Cognitive complaint in early Parkinson's disease: A pilot study.

BACKGROUND: Subjective cognitive complaint (SCC) is a criterion recommended by the Movement Disorder Society (MDS) task force for the diagnosis of mild cognitive impairment (MCI). Until now there were few specific tools for detecting SCC in PD. We sought to develop a new tool to assess SCC specifically dedicated for PD. MATERIALS AND METHODS: We set a group of experts in movements disorders and neurocognition to develop an easy-to-use tool based on a visual analogue scale (VAS) for five cognitive domains: memory, executive functions, spatial orientation, attention, and language. We use it to assess SCC twice (at a one-month interval) in PD patients with disease duration of less than 5 years. Comprehensibility of the VAS was assessed. Controls were assessed with the same VAS. Patients with PD also underwent neuropsychological testing. RESULTS: VAS was easily understandable by the 70 patients with PD. We found significant SCC for the patients with PD vs controls in three cognitive domains: executive functions (1.7 ± 1.9 vs 0.8 ± 1.1; P < .001), language (2.3 ± 2.5 vs 1.0 ± 1.3, P < .001), and attention (2.1 ± 2.2 vs 1.2 ± 1.2; P < .01). Reproducibility between the two evaluations of patients with PD was good. There was no relationship between SCC and the results of neuropsychological testing. CONCLUSIONS: SCC seems to appear early in PD, in three cognitive domains (executive functions, language, and attention), and VAS might be a good way to detect SCC in PD, but need to be validated.

Neuropsychological outcome after a first symptomatic ischaemic stroke with 'good recovery'.

BACKGROUND: Neuropsychological impairment after stroke when no motor, sensory or language deficits are left remains understudied. The primary aim of this study was to assess neuropsychological outcome in a specific population of patients after a first symptomatic stroke without previous cognitive decline and with a good motor, linguistic, and functional recovery (i.e. 'good outcome'). The secondary aims were to identify the profile of this potential impairment and relations between brain lesions and neuropsychological outcome. METHODS: Sixty consecutive patients were evaluated by a comprehensive neuropsychological assessment focusing specifically on executive and attentional functions but also on memory 109 days, on average, after the infarct. Patients were compared with 40 healthy controls matched for age and education. RESULTS: Patients showed lower performance in every cognitive domain compared with controls. Along with an important executive deficit, patients were also impaired on attention and memory. Patients were not more depressed than controls, although they were more apathetic. We also found a significant positive correlation between cognitive impairment and pre-existing white matter brain lesions assessed by MRI. CONCLUSIONS: We report the first study examining the impact of a first stroke on cognition but also on psychiatric disorders in patients with good functional outcome. We found that patients considered as asymptomatic were, in fact, exhibiting a multidomain cognitive deficit that could impact return to life as before stroke.

[Early diagnosis of Alzheimer's disease]. / Diagnostic précoce de la maladie d'Alzheimer.

INTRODUCTION: Diagnosis of Alzheimer's disease (AD) remains difficult to establish, and can only be considered as certain thanks to anatomopathological evidence, or genetic mutations. Current diagnostic criteria rely on innovative imaging and biological tools, in order to detect pathological cues from very early stages, and with best sensibility and sensitivity. STATE OF ART: Advances in neuro-imaging enabled the development of different tools to help establishing the diagnosis, such as cerebral atrophy assessment on magnetic resonance imaging (MRI), and cerebral metabolism study on positron emission tomography (PET). Besides, the increasing use of in vivo biological markers, combined to clinical criteria, enables to discriminate patients from healthy controls at even earlier stages. This includes studies on tau and beta-amyloid proteins concentrations in the cerebrosinal fluid, and amyloid-specific radioligands uptake. Familial forms of Alzheimer represent a great model for studying early or even pre-symptomatic AD, as genetic analyses constitute a diagnosis of certainty, even though they usually evolve earlier and faster. PERSPECTIVES, CONCLUSION: Diagnostic tools are more and more numerous and performant. According to patients' clinical heterogeneity, it appears essential to associate different method to investigate, in order to make a diagnosis as early and as reliable as possible.

[Anterograde declarative memory and its models]. / La mémoire déclarative antérograde et ses modèles.

