Anosognosia in Alzheimer disease: Disconnection between memory and self-related brain networks.

OBJECTIVE: Impaired awareness is a common symptom in many mental disorders including Alzheimer disease (AD). This study aims at improving our understanding of the neural mechanisms underlying anosognosia of memory deficits in AD by combining measures of regional brain metabolism (resting state fluorodeoxyglucose positron emission tomography [FDG-PET]) and intrinsic connectivity (resting state functional magnetic resonance imaging [fMRI]). METHODS: Twenty-three patients diagnosed with probable AD based on clinical and biomarker data and 30 matched healthy control subjects were recruited in this study. An anosognosia index (difference between subjective and objective memory scores) was obtained in each participant. Resting state FDG-PET for glucose metabolism measurement and resting state fMRI for intrinsic connectivity measurement were also performed. AD and control groups were compared on behavioral data, and voxelwise correlations between anosognosia and neuroimaging data were conducted within the AD group. RESULTS: AD patients underestimated their memory deficits. Anosognosia in AD patients correlated with hypometabolism in orbitofrontal (OFC) and posterior cingulate (PCC) cortices. Using OFC and PCC as seed regions, intrinsic connectivity analyses in AD revealed a significant association between anosognosia and reduced intrinsic connectivity between these regions as well as with the medial temporal lobe. INTERPRETATION: Anosognosia in AD is due not only to functional changes within cortical midline structures involved in self-referential processes (OFC, PCC), but also to disconnection between these regions as well as with the medial temporal lobe. These findings suggest that the lack of awareness of memory deficits in AD results from a disruption of the communication within, but also between, the self-related and the memory-related brain networks.

Role of hippocampal CA1 atrophy in memory encoding deficits in amnestic Mild Cognitive Impairment.

Identifying the specific substrates of memory deficits in early Alzheimer's disease would help to develop clinically-relevant therapies. The present study assesses the relationships between encoding versus retrieval deficits in patients with amnestic Mild Cognitive Impairment (aMCI) and atrophy specifically within the hippocampus and throughout the white matter. Twenty-two aMCI patients underwent T1-weighted MRI scans and neuropsychological testing. Grey matter and white matter segments obtained from the MRI images were each entered in correlation analyses, assessed only in the hippocampus for grey matter segments, with encoding and retrieval memory performances. For the grey matter segments, the resulting spmT correlation maps were then superimposed onto a 3D surface view of the hippocampus to identify the relative involvement of the different subfields, a method already used and validated elsewhere. Memory encoding deficits specifically correlated with CA1 subfield atrophy, while no relationship was found with white matter atrophy. In contrast, retrieval deficits were weakly related to hippocampal atrophy and did not involve a particular subfield, while they strongly correlated with loss of white matter, specifically in medial parietal and frontal areas. In aMCI patients, encoding impairment appears specifically related to atrophy of the CA1 hippocampal subfield, consistent with the predominance of encoding deficits and CA1 atrophy in aMCI. In contrast, episodic retrieval deficits seem to be underlain by more distributed tissue losses, consistent with a disruption of a hippocampo-parieto-frontal network.

Longitudinal Study of Cognitive and Emotional Alterations in Amyotrophic Lateral Sclerosis: Clinical and Imaging Data.

Objectives: Extra-motor manifestations occur in 50% of patients with amyotrophic lateral sclerosis (ALS). These mainly concern cognition, emotional processing and behavior. Depression and anxiety are less frequent. Little is known about how these manifestations change as the disease progresses. Similarly, although cortical thinning has been well-documented at disease onset, there are scant data about cortical thinning over time and how this correlates with extra-motor manifestations. The present study therefore assessed cognitive, emotional and psychological state and cortical thinning in a group of patients with ALS at baseline and after a follow-up period. Methods: We assessed executive functions, facial emotion recognition, depressive and anxious symptoms, and cortical thinning in 43 patients with ALS at baseline, comparing them with 28 healthy controls, and 21 of them 9 months later. We looked for links among the extra-motor manifestations and correlations with cortical thickness. Results: At baseline, patients had poor executive function and recognition of complex emotions from the eyes, and more anxious and depressive symptoms than controls. At follow-up, only inhibition abilities had worsened. Cortical thinning was observed in bilateral pre-central regions and other parts of the cerebral cortex at baseline. Over time, it worsened in motor and extra-motor areas. Executive functions correlated with thinning in the middle and inferior frontal gyrus and orbitofrontal cortex. Conclusions: During follow-up, there was little deterioration in extra-motor manifestations and psychological state, despite continuing cortical thinning. Patients with affective Theory of Mind (ToM) changes seemed less depressed than the others. Impaired mental flexibility was subtended by prefrontal regions with cortical thinning.

