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Background: Glycogen storage disease type III (GSDIII) is a rare autosomal recessive disorder due to glycogen debranching enzyme (GDE) deficiency. It results in a multisystemic disease with predominant hepatic and myopathic symptoms. While frequent social maladjustment has been observed in our clinical practice, cognitive and psychological disturbances have never been assessed. The aim of this pilot study was to examine and characterize the cognitive profile of patients with GSDIII., Methods: Seven patients (six women and one man, mean age: 38.7 ± 11.6 years) with GSDIII underwent a neuropsychological set of tests assessing global cognitive efficiency, executive functions, social cognition, apathy, and episodic memory., Results: All patients presented previous psychopathological history. We observed attention fluctuations for each patient, and impaired global cognitive efficiency with deficiencies in executive functions in 5/7 patients. Emotional skills (social cognition) were impaired in five patients. Memory was mostly preserved., Conclusion: The impairment in social cognition (recognition of emotions and ability to attribute mental states to others) and executive functions observed could be a consequence of orbito-frontal dysfunction due to the abnormal glycogen metabolism characteristic of the underlying disease. These results are consistent with the hypothesis of a central nervous system involvement in patients with GSDIII, but need to be confirmed in future research. This could explain the social and economic difficulties, and the lack of compliance to the medical follow-up presented by these patients. It suggests that these disturbances need to be taken into account when planning the medical management of patients with GSDIII.

Clinical experience and prior studies suggest that Huntington disease (HD) patients have low insight into their motor disturbances and poor real-time awareness (concurrent awareness) of chorea. This has been attributed to sensory deficits but, until now, concurrent awareness of choreic movements has not been compared to the degree of insight that presymptomatic carriers of the HD gene and healthy control subjects have into non-pathological involuntary movements. To further investigate loss of insight into motor dysfunction in HD patients, we administered a video-recorded interview and 4 experimental tasks to 68 subjects from the TRACK-HD cohort, including 28 high-functioning patients in early stages of HD, 28 premanifest mutation carriers and 12 controls. All underwent full neurological and neuropsychological evaluations and 3T MRI examinations. Subjects were asked to assess the presence, body location, frequency, practical consequences and probable causes of motor impairments, as well as the presence and body location of involuntary movements during 4 experimental tasks. The accuracy of their judgments, assessed by comparison with objective criteria, was used as a measure of their insight into motor disturbances and of their concurrent awareness of involuntary movements. Insight was poor in early HD patients: motor symptoms were nearly always underestimated. In contrast, concurrent awareness of involuntary movements, although also poor, was essentially indistinguishable across the 3 groups of subjects: non-pathological involuntary movements were as difficult to perceive by controls and premanifest carriers as was chorea for early HD patients. GLM analysis suggested that both concurrent awareness and perception of practical consequences of movement disorder had a positive effect on intellectual insight, and that mental flexibility is involved in concurrent awareness. Our results suggest that low insight into motor dysfunction in early HD, although marginally modulated by cognitive factors, is mainly non-pathological, and parallels a general tendency, shared by healthy subjects, to neglect self-generated involuntary movements in real time. This tendency, combined with the paucity of functional consequences of incipient chorea, could explain the difficulty of its discovery by the patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

While the clinical presentation of posterior cortical atrophy is clearly distinct from typical Alzheimer's disease, neuropathological studies have suggested that most patients with posterior cortical atrophy have Alzheimer's disease with an atypical visual presentation. We analysed in vivo pathophysiological markers of Alzheimer's disease such as cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B in posterior cortical atrophy to determine whether biochemical profile and fibrillar amyloid-β burden topography are associated with the clinical presentation. Nine patients with posterior cortical atrophy and nine with typical Alzheimer's disease individually matched for age, duration and severity of the disease and 10 cognitively normal age-matched controls were included. ¹¹C-labelled Pittsburgh compound-B images were analysed both using volumes of interest and on a voxel-wise basis using statistical parametric mapping, taking into account the individual regional cortical atrophy. Cerebrospinal fluid biomarkers did not differ between posterior cortical atrophy and patients with Alzheimer's disease. Compared with normal controls, both posterior cortical atrophy and Alzheimer's disease groups showed increased ¹¹C-labelled Pittsburgh compound-B uptake. No significant difference was found in regional or global ¹¹C-labelled Pittsburgh compound-B binding between posterior cortical atrophy and Alzheimer's disease groups with both volumes of interest and voxel-wise basis using statistical parametric mapping methods. Our findings demonstrate that cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B may be useful in identifying an atypical visual form of Alzheimer's disease. The similar topography of fibrillar amyloid-β deposition between typical Alzheimer's disease and posterior cortical atrophy groups suggests that, although amyloid-β accumulation plays a critical role in the pathogenesis of Alzheimer's disease, other factors such as neurofibrillary tangles may contribute to the different clinical features observed in posterior cortical atrophy.

