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ABSTRACT: Semantic dementia is characterized by semantic deficits and behavioural abnormalities that occur in the wake of bilateral inferolateral and predominantly left-sided anterior temporal lobe atrophy. The temporal poles have been shown to be involved in theory of mind, namely the ability to ascribe cognitive and affective mental states to others that regulates social interactions by predicting and interpreting human behaviour. However, very few studies have examined theory of mind in semantic dementia. In this study, we investigated both cognitive and affective theory of mind in a group of patients with semantic dementia, using separate objective and subjective assessment tasks. Results provided objective evidence of an impact of semantic dementia on cognitive and affective theory of mind, consistent with the patients' atrophy in the left temporal lobe and hypometabolism in the temporal lobes and the medial frontal cortex. However, the subjective assessment of theory of mind suggested that awareness of the affective but not cognitive theory of mind deficit persists into the moderate stage of the disease.
Brain 01/2012; 135(Pt 1):228-41. · 9.46 Impact Factor
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ABSTRACT: Semantic dementia is characterized by semantic deficits and behavioural abnormalities that occur in the wake of bilateral inferolateral and predominantly left-sided anterior temporal lobe atrophy. The temporal poles have been shown to be involved in theory of mind, namely the ability to ascribe cognitive and affective mental states to others that regulates social interactions by predicting and interpreting human behaviour. However, very few studies have examined theory of mind in semantic demen-tia. In this study, we investigated both cognitive and affective theory of mind in a group of patients with semantic dementia, using separate objective and subjective assessment tasks. Results provided objective evidence of an impact of semantic dementia on cognitive and affective theory of mind, consistent with the patients' atrophy in the left temporal lobe and hypometabolism in the temporal lobes and the medial frontal cortex. However, the subjective assessment of theory of mind suggested that awareness of the affective but not cognitive theory of mind deficit persists into the moderate stage of the disease.
Brain 01/2012; · 9.46 Impact Factor
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ABSTRACT: While the self has been extensively explored in amnesic patients with severe episodic but not semantic memory disturbance, little is known about the self in semantic dementia (SD), which generally features the reverse pattern of impairment. In the present study, we investigated the structural (self-representations) and functional (consciousness) dimensions of the self in a group of eight SD patients in the early to moderate stages of the disease. We used two original tasks designed to probe both structural characteristics, namely the strength and the certainty of self-concept and the episodic/semantic nature of self-representations, and functional characteristics, namely autonoetic/noetic level of consciousness, self-evaluation and self-projection into the past, present and future. Results for the structural self showed impairment on the semantic aspects of the self-representations, except for those related to the present. Moreover, SD patients were affected regardless of the episodic or semantic nature of self-representations into the future. As regards the functional self, self-projection and level of consciousness were only impaired for the future. This study confirms the persistence of a feeling of identity in SD over time for the past and present selves. However, it also highlights the loss of the future self in SD patients. These results are discussed in relation to models of long-term memory and future thinking focusing on the interplay of episodic and semantic memory and mental time travel.
Neuropsychologia 12/2011; 50(2):254-65. · 3.64 Impact Factor
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ABSTRACT: Considering that most semantic dementia (SD) and frontotemporal dementia (FTD) patients show no post-mortem Alzheimer's disease (AD) pathology, cerebrospinal fluid (CSF) biomarkers may be of value for distinguishing these patients from those with AD. Additionally, biomarkers may be useful for identifying patients with atypical phenotypic presentations of AD, such as posterior cortical atrophy (PCA) and primary progressive non-fluent or logopenic aphasia (PNFLA).
The authors investigated CSF biomarkers (beta-amyloid 1-42 (Aβ(42)), total tau (T-tau) and phosphorylated tau (P-tau)) in 164 patients with AD (n=60), PCA (n=15), behavioural variant FTD (n=27), SD (n=19), PNFLA (n=26) and functional cognitive disorders (FCD, n=17). The authors then examined the diagnostic value of these CSF biomarkers in distinguishing these patients from those with AD.