Differential effect of age on hippocampal subfields assessed using a new high-resolution 3T MR sequence.

Recent advances in neuroimaging have highlighted the interest to differentiate hippocampal subfields for cognitive neurosciences and more notably in assessing the effects of normal and pathological aging. The main goal of the present study is to investigate the effects of normal aging onto the volume of the different hippocampal subfields. For this purpose, we developed a new magnetic resonance sequence together with reliable tracing guidelines to assess the volume of different subfields of the hippocampus using a 3 Tesla scanner, and estimated the validity of a simpler and less time-consuming method based on the widely-used automatic Voxel-Based Morphometry (VBM) technique. Three hippocampal regions of interest were delineated on the right and left hippocampi of 50 healthy subjects between 18 and 68 years old corresponding to the CA1, subiculum and other (including CA2-3-4 and Dentate Gyrus) subfields. A strong effect of age was found on the volume of the subiculum only, with a decrease paralleling that of the global gray matter volume, while CA1 and other subfields seemed relatively spared. Although less precise than the ROI-tracing technique, the VBM-based method appeared as a reliable alternative especially to distinguish CA1 and subiculum subfields. Our findings of a specific effect of age on the subiculum are consistent with the developmental hypothesis ("last-in first-out" theory). This contrasts with the predominant vulnerability of the CA1 subfield to Alzheimer's disease reported in several previous studies, suggesting that the assessment of hippocampal subfields may improve the discrimination between normal and pathological aging.

Patterns of autobiographical memory impairment according to disease severity in semantic dementia.

Studies of autobiographical memory in semantic dementia (SD) have yielded either a reversed temporal gradient or spared performances across the entire lifetime. This discrepancy might be owing to the fact that these studies did not take into account disease severity. Our aim was to study patterns of autobiographical memory impairment according to disease severity and to unravel their mechanisms in 14 SD patients, using an autobiographical memory task assessing overall and strictly episodic memories across the entire lifetime. We divided our patients in 2 subgroups of 7 patients each, one mild and one moderate according to their level of disease severity. The results indicated for the mild subgroup selective preserved performances for the most recent time period (last 12 months period) for both autobiographical memory scores. In the moderate subgroup, performances were impaired for both scores whatever the time period. Within-group comparisons across time periods showed a recency effect and a reminiscence bump in the mild subgroup and only a less important recency effect in the moderate subgroup, suggesting that with disease severity, old memories (reminiscence bump) tend to vanish and even recent memories are less well retrieved. A correlation analysis was carried out on the entire group, between the overall autobiographical memory score and performances provided by a general cognitive evaluation (semantic memory, executive functions, working and episodic memory). The results of this analysis reflect that mechanisms of disruption of autobiographical memory in SD predominantly involve a deficit of storage of semantic information in addition to faulty executive retrieval strategies. Finally, our result and those of the literature suggest the existence of 3 distinct autobiographical memory impairment patterns in SD according to disease severity: firstly preserved performances whatever the time period, secondly a reversed temporal gradient with a reminiscence bump and thirdly the appearance of a "step-function".

Is there a specific memory signature associated with Aß-PET positivity in patients with amnestic mild cognitive impairment?

Amnestic mild cognitive impairment (aMCI) is a clinical entity with various potential etiologies including but not limited to Alzheimer's disease. We examined whether a positive ([18F]Florbetapir) beta amyloid positron emission tomography scan, supporting underlying Alzheimer's disease pathophysiology, was associated with specific memory deficits in 48 patients with aMCI (33 beta amyloid positive, 15 beta amyloid negative). Memory was evaluated using an autobiographical fluency task and a word-list learning task with 2 different encoding types (shallow/incidental versus deep/intentional). Compared with 40 beta amyloid-negative controls, both aMCI subgroups demonstrated severe deficits in the global memory score and in most subscores of both tasks. Finer-grained analyses of memory tests showed subtle association with beta amyloid status, revealing a stronger impairment of the primacy effect in beta amyloid-positive patients. Structural magnetic resonance imaging showed that both aMCI subgroups exhibited comparable atrophy patterns, with similar degrees of medial temporal volume loss compared with controls. Specifically assessing the primacy effect might complement global memory scores in identifying beta amyloid-positive patients with aMCI.

An Impairment of Prospective Memory in Mild Alzheimer's Disease: A Ride in a Virtual Town.

