Catherine Thomas-Antérion

Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation

Article abstract The authors report a presenilin 1 (PSEN1) mutation (L113P) in a family with six cases of dementia. The patients had personality changes and behavioral disorders, whereas spatial orientation and praxis were preserved late in the course of the illness. Neuroimaging features were consistent with the diagnosis of frontotemporal dementia. The authors conclude that PSEN1 mutations can be associated with clinical features of frontotemporal dementia.–1578

Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease

Background: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3). Methods: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics. Results: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 ± 10.3 years (range, 41–84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients. Conclusions: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.

Prevalence and Clinical Correlates of Restless Legs Syndrome in an Elderly French Population: The Synapse Study

BACKGROUND The occurrence of restless legs syndrome (RLS) in elderly individuals is well known but the incidence and the clinical correlates in these subjects are still unclear. The present study explores the prevalence of and assesses symptoms associated with RLS in an older French population. METHODS The study sample for this study comprised 318 subjects (219 women and 99 men), aged 68.6 +/- 0.8 years. All subjects underwent clinical assessment, nocturnal polygraphy, and cognitive and mood disorders evaluation. RLS was assessed with the standard validated criteria and severity was evaluated by the use of International Restless Legs Syndrome Study Group (IRLS) questionnaire. RESULTS RLS was present in 24.2% of the sample, prevalence being greater in women (29.7%) than in men (12.1%). The mean IRLS score was 16.6 +/- 4.8, 67% of cases having mild to moderate range. Participants with RLS reported greater hypnotic (p < .001) and antidepressant medication intake (p < .001) and had higher anxiety (p < .001) and depression (p < .001) scores. Participants with RLS had lower cognitive performances at Stroop and Verbal fluency tests than participants without RLS (p < .05 and p = .002, respectively). These associations remained significant after multivariate adjustment for medication, depression, and subjective sleep. CONCLUSIONS Presence of undiagnosed RLS is higher in healthy elderly participants without previously diagnosed sleep disorders, affecting women more often than men. The presence of RLS increased the risk of anxiety and mood disorders and predispose to preclinical cognitive decline independently of anxiety, mood disorders, duration and quality of sleep, and medication.

Memantine in Behavioral Variant Frontotemporal Dementia: Negative Results

We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinicians Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI), Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19-30). On the CIBIC-Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0.4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of score between the memantine group and the placebo group (MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10) except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated. This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.

Does subjective sleep affect cognitive function in healthy elderly subjects? The Proof cohort

OBJECTIVE Some epidemiological data are available on the association between sleep duration and sleep quality, sleep complaints, and the aging related cognitive impairment in the elderly. In this study we examined a large sample of healthy elderly subjects to assess the relationship between sleep quality, subjective cognitive complaints, and neuropsychological performance. METHODS A total of 272 elderly subjects (mean age 74.8 ± 1.1 years) were recruited from a population-based cross-sectional study on aging and cardiovascular morbidity. All subjects filled in self-assessment questionnaires evaluating cognitive function, anxiety, depression, sleep-related parameters, and the Pittsburgh Sleep Quality Index (PSQI). Ambulatory polygraphy and extensive neuropsychological tests were also performed. Based on the total PSQI score, subjects were classified as good sleepers (GS, PSQI<5, n=116) and poor sleepers (PS, PSQI≥5, n=156). RESULTS Poor sleep did not affect the subjective cognitive function score, subjective cognitive impairment being mainly related to anxiety, depression, and sleep medication intake. No significant differences were seen between GS and PS in any of the objective cognitive function tests except for the Trail Making Test A (TMA-A), processing speed being longer in the PS group (p<0.001). Neither the presence of sleep-related breathing disorders nor gender affected cognitive performance. CONCLUSIONS Our results suggest that in healthy elderly subjects, subjective sleep quality and duration did not significantly affect subjective and objective cognitive performances, except the attention level, for that the interference of sleep medication should be considered.

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease

Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-β peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aβ metabolism or signalling, and for which animal or cellular models have already been developed.

The Wechsler Digit Symbol Substitution Test as the Best Indicator of the Risk of Impaired Driving in Alzheimer Disease and Normal Aging

Aims: Our purpose was to identify cognitive tools associated with unsafe driving among elderly drivers of varying cognitive levels. Methods: Twenty drivers with early-stage dementia of the Alzheimer type and 56 nondemented drivers aged 65–85 were recruited. Various cognitive processes were measured and unsafe driving was evaluated during an in-traffic road test with 3 different indicators and a composite indicator. Results: The Wechsler Digit Symbol Substitution Test score was the best cognitive measure to detect unsafe drivers using the composite driving indicator. Conclusion: The Digit Symbol Substitution Test may be used by physicians for the evaluation and follow-up of older patients, with or without Alzheimer-type dementia, as a screening tool of unsafe driving.

Evidence for a selective deficit in automatic activation of positive information in patients with Alzheimer's disease in an affective priming paradigm

Using an affective priming paradigm, we studied the automatic and unconscious activation of emotional information in long-term memory. Participants had to judge target words preceded by various primes as positive or negative. The primes were masked and the SOA between the onset of primes and the onset of targets was 50 ms. Our results showed that in patients with dementia of the Alzheimer type (DAT), the negativity bias was preserved and the emotional priming effect was perturbed with positive targets. In control participants, this priming effect was restricted to negative targets. These findings are discussed in terms of preserved automatic activation of emotional information in Alzheimers disease (AD) and in terms of an early deficit of the left hemisphere in AD making positive information more vulnerable to disease.

TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts.

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.

Brain plasticity in the motor network is correlated with disease progression in amyotrophic lateral sclerosis

Objective: To test the influence of functional cerebral reorganization in amyotrophic lateral sclerosis (ALS) on disease progression. Methods: Nineteen predominantly right‐handed ALS patients and 21 controls underwent clinical evaluation, functional Magnetic Resonance Imaging (fMRI), and diffusion tensor imaging. Patients were clinically re‐evaluated 1 year later and followed until death. For fMRI, subjects executed and imagined a simple hand‐motor task. Between‐group comparisons were performed, and correlations were searched with motor deficit arm Medical Research Council (MRC) score, disease progression ALS Functional Rating Scale (ALSFRS), and survival time. Results: By the MRC score, the hand strength was lowered by 12% in the ALS group predominating on the right side in accordance with an abnormal fractional anisotropy (FA) limited to the left corticospinal tract (37.3% reduction vs. controls P < 0.01). Compared to controls, patients displayed overactivations in the controlateral parietal (P < 0.004) and somatosensory (P < 0.004) cortex and in the ipsilateral parietal (P < 0.01) and somatosensory (P < 0.01) cortex to right‐hand movement. Movement imagination gave similar results while no difference occurred with left‐hand tasks. Stepwise regression analysis corrected for multiple comparisons showed that controlateral parietal activity was inversely correlated with disease progression (R2 = 0.43, P = 0.001) and ipsilateral somatosensory activations with the severity of the right‐arm deficit (R2 = 0.48, P = 0.001). Conclusions: Cortical Blood Oxygen Level Dependent (BOLD) signal changes occur in the brain of ALS patients during a simple hand‐motor task when the motor deficit is still moderate. It is correlated with the rate of disease progression suggesting that brain functional rearrangement in ALS may have prognostic implications. Hum Brain Mapp 34:2391–2401, 2013.