Olivier Moreaud

Apolipoprotein E gene in frontotemporal dementia: an association study and meta-analysis

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 Alzheimers disease. If this finding was confirmed, it could provide new insights into the mechanisms of differential risk related to APOE in neurodegenerative diseases.

Impaired cerebral vasoreactivity to CO2 in Alzheimer's disease using BOLD fMRI

OBJECTIVE To evaluate the cerebral vasoreactivity using blood oxygenation level dependent functional MRI during carbogen inhalation with 7% CO(2) in Alzheimers disease and amnestic mild cognitive impairment. PARTICIPANTS AND METHODS Thirty nine subjects were included to be investigated using blood oxygenation level dependent (BOLD) functional MRI at 1.5T during a block-design carbogen inhalation paradigm, with a high concentration face-mask under physiological monitoring. Basal cerebral perfusion was measured using pulsed arterial spin labeling. Image analyses were conducted using Matlab® and SPM5 with physiological regressors and corrected for partial volume effect. RESULTS Among selected participants, 12 subjects were excluded because of incomplete protocol, leaving for analysis 27 subjects without significant microangiopathy diagnosed for Alzheimers disease (n=9), amnestic mild cognitive impairment (n=7), and matched controls (n=11). No adverse reaction related to the CO(2) challenge was reported. Carbogen inhalation induced a whole-brain signal increase, predominant in the gray matter. In patients, signal changes corrected for gray matter partial volume were decreased (0.36±0.13% BOLD/mmHg in Alzheimers disease, 0.36±0.12 in patients with mild cognitive impairment, 0.62±0.20 in controls). Cerebral vasoreactivity impairments were diffuse but seemed predominant in posterior areas. The basal hypoperfusion in Alzheimers disease was not significantly different from patients with mild cognitive impairment and controls. Among clinical and biological parameters, no effect of apoE4 genotype was detected. Cerebral vasoreactivity values were correlated with cognitive performances and hippocampal volumes. Among age and hippocampal atrophy, mean CVR was the best predictor of the mini-mental status examination. CONCLUSION This BOLD functional MRI study on CO(2) challenge shows impaired cerebral vasoreactivity in patients with Alzheimers disease and amnestic mild cognitive impairment at the individual level. These preliminary findings using a new MRI approach may help to better characterize patients with cognitive disorders in clinical practice and further investigate vaso-protective therapeutics.

CSF biomarkers in posterior cortical atrophy

Objective: To describe CSF biomarker profiles in posterior cortical atrophy (PCA), which induces high-order visual deficits often associated with Alzheimer disease (AD) pathology, and relate these findings to clinical and neuropsychological assessment. Methods: This prospective observational study included 22 patients with PCA who underwent CSF biomarker analysis of total tau (t-tau), phosphorylated tau on amino acid 181 (p-tau181), and amyloid β (Aβ42). At group level, the CSF profiles of patients with PCA were compared to those of patients with typical AD and patients with other dementia (OD). Individually, the clinical presentation of patients with PCA was correlated to their CSF profile to assess the predictability of clinical features for diagnosis of underlying AD pathology. Results: At group level, the PCA biomarker profile was not different from that of the AD group, but very different from that of the OD group (p < 0.001). More than 90% of patients with PCA had CSF profiles consistent with AD. All patients with PCA with either isolated higher-order visual deficit (n = 8) or visual deficit associated with memory impairment (n = 11) had CSF profiles consistent with AD. Only one of the 3 patients with PCA with asymmetric motor signs fulfilled biological CSF criteria for AD. Conclusions: PCA syndrome is usually associated with CSF biomarkers suggestive of AD, as shown by previous neuropathologic studies. This does not apply in case of motor signs suggesting associated corticobasal syndrome. CSF biomarkers help to discriminate AD from non-AD processes associated with this condition.

Risk of Alzheimer's disease biological misdiagnosis linked to cerebrospinal collection tubes.

Tau proteins and amyloid-β (Aβ) peptides are the current recognized cerebrospinal fluid (CSF) biomarkers used as an aid in the diagnosis of Alzheimers disease (AD). However, there is no consensus on their clinical use due to non-qualified cut-off values, probably related to the observed high pre-analytical and analytical variability. Standardized pre-analytical protocols have therefore been proposed. Importantly, these recommend the use of polypropylene collection/sampling tubes while, to date, no broad comparison of these types of tubes has been conducted. In this study, we first compared, as part of a real clinical workflow, the impact of four different collection tubes on the CSF concentration of Aβ peptides (Aβ42, Aβ40) and total (hTau) and phosphorylated (P-Tau181P) tau proteins measured using routine ELISA kits. We then extended this study to 11 polypropylene tubes used by different clinical laboratories, and investigated their plastic polymer composition using differential scanning calorimetry and Fourier Transformed Infrared spectroscopy. Significant concentration variations linked solely to the use of different types of tubes were observed. This was particularly marked for Aβ peptides, with >50% disparity occurring in less than five minutes. Polymer composition analysis revealed that most polypropylene tubes were in fact copolymers with at least polyethylene. There was no clear correlation between tube composition and pre-analytical behavior. Our results show that the use of polypropylene tubes does not guarantee satisfactory pre-analytical behavior. They also point to collection/sampling tubes being a major pre-analytical source of variability that could impact the significance of AD biological diagnosis.