Objective: Research suggests that prospective memory (PM) is impaired from the very early stages of Alzheimer's disease (AD). We sought to further characterize this impairment in patients with mild AD, using a virtual reality (VR) task to provide ecological assessment of PM. Methods: Fifteen cognitively normal older individuals (76.47 years old ± 4.14, MMSE: 28.80 ± 1.21), and 17 patients with mild AD (79.29 years old ± 4.45, MMSE: 22.82 ± 2.83) were asked to recall the prospective and retrospective components of seven intentions in a virtual town task. Six intentions were event-based, where the prospective cue was either highly (three intentions) or weakly (three intentions) associated with the retrospective component. The remaining intention was time-based. All participants completed a neuropsychological assessment of episodic memory, semantic memory and executive functioning. Non-parametric tests were used to compare the two groups on the different intentions types and components. Correlations between cognition and PM scores were then realized to further understand the cognitive correlates of the PM impairment in patients with AD. Results: Overall, patients with Alzheimer disease recalled fewer intentions than controls, with the retrospective component and time-based intentions being the most challenging for them. The strength of the association between the prospective and retrospective components, however, had no effect on their performance. Event-based PM impairment, as well as deficit in the recall of prospective component correlated with memory and executive functions performance. Conclusion: PM is impaired in AD. Both automatic and controlled processes of PM retrieval are disturbed. This study also confirms the reliability of VR for assessing complex cognitive functions such as PM.

Distinct neural substrates of affective and cognitive theory of mind impairment in semantic dementia.

Using structural MRI, we investigated the brain substrates of both affective and cognitive theory of mind (ToM) in 19 patients with semantic dementia. We also ran intrinsic connectivity analyses to identify the networks to which the substrates belong and whether they are functionally disturbed in semantic dementia. In line with previous studies, we observed a ToM impairment in patients with semantic dementia even when semantic memory was regressed out. Our results also highlighted different neural bases according to the nature (affective or cognitive) of the representations being inferred. The affective ToM deficit was associated with atrophy in the amygdala, suggesting the involvement of emotion-processing deficits in this impairment. By contrast, cognitive ToM performances were correlated with the volume of medial prefrontal and parietal regions, as well as the right frontal operculum. Intrinsic connectivity analyses revealed decreased functional connectivity, mainly between midline cortical regions and temporal regions. They also showed that left medial temporal regions were functionally isolated, a further possible hindrance to normal social cognitive functioning in semantic dementia. Overall, this study addressed for the first time the neuroanatomical substrates of both cognitive and affective ToM disruption in semantic dementia, highlighting disturbed connectivity within the networks that sustain these abilities.

Retrieval mechanisms for autobiographical memories: insights from the frontal variant of frontotemporal dementia.

Very few studies have investigated autobiographical memory in the frontal variant of frontotemporal dementia (fv-FTD). The aim of this study was therefore to unravel the mechanisms of autobiographical memory disruption in general and in the anterograde and retrograde components of amnesia in particular, in patients suffering from fv-FTD. An autobiographical memory task assessing overall (AM) and strictly episodic memories (EM) from five lifetime periods covering the entire lifespan revealed the absence of a temporal gradient for both scores, suggesting the existence of a retrieval deficit. An analysis of the correlation between these two scores and a general cognitive assessment of executive function, working, episodic (i.e. new learning ability) and semantic memory, and behavioural changes highlighted the considerable involvement of executive function, semantic memory and, to a lesser degree, episodic memory and behavioural changes. Moreover, step-wise regression analyses performed on the EM score revealed that the executive function was a better predictor of the retrograde component than of the anterograde component, which was linked principally to new episodic learning ability. All these results confirm the impact of executive dysfunction on autobiographical deficits in fv-FTD, and suggest that the mechanisms at the root of autobiographical memory disruption may also involve difficulties in new episodic learning and semantic storage, though this may be due to the fact that we studied an advanced form of fv-FTD.

Effects of partial sleep deprivation on within-format and cross-format priming.

STUDY OBJECTIVES: The purpose of this study was to examine the effects of sleep on long-term priming. We report the results of a preliminary experiment that enabled us to verify that priming can last for 4 hours, and we also report the results of a study of partial sleep-deprivation. DESIGN: Subjects performed 2 tasks: within-format and cross-format priming. SETTINGS: Sleep laboratory. PARTICIPANTS: Ninety-eight healthy young subjects participated in the 2 studies reported here: 48 in the preliminary experiment and 50 in the sleep-deprivation study. INTERVENTION: Testing after a 4-hour diurnal retention interval (Experiment 1) or after an equivalent interval filled with early or late sleep, or corresponding periods of wakefulness (Experiment 2). MEASUREMENTS AND RESULTS: A tachistoscopic identification paradigm, consisting of naming aloud briefly flashed drawings, was used to assess 2 priming conditions: a same-format or within-format condition (in which items were drawings in the study and test phases) and a different- or cross-format condition (in which the symbolic format of the items differed between the 2 phases: words/drawings). In Experiment 1, we revealed significant priming effects in both conditions after a 4-hour interval. In Experiment 2, only same-format priming effects were observed, but their magnitude was smaller than in Experiment 1. There was no significant difference in priming scores between the sleep and wake groups. CONCLUSIONS: Sleep does not appear to have a strong effect on priming. Instead, priming appears to be affected by circadian influences.