INTRODUCTION: Patient H.M.'s recent death provides the opportunity to highlight the importance of his contribution to a better understanding of the anterograde amnesic syndrome. The thorough study of this patient over five decades largely contributed to shape the unitary model of declarative memory. This model holds that declarative memory is a single system that cannot be fractionated into subcomponents. As a system, it depends mainly on medial temporal lobes structures. The objective of this review is to present the main characteristics of different modular models that have been proposed as alternatives to the unitary model. It is also an opportunity to present different patients, who, although less famous than H.M., helped make signification contribution to the field of memory. STATE OF THE ART: The characteristics of the five main modular models are presented, including the most recent one (the perceptual-mnemonic model). The differences as well as how these models converge are highlighted. PERSPECTIVES: Different possibilities that could help reconcile unitary and modular approaches are considered. CONCLUSION: Although modular models differ significantly in many aspects, all converge to the notion that memory for single items and semantic memory could be dissociated from memory for complex material and context-rich episodes. In addition, these models converge concerning the involvement of critical brain structures for these stages: Item and semantic memory, as well as familiarity, are thought to largely depend on anterior subhippocampal areas, while relational, context-rich memory and recollective experiences are thought to largely depend on the hippocampal formation.

[Functional neuroimaging and the treatment of aphasia: speech therapy and repetitive transcranial magnetic stimulation]. / Imagerie fonctionnelle cérébrale et prise en charge thérapeutique de l'aphasie : orthophonie et stimulation magnétique transcrânienne répétitive.

Functional imaging has provided new evidence of the neurobiological impact of the treatment of aphasia, including speech therapy, through the alteration of the activated language neural network. In such a way, speech therapy has proved its impact. The role of each hemisphere is still very unclear. Some of the authors link the left-lateralisation of activations to the therapeutic improvement of language and the right-activated network to a maladaptative strategy, whereas others consider the latter as a useful compensatory network for speech disorders. Repetitive trans-cranial magnetic stimulation (rTMS), first used to determine cortical activity, is now used to directly interfere with cerebral activity. In the years to come, rTMS should be developed as an adjuvant therapy for aphasia.

Use of haplotype information to test involvement of the LRP gene in Alzheimer's disease in the French population.

The low density lipoprotein receptor-related protein gene (LRP) is a good candidate gene for Alzheimer's Disease (AD). Its protein is involved in the physiopathology of AD and has been found in senile plaques; on the other hand, LRP is located in 12q, a region in which genetic linkage to AD was reported. Two common polymorphisms, a tetranucleotide repeat in the 5' untranslated region and a single nucleotide polymorphism at position 766 in exon 3, were found to be associated with AD, but contradictory results were obtained in subsequent association studies. In the absence of clear hypotheses concerning the association of these polymorphisms with AD and their functional role, our objective was to test the association between AD and the two LRP polymorphisms in a large French case-control sample (274 Caucasian AD patients and 290 matched controls) using haplotype analysis. First, the separate study of each polymorphism showed no significant difference in genotype and allele frequencies between AD cases and controls. Second, strong linkage disequilibrium was found between alleles of the two polymorphisms in controls and in cases and the linkage disequilibrium between the 91 bp and C alleles were opposite in cases and in controls. Third, we found that the frequency of the 91-C haplotype was higher in cases than in controls, but the type I error was 0.061, slightly higher than the conventional one of 5%. The haplotype frequencies did not vary significantly as a function of age and APOE epsilon4 status. One interest in this study is the use of the haplotype analysis, which can be used to combine information from several polymorphisms, taking into account their dependence.

APOE promoter polymorphisms do not confer independent risk for Alzheimer's disease in a French population.

The apolipoprotein E (APOE, gene; apoE, protein) isoforms are associated with differential risk of Alzheimer's disease (AD). An additional involvement of APOE promoter polymorphisms in AD risk has recently been suggested by several studies. Indeed, three polymorphisms of the APOE regulatory region (-219 G/T, -427 C/T and -491 A/T) have been found associated with AD even after adjustment on the apoE status. We analysed these three promoter region polymorphisms in a large French case-control study (388 AD cases and 386 controls). We found that the -427 T and -491 A alleles were associated with an increased risk of developing AD, but not the -219 G/T alleles. However, a strong linkage disequilibrium was observed between the alleles of these promoter region polymorphisms and the APOE coding region alleles. We therefore retested association after adjustment on apoE status and found that the sole association which remained significant was the association with the -427 T allele. The alpha level was equal to 0.03 (0.09 after Bonferroni correction for multiple comparisons). Analysis of promoter haplotypes also yielded non-significant results. Thus our study does not reinforce the hypothesis of an independent involvement of the APOE promoter region polymorphisms in AD risk.

