Functional imaging of working memory in Parkinson's disease: compensations and deficits.

BACKGROUND AND PURPOSE: Over and above typical motor alterations, executive and working memory (WM) impairment can also occur in early idiopathic Parkinson's disease (PD). We aimed to investigate the compensatory neural processes involved in WM performance, as well as the networks involved in the long-term memory transfer from short-term stores in PD. METHODS: Relative cerebral blood flow (rCBF) was mapped with H2O(15)-PET in eight treated nondemented PD patients while performing a WM verbal double-task (Brown-Peterson paradigm) using both short (6-second) and long (18-second) delays. RESULTS: As compared to nine age-matched healthy subjects, performance of the PD group was only slightly reduced on the short-delay but markedly impaired on the long-delay task. Underlying the relatively preserved short-delay performance, the PD group exhibited overactivation of prefrontal and parietal areas involved in attention-demanding processes, suggestive of efficient compensatory processes. Further supporting this, significant positive correlations were found between short-delay performance and rCBF in the bilateral inferior parietal cortex. In contrast, the lack of overactivation with the long-delay task together with posterior cingulate hypoactivation would support the idea of functional disconnection impairing transfer of information from prefrontal onto (para)limbic areas. These findings suggest novel areas of investigation into early cognitive impairments in PD.

Neuropsychological and 18FDG-PET studies in a family with idiopathic basal ganglia calcifications.

Idiopathic basal ganglia calcification (FIBGC) is a rare autosomal dominant neurodegenerative disease, the main clinical signs of which are parkinsonism, cognitive deterioration and/or psychiatric troubles. Familial forms are rare. The underlying basis is not known. We performed detailed neurological, neuropsychological, brain CT scans and MRI evaluations in 15 patients of a large FIBGC family. Three patients also underwent a (18)FDG-PET scan study not previously performed in patients with FIBGC. Basal ganglia calcifications were present in 8 individuals, 3 of which had schizophrenia-like psychosis, cognitive and/or extrapyramidal signs. The mean age at disease onset was 34.0+/-3.6 years. Two patients had moderate executive dysfunction, whereas the proband had more severe dementia. (18)FDG uptake was significantly reduced in striatal or cortical areas, including the precuneus, posterior cingulate and superior temporal gyri. This study shows that calcifications and striatal neuronal degeneration can occur independently, and that functional changes in cortical areas can be observed early in FIBGC. Hypometabolism in the precuneus and posterior cingulate gyrus, which are involved in episodic memory processing, could be responsible for the episodic memory deficit found in the patients. Whether the underlying mechanism involves a neuronal loss or a functional alteration remains to be elucidated.

Utility of the Mattis dementia rating scale to assess the efficacy of rivastigmine in dementia associated with Parkinson's disease.

INTRODUCTION: The severe, cortical, cholinergic depletion accompanying Parkinson's disease (PD) is considered as a highly probable correlate of cognitive and behavioural dysfunction. Recent studies have demonstrated that cholinesterase inhibitors (notably rivastigmine) are beneficial in patients suffering from dementia associated with PD (PDD). However, the primary efficacy variables used in such work came from scales designed for Alzheimer's disease (AD), even though the cognitive symptoms in PD and AD dementia do not overlap completely. The aim of the present study (a double-blind, placebo-controlled clinical trial) was to determine the utility of the Mattis dementia rating scale - the most commonly used scale in PD patients - to assess the efficacy of a 24-week rivastigmine treatment. METHODS: Twenty-eight patients with PD, who constituted a subgroup of patients enrolled to the EXPRESS study (Emre et al, N Engl J Med 2004) participated in this study. They suffered from mild to moderately severe dementia (MMSE scores above 10 and below 24), with an onset of cognitive symptoms occurring at least two years after the diagnosis of PD. Patients were randomly assigned to treatment with rivastigmine (3 to 12 mg per day) or placebo. The Mattis dementia rating scale was administered to patients from six centres in France at the baseline and end-point visits. RESULTS: Compared with placebo, a 24-week rivastigmine treatment led to a significant improvement in the overall score on the Mattis dementia rating scale (p = 0.031), with a trend towards a significant improvement in the "Attention" subscale score (p = 0.061). Correlation analysis showed that in the rivastigmine group, performance on the Mattis "Attention" and "Initiation" subscales appeared to contribute heavily to the improvement in the overall score. Moreover, the latter was also related to an improvement in activities of daily living and a reduction in behavioural disturbances. DISCUSSION: By using the Mattis dementia rating scale (which comprises items that are sensitive to executive dysfunction), the present study confirmed that rivastigmine has a beneficial effect on cognitive function in PDD. Despite our study's small sample size, the Mattis scale was able to detect this improvement and could thus be considered as an interesting outcome measure in further work.