Neural substrate of cognitive theory of mind impairment in amyotrophic lateral sclerosis.

We now know that amyotrophic lateral sclerosis (ALS) is not restricted to the motor system. Indeed, a large proportion of patients with ALS exhibit cognitive impairment, especially executive dysfunction or language impairment. Although researchers have recently turned their attention to theory of mind (ToM) in ALS, only five studies have been performed so far, and they reported somewhat contradictory results. Moreover, the neural basis of the potential ToM deficit in ALS remains largely unknown. The present study was therefore designed to clarify whether a cognitive ToM deficit is indeed associated with ALS, specify the putative link between cognitive ToM deficits and executive dysfunction in ALS, and identify the dysfunctional brain regions responsible for any social cognition deficits. We investigated cognitive ToM and executive functions in a group of 23 patients with ALS and matched healthy controls, using an original false-belief task and a specially designed battery of executive tasks. We also performed an (18)F-fluorodeoxyglucose positron emission tomography examination. Results confirmed the presence of cognitive ToM deficits in patients compared with controls, and revealed significant correlations between ToM and executive functions, although the cognitive ToM deficit persisted when a composite executive function score was entered as a covariate. Using statistical parametric mapping, we calculated positive correlations between tracer uptake and false-belief scores on a voxel-by-voxel basis in the patient sample. Results showed that the cognitive ToM deficit correlated with the dorsomedial and dorsolateral prefrontal cortices, as well as the supplementary motor area. Our findings provide compelling clinical and imaging evidence for the presence of a genuine cognitive ToM deficit in patients with ALS.

Intrinsic connectivity identifies the hippocampus as a main crossroad between Alzheimer's and semantic dementia-targeted networks.

Alzheimer's disease (AD) and semantic dementia (SD) are both characterized by severe atrophy in the hippocampus, a brain region underlying episodic memory; paradoxically, episodic memory is relatively preserved in SD. Here, we used intrinsic connectivity analyses and showed that the brain networks differentially vulnerable to each disease converge to the hippocampus in the healthy brain. As neurodegeneration is thought to spread within preexisting networks, the common hippocampal atrophy in both diseases is likely due to its location at the crossroad between both vulnerable networks. Yet, we showed that in the normal brain, these networks harbor different functions, with episodic memory relying on the AD-vulnerable network only. Overall, disease-associated cognitive deficits seem to reflect the disruption of targeted networks more than atrophy in specific brain regions: in AD, over hippocampal atrophy, episodic memory deficits are likely due to disconnection within a memory-related network.

When Higher Activations Reflect Lower Deactivations: A PET Study in Alzheimer's Disease during Encoding and Retrieval in Episodic Memory.

The aim of the present study was to explore the cerebral substrates of episodic memory disorders in Alzheimer's disease (AD) and investigate patients' hyperactivations frequently reported in the functional imaging literature. It remains unclear whether some of these hyperactivations reflect real increased activity or deactivation disturbances in the default mode network (DMN). Using positron emission tomography ((15)O-H(2)O), cerebral blood flow was measured in 11 AD patients and 12 healthy elderly controls at rest and during encoding and stem-cued recall of verbal items. Subtractions analyses between the target and control conditions were performed and compared between groups. The average signal was extracted in regions showing hyperactivation in AD patients versus controls in both contrasts. To determine whether hyperactivations occurred in regions that were activated or deactivated during the memory tasks, we compared signal intensities between the target conditions versus rest. Our results showed reduced activation in AD patients compared to controls in several core episodic memory regions, including the medial temporal structures, during both encoding and retrieval. Patients also showed hyperactivations compared to controls in a set of brain areas. Further analyses conducted on the signal extracted in these areas indicated that most of these hyperactivations actually reflected a failure of deactivation. Indeed, whereas almost all of these regions were significantly more activated at rest than during the target conditions in controls, only one region presented a similar pattern of deactivation in patients. Altogether, our findings suggest that hyperactivations in AD must be interpreted with caution and may not systematically reflect increased activity. Although there has been evidence supporting the existence of genuine compensatory mechanisms, dysfunction within the DMN may be responsible for part of the apparent hyperactivations reported in the literature on AD.

