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BackgroundThe etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach.MethodsFUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold.ResultsWe identified 73 significant gene-tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed.ConclusionsWe identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Abstract Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.

BackgroundFrontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.MethodsWe did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p

Abstract Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y). We found that p62 deficiency is associated with inhibited complex I mitochondrial respiration due to lack of NADH for the electron transport chain. This deficiency was also associated with increased levels of NADPH reflecting a higher activation of pentose phosphate pathway as this is accompanied with higher cytosolic reduced glutathione (GSH) levels. Complex I inhibition resulted in lower mitochondrial membrane potential and higher cytosolic ROS production. Pharmacological activation of transcription factor Nrf2 increased mitochondrial NADH levels and restored mitochondrial membrane potential in p62-deficient cells. Our results suggest that the phenotype is caused by a loss-of-function effect, because similar alterations were found both in the mutant fibroblasts and the p62 KD model. These findings highlight the implication of energy metabolism in pathophysiological events associated with p62 deficiency.

Background: The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools. Objective: We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients. Methods: Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS. Results: DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score ≥4) with a sensitivity of 92%, while DAPHNE-40 (score ≥15) had a specificity of 92%. Conclusion: We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD.

BACKGROUND:Many studies have highlighted the high prevalence of executive disorders in stroke. However, major uncertainties remain due to use of variable and non-validated methods. The objectives of this study were: 1) to characterize the executive disorder profile in stroke using a standardized battery, validated diagnosis criteria of executive disorders and validated framework for the interpretation of neuropsychological data and 2) examine the sensitivity of the harmonization standards protocol proposed by the National Institute of Neurological Disorders and Stroke and Canadian Stroke Network (NINDS-CSN) for the diagnosis of Vascular Cognitive Impairment. METHODS:237 patients (infarct: 57; cerebral hemorrhage: 54; ruptured aneurysm of the anterior communicating artery (ACoA): 80; cerebral venous thrombosis (CVT): 46) were examined by using the GREFEX battery. The patients' test results were interpreted with a validated framework derived from normative data from 780 controls. RESULTS:Dysexecutive syndrome was observed in 88 (55.7%; 95%CI: 48-63.4) out of the 156 patients with full cognitive and behavioral data: 40 (45.5%) had combined behavioral and cognitive syndromes, 29 (33%) had a behavioral disorder alone and 19 (21.6%) had a cognitive syndrome alone. The dysexecutive profile was characterized by prominent impairments of initiation and generation in the cognitive domain and by hypoactivity with disinterest and anticipation loss in the behavioral domain. Cognitive impairment was more frequent (p = 0.014) in hemorrhage and behavioral disorders were more frequent (p = 0.004) in infarct and hemorrhage. The harmonization standards protocol underestimated (p = 0.007) executive disorders in CVT or ACoA. CONCLUSIONS:This profile of executive disorders implies that the assessment should include both cognitive tests and a validated inventory for behavioral dysexecutive syndrome. Initial assessment may be performed with a short cognitive battery, such as the harmonization standards protocol. However, administration of a full cognitive battery is required in selected patients.

The Apostle Paul had a chronic disease. Epilepsy is offered as the most likely hypothesis. Interpretation of parts of the Pauline epistles suggests the possibility of facial motor and sensitive disturbances coming after ecstatic seizures. Though unusual, there are, however, case histories of patients who experienced ecstatic auras.

Motor attacks induced by voluntary movements are infrequent. Paroxysmal kinesigenic choreoathetosis (PKC) is rare and has only recently been individualized (Kertesz, 1967). We report the case of an 8 year-old boy who developed unilateral or bilateral attacks of abnormal, choreoathetotic movements during certain voluntary movements, especially when rising after a rest. The attacks were short (13 to 18 seconds) and frequent. Neurological examination was normal, as were the intelligence quotient, the inter-critical and critical EEG: CT and MRI. The patient's mother had suffered from the same disorder. The attacks disappeared during treatment with phenytoin but reappeared when it was stopped. This case is concordant with data from the literature, with male predominance, age from 6 to 15 years at the onset, shortness of the attacks (less than 1 minute in 80% of the cases) and normality of investigations in almost every patient. A familial factor has been found in 50% of the cases. The frequency of epilepsy in the family is above average. PKC can easily be distinguished from Mount and Reback' syndrome where the attacks are choreoathetotic but longer and unprovoked by movements and where there is also a familial factor. The relationship of PKC with epilepsy is asserted by some authors and denied by others, and in the literature the distinction between movement-induced tonic seizures and PKC is not always clear. Some authors have blamed a disturbance in the maturation of basal ganglia. To sum up, PKC is a very rare condition which is easy to diagnose, has a good prognosis and readily responds to antiepileptic drugs.