Virtual action planning in Parkinson's disease: a control study.

Cognitive planning deficits affect patients with Parkinson's disease (PD) and traditional psychometric tests meet difficulties to evaluate their impact on daily life activities. Virtual reality (VR) may provide a new means of assessment. The objective of this study was firstly to develop a virtual environment (VE) useful to explore planning and secondly to examine the effectiveness of using VR in the assessment of cognitive planning for patients with PD. A virtual supermarket (VS) was designed in which participants carried out a task close to daily activities: a test of shopping list. There were two preliminary sessions to familiarize the participants with the software and the supermarket's layout. Then, during the assessment session, participants completed the task, without any time limitation. Global intellectual efficiency was assessed in order to exclude patients with dementia. Data related to the performance in the VS were recorded. Five patients with PD and five age-matched healthy volunteers, meeting inclusion criteria, constituted our convenience sample. The patients did not perform as well as the control group. In particular, the session's duration and the distance covered were longer. The patients' path is specific with numerous stops, turning around, and hesitancies. Finally, their motivation for further training sessions is aroused. The results underline the potential of using VR in the assessment of cognitive planning in PD. A larger analysis is currently being carried out to confirm and to explore all the outcome measures.

Reduced thalamic and cerebellar rest metabolism in relapsing-remitting multiple sclerosis, a positron emission tomography study: correlations to lesion load.

Magnetic resonance imaging (MRI) is the main tool for detecting central nervous system lesions in MS. However, classical anatomical MRI is unable to assess exactly disease related injury in normal-appearing brain tissue and to give information about the functional consequences of the disease, explaining weak correlation frequently observed between lesion load and clinical data. Recently, functional brain imaging techniques have provided new insights concerning pathophysiological processes of the disease. Among them Positron Emission Tomography (PET), a sensitive technique to evaluate functional consequences of tissue injury in other neurological diseases, has rarely been used in MS. Seventeen Relapsing-Remitting (RR-) MS patients with low disability at the early stage of the disease underwent measurements of cerebral metabolic rate of glucose (rCMRglu) in resting state by PET using [(18)F] fluorodeoxyglucose (FDG) and assessment of regional cortical and white matter lesion volume (LV), using an in-house-developed semi-automatic method, was done at the same time on MRI. rCMRglu of MS patients was compared with rCMRglu of 18 normal control subjects using univariate SPM99 analysis through Matlab 5 and correlations between rCMRglu and LV were tested using multivariate linear regression using SPM99. Statistical threshold was set at p<0.05 corrected for multiple comparisons and correlations. Compared to controls, reduced rCMRglu was found in the right thalamus (p<0.001), in bilateral cerebellum (p<0.05 for right and p<0.01 for left) and the posterior part of left inferior parietal cortex (p<0.05). In addition, higher rCMRglu in patients compared to controls was observed in left inferior frontal cortex, left (anterior part) and right inferior parietal cortex (p<0.001). rCMRglu in right thalamus correlates negatively with different LV: total LV, total juxtacortical and/or overlapping cortico-subcortical LV, total and frontal deep white matter LV. rCMRglu of the right superior frontal cortex negatively correlated with total and parieto-occipital deep white matter LV. The results of this study, performed in a group of recent RR-MS patients with low disability, suggest that demyelinating lesions in MS mainly have a remote effect on cortical, basal ganglia and cerebellum metabolism and that regional cortical compensatory mechanisms may be observed concurrently.

