Mathieu Ceccaldi

Nonmotor fluctuations in Parkinson’s disease Frequent and disabling

Objective:To assess the frequency and disability caused by nonmotor fluctuations (NMF) in PD. Methods:A structured questionnaire was administered to 50 patients with PD with motor fluctuations (MF), focused on 54 nonmotor symptoms classified in three subgroups: 26 dysautonomic, 21 cognitive and psychiatric, and seven pain/sensory NMF. The link between each NMF and the motor state was determined. Patients were asked to grade their disability from 0 (no disability) to 4 (maximum discomfort) and to specify which kind of fluctuation subgroup (motor or nonmotor) was the most incapacitating. A statistical analysis was performed to determine the frequency of each NMF and to determine whether the level of disability resulting from NMF could be correlated to the main characteristics of the population. Results:All patients had had at least one type of NMF, most of which were associated with the “off” state. Anxiety (66%), drenching sweats (64%), slowness of thinking (58%), fatigue (56%), and akathisia (54%) were the most frequent NMF. Some symptoms such as anxiety or dyspnea correlated with a greater level of disability. The total number of NMF was found to be correlated with the motor disability. Incapacity resulting from the dysautonomic fluctuations was also significantly correlated with levodopa treatment. Surprisingly, 28% of the patients stated that NMF involved a greater degree of disability than MF. Conclusion:Nonmotor fluctuations are frequent and debilitating in PD.

A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimers disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD‐I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.

Evaluation of visual recognition memory in MCI patients

Background: Neurofibrillary tangles seen early in Alzheimer disease (AD) initially appear in a subregion of the perirhinal cortex. In the monkey, damage to the perirhinal cortex impairs performance on visual recognition memory tasks. The authors evaluated impairment of visual recognition memory as a potential early diagnostic marker of AD. Methods: The authors developed a visual delayed matching-to-sample task (DMS48) designed to assess visual recognition memory in humans. Twenty-three patients fulfilling the criteria of amnestic mild cognitive impairment (MCI) (mean Mini-Mental State Examination [MMSE]: 26.6, SD = 1.6) were recruited. All underwent a full neuropsychological evaluation, which included the Free and Cued Selective Reminding (FCSR) test. Their performance was compared with that of 10 patients with mild AD, 20 patients with moderate AD, 20 patients with Parkinson disease (PD), and 40 age-matched controls. Results: Control subjects and patients with PD performed close to ceiling. Patients with mild AD had very low scores, while patients with moderate AD answered at random. MCI patients obtained scores that were between those of control subjects and patients with mild AD (78%, SD = 16%). MCI patients who failed on the DMS48 had lower scores on free recall (p < 0.05) and received less benefit from cueing (p < 0.01) on the FCSR than the other MCI, suggesting a profile of genuine memory impairment related to medial temporal lobe lesions. Conclusion: The DMS48, a test of visual recognition memory, is impaired early in the course of patients with MCI. Further studies are necessary to determine whether the evaluation of visual recognition memory may contribute to the identification of patients with AD.

Holistic perception of the individual face is specific and necessary : evidence from an extensive case study of acquired prosopagnosia

We present an extensive investigation (24 experiments) of a new case of prosopagnosia following right unilateral damage, GG, with the aim of addressing two classical issues: (1) Can a visual recognition impairment truly be specific to faces? (2) What is the nature of acquired prosopagnosia? We show that GG recognizes nonface objects perfectly and quickly, even when it requires fine-grained analysis to individualize these objects. He is also capable of perceiving objects and faces as integrated wholes, as indicated by normal Navon effect, 3D-figures perception and perception of Mooney and Arcimboldo face stimuli. However, the patient could not perceive individual faces holistically, showing no inversion, composite, or whole-part advantage effects for faces. We conclude that an occipito-temporal right hemisphere lesion may lead to a specific impairment of holistic perception of individual items, a function that appears critical for normal face recognition but not for object recognition.