Brain correlates of memory processes in patients with dementia of Alzheimer's type: a SPECT Activation Study.

Task-induced changes in regional cerebral blood flow (rCBF) during verbal episodic memory activation were compared in 17 right-handed patients with dementia of the Alzheimer's type (DAT) and 20 healthy volunteers. Regional cerebral blood flow was assessed using single photon emission computed tomography (SPECT) and an injection of 133Xe (xenon, isotope of mass 133) in 21 regions of interest (ROI) during rest, passive listening to 36 words, and memorizing of a 12-word list repeated three times. In healthy subjects, memory-listening comparison showed activation of a distributed system involving several left-sided ROI, especially the posterior inferior frontal region. In patients with DAT, the same pattern of activation was found for listening-rest comparison, and no significant changes were found in memory-listening comparison. During listening compared with rest, significant activation was observed in left-sided hypoperfused regions. A significant correlation between memory performance and rCBF recorded in patients with DAT during the memory task was found only in the right lateral frontal region, a region that was not hypoperfused significantly in patients. The involvement of this region might relate to either retrieval effort or actual performance of patients with DAT on the memory task.

Apolipoprotein E epsilon4 allele and familial aggregation of Alzheimer disease.

OBJECTIVE: To investigate the relationship among risk for Alzheimer disease (AD), familial aggregation of AD, and the apolipoprotein E (apoE) epsilon4 allele in first-degree relatives of probands with AD and known apoE genotype. PATIENTS: Two hundred ninety subjects fulfilling the criteria of the National Institute of Neurological Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association for probable AD were ascertained from March 1, 1992, to December 31, 1996, through consecutive admissions in several university hospitals. DESIGN AND METHODS: Family data were collected on 1176 first-degree relatives (parents and siblings), aged 40 to 90 years. Most living relatives underwent a clinical examination, whereas we relied on family history for clinical data for deceased or unavailable relatives. First, we conducted standard survival analyses to estimate cumulative lifetime risk (LTR) for AD among relatives and to investigate for sex and apoE genotype effects on LTR. Then, we assessed to what extent clustering of secondary AD could be explained by the apoE epsilon4 allele by deriving the expected proportions of relatives with 0, 1, or 2 apoE epsilon4 alleles conditionally on the proband's genotype. RESULTS: Cumulative LTR for AD among first-degree relatives increased significantly with the number of epsilon4 alleles present in the proband. By 90 years of age, LTRs in relatives of probands with epsilon3/epsilon3, epsilon3/epsilon4, and epsilon4/epsilon4 genotypes were 29.2%, 46.1%, and 61.4%, respectively. Significant sex-by-apoE genotype interaction effects on LTR were observed. Women had about a 2-fold higher risk for AD than men among relatives of epsilon4 carriers but not among relatives of non-epsilon4 carriers. The predicted proportion of epsilon4 carriers in relatives of probands with epsilon3/epsilon3 genotype remains about 50% lower than the corresponding LTR for AD, indicating that familial clustering of AD is largely due to other factors than the apoE epsilon4 allele. Although aggregation of AD in families of probands with the epsilon4 allele is more prominent, we estimated that AD would not develop in about 30% of female and up to 60% of male relatives carrying at least 1 epsilon4 allele, even by 90 years of age. CONCLUSION: Our results support the hypothesis that the apoE epsilon4 allele enhances AD susceptibility, but putative factors enhancing risk for AD remain to be found.

Living/non-living dissociation in a case of semantic dementia: a SPECT activation study.

A category-specific dissociation with massive deficits in semantic knowledge of animals and preservation of knowledge of objects was observed in a demented patient with a left inferior temporal cortical atrophy responsible for a deficit of visual semantic processing. When the patient successfully processed the semantic feature of aurally presented object names, a SPECT study showed an activation of the left posterior and middle temporal cortex (Wernicke's area). This haemodynamic pattern was not observed during an unsuccessful processing of animal names that was associated with an activation of the left and right inferior frontal regions. Activation in Wernicke's area probably reflects an adequate matching between auditory lexical input and semantic knowledge for entities with multimodal representations, such as man-made objects. Activation in Broca's area and its right homologous region may correspond to an unsuccessful phonological strategy to evoke semantic features of animals, a category that is mainly visually represented.

Right temporal compensatory mechanisms in a deep dysphasic patient: a case report with activation study by SPECT.