Impairments of executive/attentional functions in schizophrenia with primary and secondary negative symptoms.

Frontal cognitive inabilities have been amply described in schizophrenic patients with negative symptoms, but findings are controversial. These discrepancies could be due to the fact that negative symptoms are heterogeneous, composed of primary and secondary negative symptoms. The hypothesis tested was that executive/attentional dysfunctions would be significantly more impaired in patients with primary than in patients with secondary negative symptoms independently of IQ, the severity of negative or positive symptoms, treatments and side effects. Fifty-six DSM-IV schizophrenic patients characterized either by primary or secondary negative symptoms and 56 controls matched on age, sex and level of education were assessed with executive/attentional cognitive tests. The categories score of the Modified Card Sorting Test (MCST) and the Verbal Fluency Test, which reflect solving and organizing skills, were significantly more impaired in the primary negative subtype than in the secondary negative subtype. In contrast, scores on the MCST (perseveration), the Trail Making Test and the Stroop Color Word Test, which test the ability to inhibit an automatic response, did not differ between the two subtypes. In conclusion, this study supports the view that primary and secondary negative symptoms could be associated with different levels of executive/attentional dysfunctions.

Executive processes in Parkinson's disease: FDG-PET and network analysis.

It is assumed widely that the clinical expression of Parkinson's Disease (PD), both motor and cognitive, is subtended by topographically distributed brain networks. However, little is known about the functional neuroanatomy of executive dysfunction in PD. Our objective was to validate further in a PD group the use of network analysis to assess the relationship between executive processes and pathological disorganization of frontostriatal networks. We studied 15 patients with idiopathic PD, and 7 age-matched normal controls, using resting [(18)F]fluorodeoxyglucose (FDG) and high-resolution positron emission tomography (PET). We carried out network analysis on regional metabolic data to identify specific covariation patterns associated with motor and executive dysfunction. We detected two independent patterns relating respectively to the two clinical abnormalities. The first pattern (principal component 1) was topographically similar to that described previously in other PD populations. Subject scores for this pattern discriminated patients from controls and correlated significantly with bradykinesia ratings (P = 0.013, r = 0.655) in PD patients. The second pattern (principal component 2) was characterized by relative ventromedial frontal, hippocampal, and striatal hypometabolism, associated with mediodorsal thalamic hypermetabolism. In the PD group, scores from this pattern correlated with scores on the conditional associative learning (CAL; P = 0.01, r = 0.690) and the Brown Peterson paradigm (BPP; P = 0.017, r = -0.651) tests, respectively assessing strategy and planning, and working memory. According to these findings, the networks subserving bradykinesia and executive dysfunction in PD seems to be topographically distinct and to involve different aspects of subcortico-cortical processing.

Behavioral and neurofunctional changes over time in healthy and aphasic subjects: a PET Language Activation Study.

BACKGROUND AND PURPOSE: Follow-up neuroimaging studies of aphasia never addressed a comparison between aphasic and healthy subjects. Investigation of changes over time in healthy subjects during language tasks seems a prerequisite before interpretation of longitudinal changes in aphasic patients. METHODS: Six healthy subjects and 8 aphasic patients were PET scanned twice (PET1 and PET2) at a 1-year interval during a word generation task. Using SPM99, language-rest main effect was compared at PET1 and PET2 in each group, whereas group effect was assessed at each session. Correlations were analyzed in each group between performance indexes and changes in regional cerebral flood flow (rCBF) between the 2 sessions. RESULTS: Language performances were improved in both groups. rCBF decreased from PET1 to PET2 in the healthy group and increased in the aphasic group in perisylvian regions bilaterally. Correlations between performance and rCBF changes across sessions were similar in the 2 groups; positive correlations involved superior temporal cortexes bilaterally, and negative correlations concerned superior frontal and medial temporal regions. CONCLUSIONS: Increased perisylvian activation over time probably reflects improved performance at the expenses of cognitive effort in aphasic patients. Decreased activation in different neural systems suggests a familiarization effect with reduced emotional load.