European Pentoxifylline Multi-Infarct Dementia Study

A double-blind, placebo-controlled, parallel-group, multicentre study was conducted to evaluate the efficacy of pentoxifylline (Trental) in patients with multi-infarct dementia (MID) according to DSM-III-R criteria. Men and women aged 45 years or older, with a Hachinski Ischemia Scale score > or = 7 and a Mini Mental State Examination (MMSE) score of 10-25 at entry, and computed tomographic evidence of vascular disease were enrolled. A total of 289 patients were randomised to receive either oral pentoxifylline 400 mg t.i.d. or placebo for 9 months, and efficacy was assessed every 3 months. The primary outcome variable was the difference in scores between the two treatment groups, as measured on the Gottfries, Bråne, Steen (GBS) scale. Secondary outcome variables included the scores achieved on the Sandoz Clinical Assessment Geriatric (SCAG) scale and MMSE, and a battery of psychological and other tests. The intention-to-treat analysis for patients completing the study (n = 239) showed a statistically significant difference in the total GBS score in favour of pentoxifylline (improvement of 3.5 points, p = 0.028). A significant difference in the total GBS score in favour of pentoxifylline was even almost achieved in the intention-to-treat analysis for all evaluable patients (n = 269, improvement of 2.1 points, p = 0.065). It is concluded that treatment with pentoxifylline is beneficial for patients with MID, the global results of the GBS and SCAG scales being reinforced by significant improvements in those subscales specific for intellectual and cognitive function.

Impact of harmonization of collection tubes on Alzheimer's disease diagnosis

The objective of this study was to analyze differences in biomarker outcomes before and after harmonization of cerebrospinal fluid (CSF) collection tubes in Alzheimers disease (AD) diagnosis.

Cerebrospinal Fluid Collection Tubes: A Critical Issue for Alzheimer Disease Diagnosis

To the Editor: Total tau protein (hTau),1 its phosphorylated isoform (p-Tau181P), and Aβ1–42 peptides are the currently accepted cerebrospinal fluid (CSF) biomarkers used as aids in the diagnosis of Alzheimer disease (1). Although polypropylene (PP) was previously reported as the best material for CSF collection tubes (2), heterogeneity in CSF Aβ1–42 values was observed with different PP sampling tubes (3). Because the recommendation to use PP tubes did not lead to standardization of clinical cutoff values (4), we decided to fully address this issue by comparing various types of tubes within an actual clinical work flow and by analyzing the material of different commercially available PP tubes. In the framework of an ethically approved study, we collected CSF samples from 12 patients directly (from the lumbar puncture needle) into 2 PP tubes [BD catalog no. 352096 (BD-PP); Sarstedt catalog no. 62.610.201 (ST-PP)], 1 hemolysis polyethylene tube [Fisher Scientific catalog no. ref.W1773X (HE-PE)], and 1 polystyrene tube [BD catalog no. 352095 (BD-PS)]. CSF biomarker concentrations were measured in parallel in these 4 types of tubes with Innogenetics INNOTEST® kits. We extended this analysis by comparing the results obtained with 11 different commercially available collection tubes labeled as “PP” for a series of fresh (unfrozen) …

Identification without manipulation: a study of the relations between object use and semantic memory

The role of semantic knowledge in object utilisation is a matter of debate. It is usually presumed that access to semantic knowledge is a necessary condition for manipulation, but a few reports challenged this view. The existence of a direct, pre-semantic route from vision to action has been proposed. We report the case of a patient with a disorder of object use in everyday life, in the context of probable Alzheimers disease. This patient was also impaired when manipulating single objects. He showed a striking dissociation between impairment in object use and preserved capacity to perform symbolic and meaningless gestures. To elucidate the nature of the disorder, and to clarify the relations between semantic knowledge and object use, we systematically assessed his capacity to recognise, name, access semantic knowledge, and use 15 common objects. We found no general semantic impairment for the objects that were not correctly manipulated, and, more importantly, no difference between the semantic knowledge of objects correctly manipulated and objects incorrectly manipulated. These data, although not incompatible with the hypothesis of a direct route for action, are better accommodated by the idea of a distributed semantic memory, where different types of knowledge are represented, as proposed by Allport (Allport, D. A. Current perspectives in dysphasia, pp. 32-60. Churchill Livingstone, Edinburgh, 1985).

Are semantic errors actually semantic?: evidence from Alzheimer's disease

Patients with Alzheimers disease (AD) produce a high rate of semantic errors when naming to confrontation. This is considered to be one of the many consequences of their semantic memory deficit. However, it has been shown, in aphasic patients with focal lesions, that semantic errors could arise from impairment to any one of the levels in the naming process. To check this hypothesis in AD, we assessed in 15 patients the capacity to name and access semantic knowledge (by multiple-choice probe questions) about 14 objects presented successively in the visual, tactile, auditory, and verbal modalities. In the visual naming task, 33 errors were recorded: 26 (78.8%) were semantic and 7 (21.2%) were unrelated errors. Of the 26 semantic errors, 8 were related to a deficit of the semantic knowledge related to the item and 17 to a deficit in the retrieval of the phonological form of the word. One was associated with a deficit of access to semantic knowledge in the visual modality. The 7 unrelated errors were associated with a loss of semantic knowledge for 4 and deficit of access to the phonological form for 3. In conclusion, this study shows that semantic errors do not systematically reflect a deficit of semantic knowledge in Alzheimers disease. It also seems that unrelated errors are more frequently related to semantic deficits than semantic errors in this population.

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.