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Objective: to assess the role of demotivation and various affective factors in apathy in patients with Parkinson's disease (PD) without dementia and depression., Subjects: 20 patients and 20 control subjects matched with age, education level, and genre., Methods: apathy was assessed by the Apathy evaluation scale (AES) and by a specific scale including a quantitative evaluation of 32 intentional activities and a qualitative assessment of the causes of attribution of restricted activities by a semi-structured interview (GDAS). Four causal attributions were distinguished: E = related to external factors, M = disease symptoms related, C = affective disturbances with preservation of motivation, and D = demotivation. The results were compared to a battery of tests including cognitive evaluation (mini-mental state and Mattis dementia rating scale for global evaluation, selecting reminding test for memory; Stroop test for inhibition, and six element test for planification); affective evaluation (Montgomery & Asberg and Hamilton depression rating scales for depression, emotional disturbances by the Abrams and Taylor scale, the Depression mood scale, and the International picture system), premorbid personality (NEOPI-R), and defensive psychological mechanisms (DSQ-40); functional assessment by a combined scale including the Self-maintenance physical scale and the Instrumental activities of daily living (Lawton) and the Social activities scale (Katz & Lyerly), the Disability assessment scale, and the UPDRS., Results: apathy was found in 25% of the patients according to the AES, but only in 15% according to the GDAS. Scores on cognitive and affective evaluation were higher in patients than in controls but only emotional blunting was correlated to apathy. Some results coud be interpreted in favor of a premorbid personality disorder in patients with PD, but were not correlated to apathy. Causal attribution was M in 38% of cases of reduced activities, D in 30%, E in 22%, and C in 10%., Conclusion: emotional blunting was the main correlate of apathy in PD patients without dementia and depression. Demotivation was the causal mechanism in only 30% of the patients with apathy.

Objective: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are among the most frequent neurodegenerative cognitive disorders, but their differential diagnosis is difficult. The aim of this study was to evaluate an automatic method returning the probability that a patient suffers from AD or FTD from the analysis of brain perfusion single photon emission computed tomography images., Methods and Materials: A set of 116 descriptors corresponding to the average activity in regions of interest was calculated from the images of 82 AD and 91 FTD patients. A set of linear (logistic regression and linear discriminant analysis) and non-linear (support vector machines, k-nearest neighbours, multilayer perceptron and kernel logistic PLS) classification methods was subsequently used to ascertain diagnoses. Validation was carried out by means of the leave-one-out protocol. Diagnoses by the classifier and by four physicians (visual assessment) were compared. Since images were acquired in different hospitals, the impact of the medical centre on the diagnosis of both the classifier and the physicians was investigated., Results: Best results were obtained with support vector machine and partial least squares regression coupled with k-nearest neighbours methods (PLS+K-NN), with an overall accuracy of 88%. PLS+K-NN was however considered as the best method since performances obtained with leave-one-out cross-validation were closer to whole-database learning. The performances of the classifier were higher than those of experts (accuracy ranged from 65 to 72%). Physicians found it more difficult to diagnose the images from centres other than their own, and it affected their performances., Conclusions: The performances obtained by the classifier for the differential diagnosis of AD and FTD were found convincing. It could help physicians in daily practice, particularly when visual assessment is inconclusive, or when dealing with multicentre data.

We studied the role of the frontal lobes in orienting spatial attention and inhibiting attentional capture by goal-irrelevant stimuli, using a spatial cueing method in patients with frontotemporal dementia (FTD). Two blocks of trials were presented, one with non-predictive cues and the other with counter-predictive cues. FTD patients showed a global orienting deficit, with a greater difference between invalid and valid trials than age-matched controls. However, they were able to use the (counter-) predictiveness of the cue to reduce the invalid/valid difference when targets occurred most often in the location opposite the cue. Thus, endogenous control of attention in our FTD patients was sufficient to reorient attention on the basis of the probability of events, but not to resist the capture of attention by goal-irrelevant stimuli. These results confirm the role of frontal lobes in the inhibition of attentional capture.

Background: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3)., Methods: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics., Results: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 +/- 10.3 years (range, 41-84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients., Conclusions: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.