The P-Tau/Aβ(42) ratio was found to be the best biomarker for distinguishing AD from FTD and SD, with a sensitivity of 91.7% and 98.3%, respectively, and a specificity of 92.6% and 84.2%, respectively. As expected, biomarkers were less effective in differentiating AD from PNFLA and PCA, as significant proportions of PCA and PNFLA patients (60% and 61.5%, respectively) had concurrent alterations of both T-tau/Aβ(42) and P-Tau/Aβ(42) ratios. None of the FCD patients had a typical AD CSF profile or abnormal T-tau/Aβ(42) or P-Tau/Aβ(42) ratios.
The P-Tau/Aβ(42) ratio is a useful tool to distinguish AD from both FTD and SD, which are known to involve pathological processes distinct from AD. Biomarkers could be useful for identifying patients with an atypical AD phenotype that includes PNFLA and PCA.
Journal of neurology, neurosurgery, and psychiatry 03/2011; 82(3):240-6. · 4.87 Impact Factor
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ABSTRACT: Patients suffering from Alzheimer's disease (AD) or semantic dementia (SD) both exhibit deficits on explicit tasks of semantic memory. Semantic priming (SP) paradigms provide a very pure and precise implicit measurement of semantic memory impairment, and a previous study of AD (Giffard et al., 2002) using one such paradigm revealed that AD patients in the initial stages of semantic deterioration presented an abnormally large priming effect (hyperpriming) in a category-coordinate condition, compared with controls. This astonishing phenomenon could stem from the specific loss of distinctive attributes that make it possible to distinguish between semantically close concepts, while attributes shared by different concepts belonging to a given category remain intact. To test this hypothesis and compare the degradation of semantic memory in AD and SD, we devised an SP paradigm in which word pairs had either a category-coordinate or an attribute relationship. In accordance with our hypothesis, we distinguished between shared (duck-feathers) versus distinctive attributes (zebra-stripes) and close (tiger-lion) versus distant (elephant-crocodile) category-coordinate relationships. This paradigm, together with two explicit semantic memory tasks (picture-naming and categorization), was administered to 16 AD and 8 SD patients and 30 elderly control subjects. The AD patients, at the very beginning of semantic deterioration, only displayed impaired SP effects in the distinctive attribute condition, whereas in the SD patients, who had more severe semantic deterioration, we observed an extinction of SP effects in both attribute conditions. In SD patients, we also report hyperpriming effects in both category-coordinate conditions. Our results suggest that semantic memory impairment follows the same course in both AD and SD, affecting distinctive attributes first and then shared ones. In accordance with distributed models of semantic memory, the loss of distinctive attributes leads to a confusion between close concepts and it is this which causes the transient hyperpriming phenomenon.
Cortex 01/2011; 47(1):35-46. · 6.08 Impact Factor
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ABSTRACT: Studies of autobiographical memory in semantic dementia (SD) have yielded either a reversed temporal gradient or spared performances across the entire lifetime. This discrepancy might be owing to the fact that these studies did not take into account disease severity. Our aim was to study patterns of autobiographical memory impairment according to disease severity and to unravel their mechanisms in 14 SD patients, using an autobiographical memory task assessing overall and strictly episodic memories across the entire lifetime. We divided our patients in 2 subgroups of 7 patients each, one mild and one moderate according to their level of disease severity. The results indicated for the mild subgroup selective preserved performances for the most recent time period (last 12 months period) for both autobiographical memory scores. In the moderate subgroup, performances were impaired for both scores whatever the time period. Within-group comparisons across time periods showed a recency effect and a reminiscence bump in the mild subgroup and only a less important recency effect in the moderate subgroup, suggesting that with disease severity, old memories (reminiscence bump) tend to vanish and even recent memories are less well retrieved. A correlation analysis was carried out on the entire group, between the overall autobiographical memory score and performances provided by a general cognitive evaluation (semantic memory, executive functions, working and episodic memory). The results of this analysis reflect that mechanisms of disruption of autobiographical memory in SD predominantly involve a deficit of storage of semantic information in addition to faulty executive retrieval strategies. Finally, our result and those of the literature suggest the existence of 3 distinct autobiographical memory impairment patterns in SD according to disease severity: firstly preserved performances whatever the time period, secondly a reversed temporal gradient with a reminiscence bump and thirdly the appearance of a "step-function".
