Catherine Thomas-Anterion

Early-Onset Autosomal Dominant Alzheimer Disease: Prevalence, Genetic Heterogeneity, and Mutation Spectrum

To determine the prevalence of early-onset Alzheimer disease (EOAD) and of autosomal dominant forms of EOAD (ADEOAD), we performed a population-based study in the city of Rouen (426,710 residents). EOAD was defined as onset of disease at age <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations. Using these stringent criteria, we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively. We then performed a mutational analysis of the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) in 34 families with ADEOAD ascertained in France. In 19 (56%) of these families, we identified 16 distinct PSEN1 missense mutations, including 4 (Thr147Ile, Trp165Cys, Leu173Trp, and Ser390Ile) not reported elsewhere. APP mutations, including a novel mutation located at codon 715, were identified in 5 (15%) of the families. In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no PSEN1, PSEN2, or APP mutation was identified. These results show that (1) PSEN1 and APP mutations account for 71% of ADEOAD families and (2) nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP mutations.

TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration.

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. Ann Neurol 2009;65:470–474

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.

Frontal Assessment Battery is a marker of dorsolateral and medial frontal functions: A SPECT study in frontotemporal dementia

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.

C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flow-chart for Genetic Testing

Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.

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.

The French Series of Autosomal Dominant Early Onset Alzheimer's Disease Cases: Mutation Spectrum and Cerebrospinal Fluid Biomarkers

We describe 56 novel autosomal dominant early-onset Alzheimer disease (ADEOAD) families with PSEN1, PSEN2, and AβPP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 AβPP, and 13 AβPP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization). CSF biomarkers profile was consistent with an AD diagnosis in 90% of families carrying mutations on known genes. In families without mutation, CSF biomarkers were consistent with AD diagnosis in 14/16 cases. Overall, these results support further genetic heterogeneity in the determinism of ADEOAD and suggest that other major genes remain to be characterized.

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

To the Editor:nnTotal 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.nnIn 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) …

Sleep breathing disorders and cognitive function in the elderly: an 8-year follow-up study. the proof-synapse cohort.

STUDY OBJECTIVESnSleep breathing disorder (SBD) may be an important factor in age-related cognitive decline. In a cohort of healthy elderly subjects, we performed an 8-y longitudinal study to assess whether changes in cognitive function occur in untreated elderly patients with SBD and without dementia and the factors implicated in these changes.nnnDESIGNnA population-based longitudinal study.nnnSETTINGnClinical research settings.nnnPARTICIPANTSnA total of 559 participants of the PROOF study aged 67 y at the study entry and free from neurological disorders were examined.nnnINTERVENTIONSnN/A.nnnMEASUREMENTS AND RESULTSnAbnormal breathing events were defined by an apnea-hypopnea index (AHI) > 15. The raw cognitive data and averaged Z-scores for the attentional, executive, and memory functions were collected at the baseline and follow-up. At baseline, AHI > 15 was found in 54% of subjects with 18% having an AHI > 30. At follow-up, the presence of abnormal breathing events was associated with a slight but significant decline in the attentional domain (P = 0.01), which was more evident in the subjects with an AHI > 30 (P = 0.004). No significant changes over time were observed in the executive and memory functions. Several indices of chronic hypoxemia, defined either as a cumulative peripheral oxygen saturation (SpO2) < 90% or a minimal SpO2, accounted for portions of the variance in the decline in attention. All observed effects were small, accounting for 4-7% of variance in multivariate models.nnnCONCLUSIONnIn healthy elderly subjects, various components of sleep breathing disorder at baseline were associated with small changes in selected cognitive functions specific to the attention domain after controlling for multiple comorbidities, such as sleepiness, hypertension, diabetes, anxiety, and depression.nnnCLINICAL TRIAL REGISTRATIONnClinicalTrials.gov identifiers NCT 00759304 and NCT 00766584.

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.