We report the clinical, histological and genetic findings in 10 families (19 patients) presenting mutations in the valosin-containing protein (VCP). The mean age at onset was 42 years. The clinical pattern was characterized by an early involvement of the proximal upper limbs with scapular winging. Axial and lower limb muscles were often affected, whereas facial, oculobulbar muscles were spared. Ten patients were wheelchair bound after a mean disease course of 9 years and six patients required canes for walking. Two patients required mechanically assisted ventilation and seven patients had reduced vital capacity. There was no cardiac involvement. Paget's disease of bone was observed in eight patients and cognitive impairment in nine patients. Seven patients died as a consequence of weakness and respiratory distress. Muscle biopsy showed rimmed vacuolar myopathy. Genetic analysis revealed missense heterozygous mutations mostly located in exon 5 of the VCP gene, four of which were not previously reported. We observed intrafamilial and interfamilial variability in terms of severity, distribution of weakness and presence or not of Paget's disease or cognitive impairment.

TDP-43 (TAR-DNA binding protein) aggregates in neuronal inclusions in motoneuron disease (MND), as well as in frontotemporal lobar degeneration (FTLD) and FTLD associated with MND (FTLD-MND). Mutations in TARDBP gene, coding for TDP-43, were found in patients with pure MND. We now describe TARDBP mutations in two patients with FTLD-MND, presenting with a behavioral variant of FTLD and semantic dementia, suggesting that TDP-43 may also have a direct pathogenic role in FTLD disorders.

The objective of this study is to identify the cerebral regions that are assessed by the Frontal Assessment Battery (FAB). Using SPM voxel-based analysis, we looked for correlations between FAB performance and brain SPECT perfusion in 47 patients with the frontal variant of frontotemporal dementia (fv-FTD) recruited by the French FTD research network, a multicentre initiative of French University hospitals with expertise in the field of dementia. A significant correlation was found between FAB performance and perfusion in the medial and dorsolateral frontal cortex bilaterally, independently of age, gender and MMSE. No correlations were observed with orbital frontal or parietal perfusion, in spite of the presence of hypoperfusion in these areas, or with perfusion of any other cortical or subcortical region. These findings confirm that the FAB is an adequate tool for assessing functions related to the dorsolateral and medial frontal cortex, and is thus useful for the evaluation of diseases associated with frontal dysfunction.

Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.

Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD., ((c) 2007 Wiley-Liss, Inc.)

Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD., (Copyright 2007 Wiley-Liss, Inc.)

We conducted a French multicentric cross-sectional study to describe in detail the demographic, neurological and behavioural characteristics of the frontal variant of frontotemporal dementia (fvFTD) and to characterize the pattern of brain perfusion SPECT in comparison to a healthy control group. A total of 68 fvFTD patients had technetium-99m-ECD brain perfusion SPECT at inclusion, 61 of which also underwent an in-depth evaluation including 70 items assessing behaviour, language and affect/emotion at onset and at inclusion. The mean age-at-onset was 60.4 +/- 7.8 years (35-75). Twenty-six per cent of the patients were older than 65 at onset. A positive familial history consistent with an autosomal dominant inheritance was found in 18% of the patients. At onset, the behavioural profile was predominantly inert in 25% of the patients, disinhibited in 18% and mixed in others. The behavioural features progressed to predominantly mixed or inert forms. Although, inertia was associated with predominant medial frontal and cingulate hypoperfusion, and patients with disinhibition exhibited predominant ventromedial prefrontal and temporal hypoperfusion, there were no major clinical differences between disinhibited and inert patients. Forty-five per cent of the deceased patients survived <6 years (short survival), and 34% of the patients survived >8 years (long survival). This shows that the final outcome of fvFTD is highly variable. No clinical factors predictive of short or long survival were identified. Unexpected, however, was the finding that brainstem hypoperfusion distinguished patients with a short survival from patients with long survival. In conclusion, this study shows that fvFTD is clinically a rather homogeneous entity. It also provides evidence that different behavioural presentations at onset are related to different anatomical localizations of degenerative damage. Finally, it demonstrates the prognostic value of brainstem hypoperfusion in a subgroup of patients with a short survival.

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.