A brain activation study using SPECT and 133Xe in a deep dysphasic patient with left temporal lesion is presented. The activation paradigm consisted of a passive listening to foreign language as baseline, a phoneme monitoring condition and a semantic word monitoring condition. The specific activation of the right middle temporal cortex observed in the semantic condition is congruent with the hypothesis of a compensatory role of the right hemisphere in processing concrete words. This case illustrates the interest of functional imaging for a better understanding of neural mechanisms of functional recovery after brain injury.

A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years.

We have identified a novel Alzheimer's disease family in which affected subjects had a very young age of onset (range 29-35 years). Neuropathological confirmation of the diagnosis was obtained for one patient. Molecular analysis shows that within this family the disease results from a missense mutation at codon 235 of the presenilin 1 (PS-1) gene. Two patients had exhibited generalized tonico-clonic seizures several years before the onset of dementia. Whether this particular clinical feature is a consequence of the PS-1 mutation remains to be established. The Leu235Pro mutation is, to our knowledge, the PS-1 mutation associated with the youngest age of AD onset, which suggests that it has a drastic effect on PS-1 function.

Lateral asymmetries in primary degenerative dementia of the Alzheimer type. A correlative study of cognitive, haemodynamic and EEG data, in relation with severity, age of onset and sex.

Cognitive, haemodynamic and EEG lateral asymmetries have been quantified in 20 patients with Primary Degenerative Dementia (PDD) and in 20 age-matched normal volunteers. Normalized asymmetry scores were calculated from the data obtained with a test battery, with SPECT and with quantitative EEG. Significant correlations were found between cognitive, haemodynamic and EEG scores in patients but not in controls. The functional asymmetries correlated to the Mini Mental State (MMS) score, the lowest MMS values being observed in patients with right hemisphere predominant impairment. Besides, in these patients, a significant correlation was observed between age at onset and MMS score so that, in this subgroup only, the earlier the onset the more severe the disease. Finally, the prevalence of pronounced functional asymmetry seemed to be higher in our male patients. Our study shows that lateral asymmetries are frequent in patients with PDD and that preferential lateralization of the abnormalities should be given further attention, especially with regards to age, sex and overall severity.

Brain functional profiles in formal and semantic fluency tasks: a SPECT study in normals.

SPECT method is used to analyze changes in regional cerebral blood flow in a group of 19 normal subjects during a baseline task (repetition of two words) and two verbal fluency tasks, a semantic fluency and a formal fluency. The semantic fluency task was associated with a relative CBF increase in the right dorso-lateral and medial frontal region when compared with that seen in the baseline condition. No specific activation was found for the formal fluency task compared to that seen in the baseline task. We suggest that the activation of the right frontal region reflects semantic categorization strategies in semantic fluency. The lack of activation of the left frontal region may be due to an activation induced by the nature of the baseline task (i.e., a self-paced repetition task).

Lexical therapy and episodic word learning in dementia of the Alzheimer type.

The effect of a language therapy in a group of eight anomic mild patients (the Lexical Therapy group) was assessed by using a 5-month long Lexical Therapy in comparison with an occupational program used in a matched control group (AD; n = 8). The Lexical Therapy group benefited significantly from a language therapy as shown by the naming improvement postintervention. The improvement reached significance only for items that were included in the language therapy protocol and no significant generalization to untreated items was observed. In mild AD patients with anomia and no severe semantic impairment, a reinforcement of the relationship between the form of the object and the corresponding lexical label in episodic long term memory during language therapy may account for the observed lexical improvement.

[Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level]. / Evocation lexicale formelle et sémantique chez des sujets normaux. Performances et dynamiques de production en fonction du sexe, de l'âge et du niveau d'étude.

A protocol of formal lexical evocation (words beginning with a letter) and semantic evocation was applied to 168 normal subjects evenly distributed on the basis of three factors (sex, three age classes and two levels of education). Correct answers, their distribution within the allotted time (proportions of correct answers in four thirty-second periods) and errors were analysed globally and in relation to the said factors. Level of education had a decisive influence in all tests; age had no influence on performance in formal evocation, whereas the subjects in the middle age class presented the best performance in semantic evocation. Distribution of the answers over time was unrelated to any of the factors considered. Errors were related to age in half the test.

[Role of the thalamus in subcortical aphasias]. / Le rôle du thalamus dans les aphasies sous-corticales.