Semantic dementia (SD) is a syndrome of progressive loss of semantic knowledge for objects and people. International criteria propose that SD be included in the frontotemporal lobar degeneration syndromes, with progressive non-fluent aphasia and frontotemporal dementia (FTD). However, several related syndromes have been defined that clinically and conceptually share both similarities and differences with SD: fluent progressive aphasia, progressive prosopagnosia, temporal variant of FTD. In order to establish a French consensus for the diagnosis and modalities of evaluation and follow-up of SD, a working group, composed of neurologists, neuropsychologists and speech-therapists, was established by the Groupe de réflexion sur les évaluations cognitives (GRECO). New criteria were elaborated, based on clinical, neuropsychological, and imaging data. They define typical and atypical forms of SD. A diagnosis of typical SD relies on an isolated and progressive loss of semantic knowledge, attested by a deficit of word comprehension and a deficit of objects and/or people identification, with imaging showing temporal atrophy and/or hypometabolism. SD is atypical if the deficit of semantic knowledge is present only within a single modality (verbal versus visual), or if non-semantic deficits (mild and not present at onset) and/or neurological signs, are associated with the semantic loss.

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.

Mutations and deletions in the SPG4 gene are responsible for up to 40% of autosomal dominant hereditary spastic paraplegia (HSP). Patients have pyramidal signs in the lower limbs and some present additional features including cognitive impairment such as executive dysfunction or subcortical dementia. We report 13 patients from three SPG4 families, who had spastic paraplegia associated with mental retardation (n=1), extensive social dependence (n=10), or isolated psychomotor delay (n=2). In family FSP-698, 10 affected individuals had both HSP and mental deficiency leading to social dependence in 9 and institutionalization in 5. The mean age at onset of spastic paraplegia was 11+/-20 years, ranging from 1 to 51 years. This phenotype segregated either with a novel p.Glu442Lys mutation or the two previously described p.Arg459Thr and p.Arg499Cys substitutions in the SPG4 gene. Since two of these mutations were previously reported in families with a pure form of the disease, another genetic factor linked to SPG4 could be responsible for this complex phenotype.

Background: Juvenile Huntington disease (JHD) is a rare clinical entity characterized by an age at onset younger than 20 years. Patients usually have an expansion of more than 60 CAG repeats in the Huntington disease (HD) gene, and the disease is usually inherited from the father. In general, precise age at onset is difficult to assess in HD because of insidious onset and anosognosia. Onset of motor difficulty signs is usually used to define age at onset., Objectives: To evaluate diagnosis delay in patients with JHD and to analyze the clinical and genetic features of JHD., Design: Retrospective clinical and genetic review., Setting: Referral center for HD at Salpêtrière Hospital, Paris, France., Patients: Twenty-nine patients with HD with onset before or at age 20 years who carried an abnormal CAG repeat expansion in the HD gene., Results: The mean +/- SD delay before diagnosis was 9 +/- 6 years (range, 0-21 years). The most remarkable signs at onset were severe psychiatric and cognitive disturbances (19 of 29 [65.5%]); rigidity was absent. Unusual signs at onset included myoclonic head tremor in 3 patients, severe isolated drug or alcohol addiction in 2, psychotic disorder in 1, and difficulty writing in 1. One patient had progressive cerebellar signs associated with cerebellar atrophy on cerebral magnetic resonance imaging before signs suggestive of HD appeared. During the course of the disease, psychiatric disturbances were severe, with at least 1 suicide attempt in 7 of 29 patients. Transmission was maternal in 25% of patients. Forty-six percent of patients with JHD had fewer than 60 CAG repeats; 6 of these patients inherited the disease from their father. Anticipation (mean +/- SD, 18 +/- 9 vs 25 +/- 11 years; P = .27) and age at onset (mean +/- SD, 17.14 +/- 2.2 vs 13.29 +/- 5.5 years; P = .09) was similar in patients with maternal compared with paternal transmission, respectively., Conclusions: Patients with JHD started showing disease symptoms through nonspecific features, mostly psychiatric and cognitive difficulties. This led to misdiagnosis or diagnosis delay, especially in cases without a familial history of HD. Maternal transmissions and expansions of fewer than 60 CAG repeats were unexpectedly frequent in this series and should not be considered exceptional.

