was used for three-alternative forced-choice recognition. Relative to the comparison group, MCI had significantly fewer hits and more false alarms in yes/no recognition, and were less accurate in forced-choice recognition. Signal detection analysis showed that group differences were not due to response bias. Discriminant function analysis showed that yes/no recognition was a better predictor of group membership than free recall or forced-choice measures. MCI subjects recalled fewer items than comparison subjects, with no group differences in repetitions, intrusions, serial position effects, or measures of recall strategy (subjective organization, recall consistency). Performance deficits on free recall and recognition in MCI suggest a combination of both tests may be useful for defining episodic memory impairment associated with MCI and early Alzheimer's disease.     

“The Castle of Remembrance”: New insights from a cognitive training programme for autobiographical memory in Alzheimer's disease

Autobiographical memory deficits are prominent from the early stages of Alzheimer's disease (AD) and result in a loss of personal identity. Nevertheless, standardised methods of autobiographical memory stimulation for the neuropsychological rehabilitation of patients with AD remain underdeveloped. Our aim was to evaluate the impact of a new cognitive training programme for autobiographical memory (REMau) on both the episodic and semantic components of autobiographical memory performance across lifetime periods, as well as on mood. Pre/post evaluations were conducted on two groups of patients with early to moderate AD, assigned to one of two different training activities: either the REMau or a cognitive training programme focused on collective semantic memory. Statistical comparisons showed significant improvement of episodic and semantic autobiographical memory performance in the REMau group, which was more pronounced for the semantic component, as well as improved mood. By contrast, deleterious pre/post differences were observed in the other group. Most interestingly, this study showed that the REMau programme boosted autobiographical memory from the reminiscence bump period, which is considered crucial for the construction and maintenance of personal identity. We discuss the theoretical and practical implications of these results for the reduction of autobiographical memory deficits in AD.     

The cognitive and neural expression of semantic memory impairment in mild cognitive impairment and early Alzheimer's disease

Semantic deficits in Alzheimer's disease have been widely documented, but little is known about the integrity of semantic memory in the prodromal stage of the illness. The aims of the present study were to: (i) investigate naming abilities and semantic memory in amnestic mild cognitive impairment (aMCI), early Alzheimer's disease (AD) compared to healthy older subjects; (ii) investigate the association between naming and semantic knowledge in aMCI and AD; (iii) examine if the semantic impairment was present in different modalities; and (iv) study the relationship between semantic performance and grey matter volume using voxel-based morphometry. Results indicate that both naming and semantic knowledge of objects and famous people were impaired in aMCI and early AD groups, when compared to healthy age- and education-matched controls. Item-by-item analyses showed that anomia in aMCI and early AD was significantly associated with underlying semantic knowledge of famous people but not with semantic knowledge of objects. Moreover, semantic knowledge of the same concepts was impaired in both the visual and the verbal modalities. Finally, voxel-based morphometry analyses revealed that semantic impairment in aMCI and AD was associated with cortical atrophy in the anterior temporal lobe (ATL) region as well as in the inferior prefrontal cortex (IPC), some of the key regions of the semantic cognition network. These findings suggest that the semantic impairment in aMCI may result from a breakdown of semantic knowledge of famous people and objects, combined with difficulties in the selection, manipulation and retrieval of this knowledge.     

Patterns of impairment in autobiographical memory in the degenerative dementias constrain models of memory

Detailed study of the autobiographical memory (ABM) impairments seen in different forms of degenerative dementia, in particular Alzheimer's disease (AD) and semantic dementia (SD) can inform neuropsychological models of memory. A modified ABM questionnaire which allowed more detailed analysis of episodic and semantic ABM was used to study the pattern of deficits in patients with minimal to mild Alzheimer's disease (AD) and in two patients with mild and moderate semantic dementia (SD). The questionnaire tested both cued and free recall. A group of healthy elderly was also tested. AD patients differed from controls in all measures. There was no clear temporal gradient for episodic ABM, but a modest gradient was observed for semantic ABM. The mild SD patient performed at control level for episodic ABM but showed a deficit within the range of the AD patients for semantic ABM except for the most recent life period. In contrast the moderate SD patient was impaired within the range of the AD patients for both episodic and semantic ABM. The evidence for differential impairment of episodic and semantic ABM retrieval in AD and SD is interpreted as supporting the multiple trace model of memory.