Cortex 05/2009; 45(4):456-72. · 6.08 Impact Factor
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ABSTRACT: Verbal fluency tasks are commonly used to explore semantic memory and executive functions. The aim of this study was to gain a better understanding of the cognitive and neural mechanisms underlying verbal fluency impairment in the frontal variant of frontotemporal dementia (fv-FTD) and in semantic dementia (SD). Semantic and phonemic fluency tasks were performed by 36 fv-FTD and SD patients and 18 elderly controls. We also carried out a neuropsychological investigation of semantic memory, working memory and shifting and updating processes. We performed correlative and regression analyses of fluency scores and neuropsychological data. In addition, patients underwent a resting positron emission tomography examination, and statistical parametric mapping was used to establish correlations between resting-state FDG uptake in the whole brain and fluency scores for each patient group. Both patient groups displayed impaired performances on both fluency tasks compared with controls, but with different patterns. While fv-FTD patients scored higher than SD patients on semantic fluency, their performances on the phonemic task did not differ. Correlation and regression analyses clearly demonstrated that the fv-FTD patients' performances on both fluency tasks depended on their executive abilities, while those of the SD patients were hampered by the impairment of their semantic memory store. Correlations with resting FDG uptake were consistent with the results of the cognitive study. In fv-FTD, both fluency performances were related to the metabolism of the frontal lobes, while we observed significant correlations between performances on both fluency tasks and the left temporal lobe metabolism in SD.
Journal of Neurology 05/2009; 256(7):1083-94. · 3.47 Impact Factor
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Isabelle Le Ber,
Agnès Camuzat,
Didier Hannequin,
Florence Pasquier,
Eric Guedj,
Anne Rovelet-Lecrux,
Valérie Hahn-Barma,
Julie van der Zee,
Fabienne Clot,
Serge Bakchine, [......], Serge Belliard,
Martine Vercelletto,
Christian Meyrignac,
Christine Van Broeckhoven,
Jean-Charles Lambert,
Patrice Verpillat,
Dominique Campion,
Marie-Odile Habert,
Bruno Dubois,
Alexis Brice
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ABSTRACT: 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.
Brain 04/2008; 131(Pt 3):732-46. · 9.46 Impact Factor
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ABSTRACT: Rare studies have used magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to assess atrophy, and only two positron emission tomography (PET) studies used SPM to examine functional changes in semantic dementia (SD). Our aim was to highlight both morphological and functional abnormalities in a same group of 10 SD patients, in the entire brain, using a "state of the art" methodology (optimized VBM procedure, PET data corrected for partial volume effects and voxel-based analyses). We also used an extensive neuropsychological battery. We showed that main alterations concerned the left temporal lobe, in accordance with the striking impairment of semantic memory in SD patients, as well as the hippocampal region, which may partly explain their moderate episodic memory deficits. Hypometabolism was more extensive than grey matter loss in both temporal lobes, and specifically concerned the orbitofrontal areas, consistent with the moderate impairment of executive functions and behavioural changes. While PET is more sensitive than MRI, there is striking concordance between morphological and functional abnormalities, which contrasts with the discordance observed in Alzheimer's disease and might be a typical feature of SD.
Neurobiology of aging 01/2008; 28(12):1904-13. · 5.94 Impact Factor
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ABSTRACT: Semantic dementia (SD) is characterized by an assymetric atrophy of the temporal lobes and, clinically, by an impairment of the semantic memory associated to psychobehavioral symptoms. The concept of SD was defined in 1989 and still remains controversial. Some authors consider DS as a specific entity, others as part of the frontotemporal dementia (FTD) or a variant of the progressive aphasia syndrome. Many arguments tend to include SD in the FTD. However, SD presents a high interest for the comprehension of the organization of semantic memory in man, and is often associated with specific histopathologic lesions (ubiquitine positive and tau negative). Therefore SD should be considered as a clinical specific entity.