Background: We have previously reported the efficacy and safety of bilateral pallidal stimulation for primary generalised dystonia in a prospective, controlled, multicentre study with 1 year of follow-up. Although long-term results have been reported by other groups, no controlled assessment of motor and non-motor results is available. In this prospective multicentre 3 year follow-up study, involving the same patients as those enrolled in the 1 year follow-up study, we assessed the effect of bilateral pallidal stimulation on motor impairment, disability, quality of life, cognitive performance, and mood., Methods: We studied 22 patients with primary generalised dystonia after 3 years of bilateral pallidal stimulation. We compared outcome at 3 years with their status preoperatively and after 1 year of treatment. Standardised video recordings were scored by an independent expert. Data were analysed on an intention-to-treat basis., Findings: Motor improvement observed at 1 year (51%) was maintained at 3 years (58%). The improvement in quality of life (SF-36 questionnaire) was similar to that observed at 1 year. Relative to baseline and to the 1 year assessment, cognition and mood were unchanged 3 years after surgery, but slight improvements were noted in concept formation, reasoning, and executive functions. Pallidal stimulation was stopped bilaterally in three patients because of lack of improvement, technical dysfunction, and infection, and unilaterally in two patients because of electrode breakage and stimulation-induced contracture. No permanent adverse effects were observed., Interpretation: Bilateral pallidal stimulation provides sustained motor benefit after 3 years. Mild long-term improvements in quality of life and attention were also observed.

The visual system of literate adults develops a remarkable perceptual expertise for printed words. To delineate the aspects of this competence intrinsic to the occipitotemporal "what" pathway, we studied a patient with bilateral lesions of the occipitoparietal "where" pathway. Depending on critical geometric features of the display (rotation angle, letter spacing, mirror reversal, etc.), she switched from a good performance, when her intact ventral pathway was sufficient to encode words, to severely impaired reading, when her parietal lesions prevented the use of alternative reading strategies as a result of spatial and attentional impairments. In particular, reading was disrupted (a) by rotating word by more than 50 degrees , providing an approximation of the invariance range for words encoding in the ventral pathway; (b) by separating letters with double spaces, revealing the limits of letter grouping into perceptual wholes; (c) by mirror-reversing words, showing that words escape the default mirror-invariant representation of visual objects in the ventral pathway. Moreover, because of her parietal lesions, she was unable to discriminate mirror images of common objects, although she was excellent with reversible pseudowords, confirming that the breaking of mirror symmetry was intrinsic to the occipitotemporal cortex. Thus, charting the display conditions associated with preserved or impaired performance allowed us to infer properties of word coding in the normal ventral pathway and to delineate the roles of the parietal lobes in single-word recognition.