In frontotemporal dementia (FTD), evaluation scales and measurement instruments are less codified than in Alzheimer's disease. Some nonspecific scales are available, two of which are very useful for early diagnose of the disease: Lebert and Pasquier's Frontotemporal Behavioral Scale (FBS) to assess behavioral disturbances and Dubois's Frontal Assessment Battery (FAB) to assess executive ability. However, these scales do not contain enough items to follow up FTD. The main scale used to follow up the disease is the Neuropsychiatric Inventory (NPI). The Frontal Behavioural Inventory (Kertesz) seems to be interesting, but has not yet been validated in France. The Mattis Dementia Rating Scale, not specific for FTD, is used to assess the cognitive rate. The activities of daily living scales and caregiver burden are not well known in FTD.

Data from the literature devoted to the relationships between dementia and depression are controversial on account of numerous methodological biases (community studies or from neurological or psychiatric departments), categorical versus dimensional approaches and variability of assessment tools for depression, aim of the study (depression versus dementia or versus Alzheimer's disease, AD). The difficulty to discriminate depression from AD is largely overestimated due to the confusion between depression, depressive symptomatology and apathy. The distinction is greatly facilitated by taking into account the qualitative differences of the memory deficits and cerebral imagery. Distinction of depression from frontotemporal or subcortical dementias could be much more difficult. Relationships between depression and AD are controversial. Most reports of depression as a risk factor for AD in the subsequent years, actually describe depressed symptomatology linked to apathy in preclinical AD. However, some studies found a relationship between AD and depression occurring more than 10 years before the onset of AD symptomatology, suggesting some common risk factors. The so-called symptoms of depression in AD are more related to apathy and affective disturbances than to dysphoria. The frequency of major depressive episode (MDE), greatly varies according to studies, but the frequency of suicide is low. Depression in dementia is related to neurobiological factors as well as to psychological mechanisms. Therefore, its treatment should associate antidepressant drugs and psychological support directed to the patient and family.

We studied preparatory attention in patients suffering from frontotemporal dementia in the beginning stages of the disease, using an experimental test developed by LaBerge, Auclair, and Siéroff (2000). In this experimental test, a distracter can appear while subjects have to prepare to respond to a simple target. The probability that a distracter can appear in a trial is varied across three blocks. Normal controls show an increase of response times to targets (slope) as a function of the distracter probability, preparatory attention to the target is reduced by the increase of the distracter probability. Patients suffering from frontotemporal dementia show a slope of response times which is more than twice as large as the slope obtained by their matched controls. Such an abnormal increase of response times to targets is interpreted as a deficit in preparatory attention. Patients also show more omissions than controls. We suggest that this deficit in preparatory attention is related to the frontal lesion presented by the patients and can result in higher distractibility, a symptom frequently encountered in these patients.

Objective: To study the relationship between the disturbances in activities of daily living and the scores on tests assessing planning activities in frontotemporal dementia (FTD) and Alzheimer's disease (AD)., Methods: Eleven patients with FTD were compared to 11 patients with AD and 29 healthy controls. Cognitive status, evaluated by the Dementia Rating Scale (DRS) and the Mini Mental State Examination (MMSE) was identical in the two groups of patients. Activities of daily living were assessed by three questionnaires completed by the main caregiver: (1) the Cognitive Difficulties Scale (CDS); (2) the NADL, a composite scale including the Physical self-maintenance scale (ADL) the Instrumental activities of daily living (IADL) the social activities scale, (SADL); (3) the Dysexecutive Questionnaire (DEX) from the Behavioural Assessment of the Dysexecutive Syndrome. Planning abilities were assessed by the tower of London and three tests from the BADS: the key search, the zoo map and the six elements., Results: No quantitative differences were found between FTD and AD patients in daily living activities disturbances or scores on planning tests. Both were closely related to the global cognitive performance assessed by the DRS or the MMSE but no clear relationship was found between them. The scores on the tower of London were not correlated to those on the tests from the BADS., Conclusion: Neither assessment of activities of daily living or scores on the planning tests could differentiate FTD from AD. Planning appears as a multidimensional construct poorly assessed by the usual assessment tools.