Psychologie & neuropsychiatrie du vieillissement 07/2007; 5(2):127-38. · 0.45 Impact Factor
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Cecile Dumanchin,
Isabelle Tournier,
Cosette Martin,
Mira Didic, Serge Belliard,
Bertrand Carlander,
François Rouhart,
Charles Duyckaerts,
Jean-François Pellissier,
Jean Baptiste Latouche,
Didier Hannequin,
Thierry Frebourg,
Mario Tosi,
Dominique Campion
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ABSTRACT: We describe the biological consequences on PSEN1 exons 8 or 9 splicing and Abeta peptides production of four PSEN1 mutations associated with a phenotypic variant of Alzheimer disease, which includes cotton wool plaques and spastic paraparesis (CWP/SP). Two of these mutations (c.869-22_869-23ins18 and c.871A > C, p.T291P) are novel mutations located in intron 8 and exon 9, respectively. The c.869-22_869-23ins18 mutation caused exon 9 skipping whereas the c.871A > C (p.T291P) mutation showed only a modest effect on exon 9 skipping. The previously reported E280G and P264L mutations, located in exon 8, had no effect on mRNA splicing. Infection of cells with mutant T291P, E280G, or P264L cDNAs caused a variable increase in secreted Abeta42. We conclude that none of the previously proposed mechanisms, i.e. exceptionally large increases in secreted Abeta42 levels or loss of PSEN1 exons 8 or 9, provides complete explanation of the CWP/SP phenotype.
Human Mutation 10/2006; 27(10):1063. · 5.69 Impact Factor
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ABSTRACT: Medical treatment of severe dementia is now available. Decrease of psychobehavioral disturbances, autonomy loss or care-giver burden appear as the main objective rather than reduction of cognitive deficits. Acetylcholinesterase inhibitors (AChE-I) should be maintained in patients with severe dementia when initiated in mild or moderate dementia. Memantine is the specific treatment for patients with severe dementia, even if they received AChE-I. To treat the psychobehavioral disturbancies, serotoninergic agents and thymoregulators are the first line drugs. Medical treatment should only be co-prescribed with a global care of all co-morbidities, autonomy loss and patient's and care-giver's burden, and associated with psychological and organisational support.
Psychologie & neuropsychiatrie du vieillissement 04/2005; 3 Suppl 1:S51-5. · 0.45 Impact Factor
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ABSTRACT: Few studies have investigated autobiographical amnesia in neurodegenerative diseases and yet these pathologies are particularly relevant when addressing the issue of theories of long-term memory consolidation. According to the standard model, the medial temporal lobe (MTL) is involved in the storage and retrieval of episodic and semantic memories during a limited period of years. An alternative model, the multiple trace theory (MTT), suggests that the capacity of the MTL to recollect episodic memories is of a more permanent nature. In order to test these models, we studied three groups of patients with a neurodegenerative disease predominantly affecting different cerebral structures namely the MTL (13 patients in the early stages of Alzheimer's disease) and the neocortex involving either the anterior temporal lobe (10 patients with semantic dementia) or the frontal lobe (15 patients with the frontal variant of frontotemporal dementia, fv-FTD). We compared these groups of patients with control subjects using an original and reliable autobiographical memory task designed specially to assess strictly episodic memory over the entire lifespan. This task, developed on the basis of the most up-to-date definition of episodic memory, takes into account the ability to mentally travel back in time and re-experience the source of acquisition (remembering, i.e. autonoetic consciousness) via the remember/know paradigm. All three groups of patients produced strongly contrasting profiles of autobiographical amnesia (regardless of the nature of the memories), which also differed markedly from that of the control group: temporally graded memory loss in Alzheimer's disease, showing that remote memories are better preserved than recent ones; memory loss with a reversed gradient in semantic dementia; and memory loss without any clear gradient in fv-FTD. Most strictly episodic memories (i.e. unique, specific in time and space, and detailed) were impaired, whatever the time interval considered in the three groups, though the memory loss was ungraded in Alzheimer's disease and fv-FTD, and temporally graded in semantic dementia, sparing the most recent period. A deficit of autonoetic consciousness emerged in Alzheimer's disease and fv-FTD, but not in semantic dementia, though beyond the most recent 12-month period, the latter group could not justify their subjective sense of remembering to the same extent as the controls, in terms of the actual contextual information retrieved-phenomenological, spatial or temporal details. Our results demonstrate that autobiographical amnesia varies according to the nature of the memories under consideration and the locus of cerebral dysfunction. They are discussed in the light of the two competing models of long-term memory consolidation and recent conceptions of autobiographical recollection: new insights based on current concepts of episodic memories challenge the standard model and tend to support the MTT instead.