Functional imaging of cognition in Parkinson's disease.

PURPOSE OF REVIEW: Cognitive deficits that occur even early in the course of Parkinson's disease have received increasing attention in current imaging research. The exact physio-pathological processes mediating the deficits and the complex relationship of cognitive signs and antiparkinsonian treatment are not well understood. A clearer understanding of these mechanisms could potentially influence treatment choices, drug development and, ultimately, patient care. RECENT FINDINGS: Abnormal networks identified in studies of resting state metabolism in Parkinson's disease represent metabolic markers for remote effects of striato-nigral degeneration. These metabolic changes include subcortico-cortical networks, in particular cognitive cortico-striato-pallidal-thalamocortical loops. Recent brain studies focus on intervention-related brain changes. They illustrate different task-specific changes in brain activation with deep brain stimulation and with levodopa. Variable results of stimulation can be attributed to different effects on segregated cortico-striato-pallidal-thalamocortical loops during stimulation. By contrast, the heterogeneity observed in studies with levodopa possibly reflects the disease-stage and task-specific effects of levodopa. A decline in caudate dopamine modulated basal ganglia outflow appears to contribute to executive dysfunction and to brain activation changes in these loops at early Parkisnon's disease stages, while mesocortical degeneration mediated increases of inefficient dorsolateral prefrontal cortex activation may display a feature of more advanced disease stages only. SUMMARY: Despite evidence for the role of dopamine and cortico-striato-pallidal-thalamocortical loops in cognition, the specific contributions of mesocortical dopamine depletion and striatal dysfunction with downstream consequences on the loops remain to be separated. Additionally, more research is needed into the role of non-dopaminergic pathology in cognitive decline in Parkinson's disease.

Verbal learning and memory in schizophrenic and Parkinson's disease patients.

The purpose of this study was to investigate the neurofunctional substrate of verbal learning and memory impairments in schizophrenic patients. In this pilot study, our aim was to compare the memory disturbance of schizophrenic patients to the subcortico-frontal memory profile of Parkinson's disease (PD) patients. The California Verbal Learning Test, a verbal episodic memory test, was administered to 60 subjects, 20 patients with schizophrenia, 20 patients with PD and 20 healthy control subjects. All subjects were aged between 50 and 70 years and all patients were in a stable phase. Like the Parkinson patients, the schizophrenic patients showed a major deficit of retrieval characterized by deficit of recalls but contrarily to PD patients, schizophrenic patients' encoding scores were altered. These impairments in episodic memory could suggest a dysfunction of the subcortico-frontal circuits in schizophrenic patients. However, they demonstrated an additional encoding deficit associated with probable frontal in situ alteration.

Working memory and dopamine: clinical and experimental clues.

Working memory has been successively considered as a mnesic or executive process. The cognitive processes involved in working memory and the executive functions are closely linked. Most authors currently agree that executive functions include planning, attentional maintenance, mental flexibility and attentional inhibition. Considering that the role of the central administrator, the main module of the working memory model, is to manage new situations, inhibit old non-pertinent schemes, or carry out attentional control, it is clear that it involves the different executive processes mentioned above. Therefore, even though the working memory model has its origins in the classic concept of short-term memory, it is now situated at the interface between memory and executive functions. The identification of the neuroanatomical support of these processes has been widely explored for many years. The involvement of monoaminergic neurotransmitter systems, and in particular of the dopaminergic system, in these complex cognitive functions has been suggested by numerous studies, both in humans and in non-human primates.

Executive/attentional cognitive functions in schizophrenic patients and their parents: a preliminary study.

The aim of this study was to determine whether executive/attentional cognitive performances could be considered as markers of vulnerability to schizophrenia. The Stroop Color Word and fluency tests were significantly impaired in schizophrenic patients and their parents compared to controls matched on age and sex while performances on Nelson's Modified Card Sorting Test and the Trail Making Test did not differ. The impairments on the Stroop and fluency could be considered as endophenotypic markers of schizophrenia.