Recommendations for the use of Serious Games in people with Alzheimer's Disease, related disorders and frailty.

Alzheimers disease and other related disorders (ADRD) represent a major challenge for health care systems within the aging population. It is therefore important to develop better instruments to assess the disease severity and progression, as well as to improve its treatment, stimulation, and rehabilitation. This is the underlying idea for the development of Serious Games (SG). These are digital applications specially adapted for purposes other than entertaining; such as rehabilitation, training and education. Recently, there has been an increase of interest in the use of SG targeting patients with ADRD. However, this field is completely uncharted, and the clinical, ethical, economic and research impact of the employment of SG in these target populations has never been systematically addressed. The aim of this paper is to systematically analyze the Strengths, Weaknesses, Opportunities, and Threats (SWOT) of employing SG with patients with ADRD in order to provide practical recommendations for the development and use of SG in these populations. These analyses and recommendations were gathered, commented on and validated during a 2-round workshop in the context of the 2013 Clinical Trial of Alzheimers Disease (CTAD) conference, and endorsed by stakeholders in the field. The results revealed that SG may offer very useful tools for professionals involved in the care of patients suffering from ADRD. However, more interdisciplinary work should be done in order to create SG specifically targeting these populations. Furthermore, in order to acquire more academic and professional credibility and acceptance, it will be necessary to invest more in research targeting efficacy and feasibility. Finally, the emerging ethical challenges should be considered a priority.

Patterns of semantic memory impairment in Mild Cognitive Impairment

Although the semantic memory impairment has been largely documented in Alzheimers disease, little is known about semantic memory in the preclinical phase of the disease (Mild Cognitive Impairment). The purpose of this study was to document the nature of semantic breakdown using a battery of tests assessing different aspects of conceptual knowledge: knowledge about common objects, famous people and famous public events. Results indicate that all domains of semantic memory were impaired in MCI individuals but knowledge about famous people and famous events was affected to a greater extent than knowledge about objects. This pattern of results suggests that conceptual entities with distinctive and unique properties may be more prone to semantic breakdown in MCI. In summary, results of this study support the view that genuine semantic deficits are present in MCI. It could be useful to investigate the etiological outcome of patients failing or succeeding at such tests.

Profile of memory impairment and gray matter loss in amnestic mild cognitive impairment

The present study assessed the patterns of cortical gray matter (GM) loss in patients with amnestic mild cognitive impairment (aMCI) with distinct profiles of memory impairment, i.e. aMCI patients failing on both recall and recognition memory vs. aMCI patients showing impaired recall but preserved recognition memory. This distinction is usually not taken into account in studies on aMCI and the aim of the present study was to assess whether this distinction is useful. Twenty-eight aMCI patients and 28 matched controls subjects were included. All aMCI patients failed a recall memory task (inclusion criteria). All underwent a visual recognition memory task (DMS48). However, 12 succeeded on this task while 16 failed. Relative gray matter (GM) loss was measured using voxel-based morphometry. When comparing aMCI patients to controls regardless of the profile of memory impairment, GM loss was found in temporal, parietal and frontal areas. However, in aMCI patients with preserved recognition (but impaired recall), GM loss was confined to frontal areas. This contrasted with GM loss in the right medial temporal lobe and bilateral temporo-parietal regions in aMCI patients with impaired recall and recognition memory, a pattern of GM loss usually described in early AD. We conclude that different profiles of memory impairment in aMCI patients are associated with distinct patterns of GM loss.