Brain 11/2003; 126(Pt 10):2203-19. · 9.46 Impact Factor
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ABSTRACT: Investigations of retrograde amnesia have contributed to a better understanding of the cerebral structures involved in remote memory. Such studies have suggested that neocortical regions such as the anterior temporal lobe play a major role in both the storage and retrieval of remote episodic and semantic information. Semantic dementia (SD), characterised as a focal anterior temporal lobe atrophy, offers an opportunity to study episodic remote memory, especially in the absence of day-to-day memory dysfunctioning, which takes place in permanent amnesic syndromes. Few studies have investigated autobiographical retrograde amnesia in SD. We present the findings from a patient (AT) at the early stage of SD. First, we have compared episodic and semantic components of autobiographical memory using two specially designed fluency tasks. The results demonstrated good recall of autobiographical events from all time periods and poor retrieval of names of acquaintances, albeit to a lesser degree, with respect to recent life. Second, we have investigated strictly episodic autobiographical memory and autonoetic consciousness by means of a sophisticated autobiographical test and the Remember/Know procedure which used a more stringent criterion of episodicity. The results demonstrated a relatively good recall of autobiographical memories (whatever their nature) but poor retrieval of remote specific detailed memories compared to recent ones. Moreover, patient AT provided Remember judgements to the same extent as control subjects regardless of the time interval covered although his responses were not justified in terms of the actual contextual information retrieved beyond the last 5 years. These findings provide further evidence that strictly episodic recollection is restricted to the recent past in SD. These data are discussed according to their relevance to the episodic and semantic distinction and to models of long-term memory consolidation.
Cognitive Neuropsychology 10/2003; 20(7):619-39. · 2.13 Impact Factor
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ABSTRACT: Frontal lobe dementia, or more generally frontotemporal dementia (FTD), includes several clinical entities and, although highly prevalent, lacks any codified therapeutic strategy. The present review is an attempt to depict the main neurochemical correlates of FTD and, as a consequence, to propose the most sound targets for symptomatic drugs. Large scale double-blind controlled clinical trials should be carried out to test any hypothesis: serotonergic agents, glutamate neurotransmission enhancers, monoamine oxidase inhibitors. The recent discovery of tau gene mutations in FTD with Parkinsonism linked to chromosome 17 has reinforced the direct role attributed to abnormal tau proteins (hyperphosphorylation) and thus raised the possibility to target specifically these processes by drugs (aetiopathogenic compounds).
Human Psychopharmacology Clinical and Experimental 05/2003; 18(3):221-5. · 2.48 Impact Factor
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Patrice Verpillat,
Agnès Camuzat,
Didier Hannequin,
Catherine Thomas-Anterion,
Michèle Puel, Serge Belliard,
Bruno Dubois,
Mira Didic,
Lucette Lacomblez,
Olivier Moreaud,
Véronique Golfier,
Dominique Campion,
Alexis Brice,
Françoise Clerget-Darpoux
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ABSTRACT: 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.
European Journal of HumanGenetics 08/2002; 10(7):399-405. · 4.40 Impact Factor
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Patrice Verpillat,
Agnès Camuzat,
Didier Hannequin,
Catherine Thomas-Anterion,
Michèle Puel, Serge Belliard,
Bruno Dubois,
Mira Didic,
Bernard-François Michel,
Lucette Lacomblez,
Olivier Moreaud,
François Sellal,
Véronique Golfier,
Dominique Campion,
Françoise Clerget-Darpoux,
Alexis Brice
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ABSTRACT: 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.
To confirm or refute the association between the H1 haplotype or the H1H1 genotype of the tau gene and FTD.
Case-control study.
Neurology departments of 12 French university hospitals.
One hundred unrelated patients with FTD and 79 controls.
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.
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).
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.
Archives of Neurology 07/2002; 59(6):935-9. · 7.58 Impact Factor