27 cases of patients who presented language disorders of aphasic nature consecutive to a strictly subcortical lesion of vascular origin are reported. From a topographic point of view, the population is divided into 3 groups: thalamic lesions (15 cases), striatal lesions (9 cases), isolated lesions of the white matter (3 cases). The results of the neurolinguistic analysis of the aphasia show a great symptomatological variety. Nevertheless, in spite of this apparent diversity, certain semiologic elements appear to be common to all of the observed linguistic profiles, no matter where the lesion is: hypophonia, non fluent speech, verbal paraphasias, normal repetition, comprehension generally good. A discussion is proposed as to the specific part which certain structures, notably the thalamus, might play in the origin of these various disturbances.

[Subcortical aphasia. Neruolinguistic and x-ray computed tomography studies of 25 cases]. / Aphasies sous-corticales. Etude neurolinguistique avec scanner X de 25 cas.

Twenty five cases of subcortical aphasia of vascular origin (15 haemorrhagic, 10 ischaemic), have been studied in detail by means of neurolinguistic and brain-scanning approaches. The neurolinguistic investigation allowed three groups to be distinguished. Group 1 comprised 4 cases of dysarthria. Group 2 was made up of 9 classical syndromes of aphasia: 2 global aphasias, 3 Broca's aphasias, 3 cases of Wernicke's aphasia and 1 case of conduction aphasia. Group 3 consisted in 12 unusual aphasic syndromes, i.e. 2 mixed aphasias and 10 cases which did not correspond with any traditional semiological description and are spoken of as "dissident" (or anomalous) cases. The CT scan results revealed a wide range of focal lesions for the same clinical syndrome; the 10 "dissident" cases were, in particular, associated with a large variety of lesions. After a discussion of the anatomical limits of the subcortical lesions, 2 points emerge: 1) in the current state of technological experience no anatomo-clinical correlation can be drawn as regards language-deficiencies of subcortical origin. 2) in almost half the cases a "unique" syndrome of aphasia has been observed and described, which at first might suggest the diagnosis of a subcortical lesion.

[Crossed aphasia in right-handed patients. I. Review of the literature]. / Aphasie croisée chez les droitiers. I. Revue de la littérature.

More than 70 cases of crossed dextral aphasia have been reported in the literature since the end of the XIXth century. If a genetic, environmental or even pathological factor--or lack of information about it--could be suspected to be responsible of a majority of these cases, 10 of them in which all these factors were eliminated still remain. A summary of the neurological, neuropsychological and neurolinguistic features of these 10 cases shows, among other things: 1. that nearly all of them present a (left) motor deficit associated with a quite large and deep right-hemispheric lesion; 2. that most of them also report the presence of one or the other of the neuropsychological signs usually seen in right hemisphere lesions in dextrals; 3. that if reduction and agrammatism are frequent aphasic signs, fluent jargon is also reported, more so in written than in oral expression. Some of the hypotheses put forward to explain crossed aphasia in dextrals are discussed in the light of these facts. It appears that none of these hypotheses can satisfactorily account for the occurrence of a right hemisphere aphasia in some dextrals.

[Standardization of a modular and hierarchic cognitive evaluation scale applicable to dementia. A French version of the Hierarchic Dementia Scale]. / Etalonnage d'une échelle d'évaluation cognitive de structure modulaire et hiérarchisée applicable aux démences. Version française modifiée de la Hierarchic Dementia Scale.

We tested a revised version of the Hierarchic Dementia Scale (HDS), proposed by Cole and Dastoor (1980), in order to improve its clinical usefulness and to enrich our knowledge about ageing. The scale was built with 20 subtests which covered the entire range of cognitive and motor functions. Each subtest was hierarchically organized so that success in a item implied success in inferior items. This hierarchical principle was time-saving and was validated by Cole and Dastoor. 149 control subjects performed this test. They were equally divided in 4 age-groups (55-64, 65-74, 75-84, 85-97) and 2 educational levels. None of these subjects had previous history of somatic or neuropsychiatric disease. They were completely self-sufficient in daily life. A large part of the controls failed in the most difficult items of some subtests: Learning, Calculation, Mental Control, Drawing, Recall, Similarities, Constructional Praxis. For these subtests, significantly different mean-scores were observed between age-groups and educational levels. However, the influence of each factor was variable from one subtest to another. Moreover, subgroups seem to exist in our population according to specific difficulties in some of these subtests. This study calls for caution in the interpretation of results in demented patients. Comparisons with other psychometric tools remain to be performed. This scale seems to be more useful for the quantification and follow-up of cognitive deficits than for the early diagnosis of dementia. In addition, this scale, which briefly explores many aspects of cognitive functions, seems especially useful to approach the heterogeneity of DAT.