Influence of patients' emotional state on the recovery processes after a transient global amnesia.

INTRODUCTION: Currently, there is no consensus on the delay necessary to a complete recovery after a transient global amnesia (TGA). However, it seems that slight episodic memory disorders extend beyond 24h. Although this impairment is probably a consequence of the TGA attack, other factors such as patients' emotional state can intervene in the slow recovery process. METHODS: In a first experiment, we studied the dynamic of recovery processes after a TGA. Thus, we assessed the anterograde and retrograde components of episodic memory in 19 patients one day, one month and one year after the attack. In a second experiment, we examined the impact of patients' emotional state on memory disorders, in using an original neuropsychological protocol (using material with emotional features) and an assessment of anxiety and depressive mood. This protocol was carried out in 19 other patients examined four months and one year after TGA. RESULTS: In the first experiment, we highlighted mild memory disorders affecting the anterograde component of episodic memory one day after the episode. In the second experiment, we showed these mild memory disorders could be detected several months after TGA. Moreover, patients who had the more depressive tendencies recognized the fewer items and those who displayed the highest level of anxiety supplied the fewer specific remote memories. CONCLUSIONS: Our results showed that patients displayed very mild memory disorders several months after the episode of TGA, not affecting the daily routine. This impairment was influenced by patients' emotional state, which could suggest that a high level of anxiety or depression can slow down the recovery. However, we cannot be sure that the deleterious effect of patients' emotional state on their cognitive performances is specific to TGA. Other investigations are necessary to unravel this issue.

Autonoetic consciousness in Alzheimer's disease: neuropsychological and PET findings using an episodic learning and recognition task.

OBJECTIVE: This study aims to map in patients with mild Alzheimer's disease (AD) the correlations between resting-state brain glucose utilization measured by FDG-PET and scores reflecting autonoetic consciousness in an episodic learning and recognition task. METHODS: Autonoetic consciousness, that gives a subject the conscious feeling to mentally travelling back in time to relive an event, was assessed using the Remember/Know (R/K) paradigm. RESULTS: AD patients provided less R responses (reflecting autonoetic consciousness) and more K ones (indicating the involvement of noetic consciousness) than healthy controls. Correct recognitions associated with a R response correlated with the metabolism of frontal areas bilaterally whereas those associated with a K response mainly correlated with the metabolism of left parahippocampal gyrus and lateral temporal cortex. CONCLUSIONS: These data show that recollection is impaired in AD and recognition is more based on a feeling of familiarity than in controls. In addition, the findings of our correlative approach indicate that the impairment of episodic memory is mainly subserved by the dysfunction of frontal areas and of the hippocampal region.

FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment.

The accurate prediction, at a pre-dementia stage of Alzheimer's disease (AD), of the subsequent clinical evolution of patients would be a major breakthrough from both therapeutic and research standpoints. Amnestic mild cognitive impairment (MCI) is presently the most common reference to address the pre-dementia stage of AD. However, previous longitudinal studies on patients with MCI assessing neuropsychological and PET markers of future conversion to AD are sparse and yield discrepant findings, while a comprehensive comparison of the relative accuracy of these two categories of measure is still lacking. In the present study, we assessed the global cognitive decline as measured by the Mattis scale in 18 patients with amnestic MCI over an 18-month follow-up period, studying which subtest of this scale showed significant deterioration over time. Using baseline measurements from neuropsychological evaluation of memory and PET, we then assessed significant markers of global cognitive change, that is, percent annual change in the Mattis scale total score, and searched for the best predictor of this global cognitive decline. Altogether, our results revealed significant decline over the 18-month follow-up period in the total score and the verbal initiation and memory-recall subscores of the Mattis scale. The percent annual change in the total Mattis score significantly correlated with age and baseline performances in delayed episodic memory recall as well as semantic autobiographical and category word fluencies. Regarding functional imaging, significant correlations were also found with baseline PET values in the right temporo-parietal and medial frontal areas. Age and right temporo-parietal PET values were the most significant predictors of subsequent global cognitive decline, and the only ones to survive stepwise regression analyses. Our findings are consistent with previous works showing predominant delayed recall and semantic memory impairment at a pre-dementia stage of AD, as well as early metabolic defects in the temporo-parietal associative cortex. However, they suggest that only the latter predictor is specifically and accurately associated with subsequent cognitive decline in patients with MCI within 18 months of first assessment.