From the analysis of 115 cases of primary generalized epilepsies treated for a mean duration of 43 months with sodium valproate as sole therapy, it appears that: the mean effective daily dosage is 21 mg/kg; the efficacy of valproate proved excellent in 82.6% of cases (seizures fully controlled: 74%, seizures occurring exceptionally: 9%); a loss of activity was never observed; in these circumstances of prolonged administration of the drug, no signs of major intolerance were seen; side-effects occurred in 29% of cases, including 20% long-term effects (weight gain, essential tremor); 64 series of laboratory tests including 15 parameters made it possible to evaluate the hematological, hepatic and pancreatic tolerance of valproate: the majority of the tests were normal. The authors believe that during long-term therapy with valproate, monitoring does not need to include the routine performance of liver function tests, but that it would be more advisable, should a suggestive clinical sign be noted, to investigate the platelet count, coagulation (partial activated thromboplastin time) and protein synthesis (fibrinogen).

Three percent of epileptic patients have their first seizure after the age of 60. More than at other ages, the real nature of such fits is very difficult to assert. Most of the reversible attacks occurring at this age are not of grave nature, syncopes are much more frequent. Some semeiological aspects are discussed. Focal seizures are more frequent after the age of 60. Absence status may be the first epileptic symptom in some rare cases (almost all of them being women). 100 patients whose ages ranged from 60 to 83 years, were examined after their first seizure and aetiological problems were examined. The following topics are discussed:--The possible onset of a primary epilepsy, extremely rare at that age;--The incidence of neoplasms, not exceeding 10% for patients whose late onset epilepsy is still an isolated symptom, and who have not been selected from specialized neurological or neurosurgical hospital departments;--The role of vascular epilepsy; in a very few cases, but of great practical interest, the epilepsy may announce a cerebrovascular accident which will occur later. It is, however, difficult to specify the vascular origin of a certain number of temporary unexplained late onset epilepsies. Some other aetiological factors are taken into account: antecedents of trauma, alcoholism, and dementia. The authors agree that in 50% of the cases the aetiology is not obvious. In this group of unknown aetiology it seemed interesting to isolate the following electroclinical form;--Epilepsy grand mal, with apparently generalized seizures; no special pathological antecedents; the neuropsychological and neurological examinations are normal, showing no intellectual disorders; the EEG generally shows slight modifications: quick rhythms, some sharp waves; a global cerebral atrophy is seen by the scanner. Such patients have been called victims of 'secondary late-onset generalized epilepsy'. They form 16% of a series of 156 epileptic patients who were over 65 years old, and 21% of our own 100 patients.

Eleven cases of primary reading epilepsy are reported. They confirm Bickford's description. These patients were otherwise normal. A family history of seizures was present in 6 cases. The first seizure occurred between 12 and 25 years. After a variable period of reading all patients developed a tightness and jerking in throat and jaw muscles. In 4 cases, occasionally, speaking could cause jaw or throat jerks. Whilst reading out loud or silently (exclusively in reading aloud in 1 patient) bilateral discharges were recorded in EEG, sometimes on the left hemisphere. The mechanisms are discussed. Seizures in primary reading epilepsy are facilitated by saccadic eye movements, impulse language muscles and mental concentration. The role of higher integrating systems of language is emphasized. Therapy is discussed.

A 7 year-old child with congenital oculomotor apraxia (Cogan's syndrome) presented with mainly voluntary horizontal saccadic movements. Fixation of a visual target could be obtained only by a sudden movement of the head preceded by eyelid blinking. Electro-oculography confirmed the predominant disturbance of saccadic movements (delay in onset, hypometria). CT scan showed agenesis of the corpus callosum and atrophy of the vermis together with enlargement of the 4th ventricle and pre-pontine cisternae. The role of these anomalies in the pathogenesis of this rare congenital syndrome of good prognosis is discussed.