No definite genetic risk factor of non-monogenic frontotemporal dementia (FTD) has yet been identified. Several groups have examined the potential association of FTD with the apolipoprotein E (APOE) gene, but the results are inconsistent. Our objective was to determine whether APOE is a risk factor of FTD, using the largest series of patients with FTD and controls analysed so far (94 unrelated patients and 392 age and sex-matched controls), and a meta-analysis. Homozygosity for the E2E2 genotype was significantly associated with FTD (odds ratio (OR)=11.3; P=0.033, exact test). After stratification on familial history (FH) for FTD, the OR for E2E2 was still found significant when analysing only patients with a positive FH (OR=23.8; P=0.019). The meta-analysis, using 10 case-control studies with available genotype or allele information, comprising a total of 364 FTD patients and 2671 controls, including the patients of the present study, did not reach statistical significance even if the E2E2 genotype was more frequent in patients than in controls (0.018 vs 0.006, respectively). Because of studies heterogeneity (Mantel-Haenszel statistics: P=0.004), we analysed on one hand the neuropathologically-confirmed studies, and on the other hand the clinical-based studies. In the neuropathologically-confirmed studies (Mantel-Haenszel statistics: P=ns), we found a significant increase of the E2 allele frequency in FTD patients (OR[E2 vs E3]=2.01; 95% CI=1.02-3.98; P=0.04). The same result was found in the clinical-based studies, but studies heterogeneity remained. No result was significant with the E4 allele. The E2 allele seems so to be a risk factor of FTD whereas this allele is associated with the lowest risk in Alzheimer's disease. If this finding was confirmed, it could provide new insights into the mechanisms of differential risk related to APOE in neurodegenerative diseases.

Background: Recent studies have shown an association between an extended tau haplotype (H1) that covers the entire human tau gene and progressive supranuclear palsy or, more inconsistently, other neurodegenerative disorders, such as corticobasal degeneration, Parkinson disease, Alzheimer disease, and frontotemporal dementia (FTD). In addition, disease-causing mutations in the tau gene on chromosome 17 have been detected in some families with autosomal dominant FTD and parkinsonism. In FTD, the pathological accumulation of the microtubule-associated protein tau suggests that the tau gene may be a genetic risk factor for this disorder., Objective: To confirm or refute the association between the H1 haplotype or the H1H1 genotype of the tau gene and FTD., Design: Case-control study., Setting: Neurology departments of 12 French university hospitals., Participants: One hundred unrelated patients with FTD and 79 controls., Methods: Tau genotype (contiguous polymorphisms in exons 1, 7, and 13 and in intron 9 used to reconstruct the extended haplotypes H1 and H2). Clinical examination, psychometric testing, laboratory tests, computed tomography and magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography for patients with FTD., Results: The H1H1 genotype was significantly overrepresented in patients with FTD compared with controls (62% vs 46%; P=.01, 1-sided; odds ratio adjusted for age and sex, 1.95). After stratification according to apolipoprotein E (APOE) genotype, we found a significant interaction between APOE and tau genotypes (P=.03)., Conclusions: This study of the largest series of patients with FTD confirms the primary role of tau in FTD and establishes that the H1 haplotype of the tau gene and the E2 allele of APOE interact by an unknown mechanism that increases the risk of FTD.

THE PREDEMENTIA PHASE: Alzheimer's disease is a progressive condition. The state of dementia defined by international criteria only appears after brain lesions have become important. Dementia is defined by the presence of multiple cognitive deficits and restricted independence. Prior to this, the patient experiences isolated memory impairment, either alone or associated with behavior changes which have little effect on his/her independence (predementia phase). The goal of diagnosis at this time is to reduce psychic suffering for the patient and family as well as the social cost of the disease by retarding the onset of dementia. DIAGNOSIS IN THE PREDEMENTIA PHASE: Diagnosis is based on i) evidence of an alteration of the internal temporal regions leading to memory deficit due to impaired memorization processes. There is an elective impairment of recent memory rapidly leading to difficulties perceived by the family and which diminish performance in complex activities of daily living. Recall processes lose their efficacy. ii) Tomoscintigraphic evidence of a perfusion defect or structural imaging evidence of atrophy of the hippocampal regions. iii) Presence of associated psychoaffective changes (apathy). When these three elements are found, the diagnosis of Alzheimer's disease is highly probable and should be made. If all three are not present, it would be advisable to diagnose what is termed "mild cognitive impairment", defined as a group of subjects with a high risk of progressing to dementia in a few years. PATIENT CARE AT THIS PHASE: Neuroprotective drugs may be prescribed in association with psychological and cognitive support within the framework of regular follow-up.