Basal functional connectivity within the anterior temporal network is associated with performance on declarative memory tasks

Spontaneous fluctuations in the blood oxygenation level-dependent (BOLD) signal, as measured by functional magnetic resonance imaging (fMRI) at rest, exhibit a temporally coherent activity thought to reflect functionally relevant networks. Antero-mesial temporal structures are the site of early pathological changes in Alzheimers disease and have been shown to be critical for declarative memory. Our study aimed at exploring the functional impact of basal connectivity of an anterior temporal network (ATN) on declarative memory. A heterogeneous group of subjects with varying performance on tasks assessing memory was therefore selected, including healthy subjects and patients with isolated memory complaint, amnestic Mild Cognitive Impairment (aMCI) and mild Alzheimers disease (AD). Using Independent Component Analysis on resting-state fMRI, we extracted a relevant anterior temporal network (ATN) composed of the perirhinal and entorhinal cortex, the hippocampal head, the amygdala and the lateral temporal cortex extending to the temporal pole. A default mode network and an executive-control network were also selected to serve as control networks. We first compared basal functional connectivity of the ATN between patients and control subjects. Relative to controls, patients exhibited significantly increased functional connectivity in the ATN during rest. Specifically, voxel-based analysis revealed an increase within the inferior and superior temporal gyrus and the uncus. In the patient group, positive correlations between averaged connectivity values of ATN and performance on anterograde and retrograde object-based memory tasks were observed, while no correlation was found with other evaluated cognitive measures. These correlations were specific to the ATN, as no correlation between performance on memory tasks and the other selected networks was found. Taken together, these findings provide evidence that basal connectivity inside the ATN network has a functional role in object-related, context-free memory. They also suggest that increased connectivity at rest within the ATN could reflect compensatory mechanisms that occur in response to early pathological insult.

The right temporal lobe variant of frontotemporal dementia : Cognitive and neuroanatomical profile of three patients.

The right temporal variant of frontotemporal lobar degeneration (Rtv-FTLD) is a focal degenerative condition affecting predominantly the right temporal lobe. The aim of this study was to further characterize the profile of cognitive impairment and the neuroanatomical basis of Rtv-FTLD patients without behavioural disturbances. A group of three patients with this syndrome had a detailed neuropsychological assessment, along with Voxel-Based Morphometry (VBM) of their brain to determine location of cortical atrophy. VBM analyses showed a pattern of atrophy that was predominant in the right hemisphere and concerned primarily the right anterior temporal lobe region. Patients carried out a test of famous people in which their ability to recognize, name and provide semantic information about famous persons from their faces, their voices and their names was investigated. They all showed a severe defect in recognizing, naming and identifying famous people irrespective of modality. Therefore, their inability to recognize famous people resulted from a multimodal defect (semantic). These results highlight the semantic nature of the defect, and suggest that the anterior right temporal lobe may have a prominent role in processing person-based semantic knowledge. This study helps in further understanding the neuropsychological profile of patients with Rtv-FTLD.

Functional connectivity changes differ in early and late-onset alzheimer's disease

At a similar stage, patients with early onset Alzheimers disease (EOAD) have greater neocortical but less medial temporal lobe dysfunction and atrophy than the late‐onset form of the disease (LOAD). Whether the organization of neural networks also differs has never been investigated. This study aims at characterizing basal functional connectivity (FC) patterns of EOAD and LOAD in two groups of 14 patients matched for disease duration and severity, relative to age‐matched controls. All subjects underwent an extensive neuropsychological assessment. Magnetic resonance imaging was used to quantify atrophy and resting‐state FC focusing on : the default mode network (DMN), found impaired in earlier studies on AD, and the anterior temporal network (ATN) and dorso‐lateral prefrontal network (DLPFN), respectively involved in declarative memory and executive functions. Patterns of atrophy and cognitive impairment in EOAD and LOAD were in accordance with previous reports. FC within the DMN was similarly decreased in both EOAD and LOAD relative to controls. However, a double‐dissociated pattern of FC changes in ATN and DLPFN was found. EOAD exhibited decreased FC in the DLPFN and increased FC in the ATN relative to controls, while the reverse pattern was found in LOAD. In addition, ATN and DLPFN connectivity correlated respectively with memory and executive performances, suggesting that increased FC is here likely to reflect compensatory mechanisms. Thus, large‐scale neural network changes in EOAD and LOAD endorse both common features and differences, probably related to a distinct distribution of pathological changes. Hum Brain Mapp 35:2978–2994, 2014.