Background: The different distribution of pathologic features in frontotemporal dementia (FTD) and Alzheimer disease (AD) predicts a predominant dysexecutive syndrome in FTD. The Frontal Assessment Battery (FAB) has previously been validated in diseases associated with a frontal lobe dysfunction., Objective: To evaluate the sensitivity of the FAB to differentiate FTD and AD., Design: Comparison study., Setting: Memory Clinic of the Salpêtrière Hospital, Paris, France., Patients: Twenty-six patients with FTD and 64 patients with AD., Main Outcome Measures: Comparison of FAB and Mini-Mental State Examination (MMSE) scores between patients with FTD and those with AD., Results: The mean +/- SD FAB scores significantly differed between patients with FTD (7.6 +/- 4.2) and those with AD (12.6 +/- 3.7) (P<.001), but not MMSE scores. The FAB correctly identified 78.9% of the patients. These results were maintained in a subgroup of mildly demented patients (MMSE score, > or =24). In these patients, a cutoff score of 12 on the FAB was optimal to differentiate both disorders (sensitivity, 77%; specificity, 87%)., Conclusions: The FAB takes less than 10 minutes to administer and provides an objective measure to distinguish FTD from AD in mildly demented patients.

Background: The most frequent form of autosomal dominant hereditary spastic paraparesis is associated with the SPG4 locus, described originally as a pure form of the disease. Mutations of the SPG4 gene have been increasingly associated with reports of cognitive impairment., Objective: To investigate cognitive function in 10 families with hereditary spastic paraparesis due to mutations in the SPG4 gene, using intrafamilial control subjects., Patients and Methods: Neuropsychological examinations, including the Cambridge Cognitive Evaluation, were conducted in 29 carriers with identified SPG4 mutations and 29 intrafamilial controls., Results: Carriers were not demented but had a subclinical cognitive impairment primarily affecting executive functions. The dysfunction was more severe in those carriers older than 50 years, but was correlated with the progression of the disease, not with age. Disease progression and cognitive impairment appeared to be more severe in the carriers of missense mutations than in those with truncating mutations., Conclusion: Asymptomatic cognitive impairment mostly affecting executive functions is present in SPG4 mutation carriers and is more frequent in those with missense mutations.

There has been considerable interest in cognitive deficits associated with Alzheimer's disease (AD) and relationships between these impairments and specific cortical atrophies. Two previous studies [Neuropsychologia 28 (1990) 1197; Dementia 3 (1992) 350] have found that AD patients exhibit significant impairments in the attentional ID/ED set-shifting tasks of the CANTAB battery which involved attentional shifting abilities. But, at present, no study has examined the neural bases of these abilities in AD patients. In the present study, the relationship between performances on this attentional test and morphometry of the anterior and posterior corpus callosum is examined in AD patients in the mild to moderate stages of the disease (n=30, mean age=74.1+/-4.9 years, mean MMSE score=23.9+/-2.6). A control group is constituted (n=20, mean age=73.15+/-5.5 years) for comparison of cerebral measurements. The stepwise multiple regression analysis indicates that the relative contribution for the total callosal and the anterior CC areas of the simple discrimination subtest is significantly positive whereas for the posterior callosal areas the relative contribution of the more complex subtest is significantly positive. AD patients from the subgroup "low", who failed to do the nine subtests of the attentional set-shifting tasks, exhibit smaller callosal areas than control subjects. There is no significant difference for all callosal measurements between AD patients from the subgroup "high", who completely succeeded the test, and control subjects. Our findings suggest that the anterior corpus callosum would be related to attentional shifting abilities in AD patients. Moreover, these patients with probable AD seem heterogeneous for performances in the attentional test of the CANTAB and for callosal atrophies.

Spatial memory has been found to be impaired in Parkinson's disease (PD). To determine the nature of the deficit, we compared the performance of'standard' levodopa-treated patients with PD to that of matched control subjects in different situations: (i) spatial versus verbal conditional associative learning; (ii) 'global' versus 'local' contextual encoding; (iii) pattern span and related supraspan learning. The relationship between dopaminergic depletion, which characterizes the disease, and the impaired memory processes was investigated by comparing the performance of 'de novo' not yet treated PD patients to that of matched control subjects. Both groups of PD patients were impaired in all situations requiring strategic processes, shared a decreased pattern span and had a normal visuospatial learning once the pattern span was taken into account. All these results suggest that the memory deficit for spatial location observed in PD results mainly from a disturbance of strategic processes and from decreased attentional resources, which may be due, at least in part, to the dopaminergic depletion and related striatofrontal dysfunction.