Christian Geny

Correlations between soluble α/β forms of amyloid precursor protein and Aβ38, 40, and 42 in human cerebrospinal fluid

Cerebrospinal fluid (CSF) biomarkers are now widely used for diagnosis of Alzheimer disease (AD) in atypical clinical forms, for differential and early diagnosis, or for stratification of patients in clinical trials. Among these biomarkers, different forms of amyloid peptides (Aβ) produced by the cleavage of a transmembrane precursor protein called APP (amyloid precursor protein) have a major role. Aβ peptides exist in different length the most common ones having 40 (Aβ40), 42 (Aβ42), or 38 (Aβ38) amino acids in length. APP processing by gamma-secretase releases also an amino-terminal secreted fragment called sAβPP-beta while an alternative nonamyloidogenic cleavage of APP, through an alpha-secretase, liberates another fragment called sAβPP-alpha. To decipher the molecular and pathological mechanisms leading to the production and the detection of these entities is essential for the comprehension and the prevention of AD. In this report, we present the results of the multiplex measurement of CSF Aβ38, Aβ40, Aβ42, sAβPP-alpha, and sAβPP-beta in 60 patients mostly with dementia eventually segregated between neurochemical dementia diagnostic (NDD) positive and negative groups. The NDD classification was based on our routine Tau, P-tau(181), and Aβ(42) cutoff values. We confirmed previous findings regarding the correlation between sAβPP-alpha and sAβPP-beta, as well as the potential interest of these new biomarkers. We also studied the correlation between sAβPPs and Aβ peptides, as well as between Aβ peptides themselves. We observed a strong correlation between Aβ38 and sAβPP-beta which suggested that the production of this peptide was in direct relation with β secretase activities. We also reported a strong correlation between Aβ38 and Aβ40, while Aβ42 was correlated to these fragments only in nonpathological situations. These results enlighten the complex relationships between these molecular markers in both physiological and pathological situations. Our results are important for the further use of these analytes for AD diagnosis as well as for validating the cell biological hypotheses of APP processing and Aβ fragment production.

Detection of Freezing of Gait in Parkinson Disease: Preliminary Results

Freezing of gait (FOG) is a common symptom in Parkinsonism, which affects the gait pattern and is associated to a fall risk. Automatized FOG episode detection would allow systematic assessment of patient state and objective evaluation of the clinical effects of treatments. Techniques have been proposed in the literature to identify FOG episodes based on the frequency properties of inertial sensor signals. Our objective here is to adapt and extend these FOG detectors in order to include other associated gait pattern changes, like festination. The proposed approach is based on a single wireless inertial sensor placed on the patients lower limbs. The preliminary experimental results show that existing frequency-based freezing detectors are not sufficient to detect all FOG and festination episodes and that the observation of some gait parameters such as stride length and cadence are valuable inputs to anticipate the occurrence of upcoming FOG events.

Pathological Tremor and Voluntary Motion Modeling and Online Estimation for Active Compensation

This paper presents an algorithm to perform online tremor characterization from motion sensors measurements, while filtering the voluntary motion performed by the patient. In order to estimate simultaneously both nonstationary signals in a stochastic filtering framework, pathological tremor was represented by a time-varying harmonic model and voluntary motion was modeled as an auto-regressive moving-average (ARMA) model. Since it is a nonlinear problem, an extended Kalman filter (EKF) was used. The developed solution was evaluated with simulated signals and experimental data from patients with different pathologies. Also, the results were comprehensively compared with alternative techniques proposed in the literature, evidencing the better performance of the proposed method. The algorithm presented in this paper may be an important tool in the design of active tremor compensation systems.

Daytime sleepiness in Parkinson's disease: a reappraisal.

Background Excessive daytime sleepiness is a frequent complaint in Parkinson’s disease (PD); however the frequency and risk factors for objective sleepiness remain mostly unknown. We investigated both the frequency and determinants of self-reported and objective daytime sleepiness in patients with Parkinson’s disease (PD) using a wide range of potential predictors. Methods One hundred and thirty four consecutive patients with PD, without selection bias for sleep complaint, underwent a semi-structured clinical interview and a one night polysomnography followed by a multiple sleep latency test (MSLT). Demographic characteristics, medical history, PD course and severity, daytime sleepiness, depressive and insomnia symptoms, treatment intake, pain, restless legs syndrome, REM sleep behaviour disorder, and nighttime sleep measures were collected. Self-reported daytime sleepiness was defined by an Epworth Sleepiness Scale (ESS) score above 10. A mean sleep latency on MSLT below 8 minutes defined objective daytime sleepiness. Results Of 134 patients with PD, 46.3% had subjective and only 13.4% had objective sleepiness with a weak negative correlation between ESS and MSLT latency. A high body mass index (BMI) was associated with both ESS and MSLT, a pain complaint with ESS, and a higher apnea/hypopnea index with MSLT. However, no associations were found between both objective and subjective sleepiness, and measures of motor disability, disease onset, medication (type and dose), depression, insomnia, restless legs syndrome, REM sleep behaviour disorder and nighttime sleep evaluation. Conclusion We found a high frequency of self-reported EDS in PD, a finding which is however not confirmed by the gold standard neurophysiological evaluation. Current treatment options for EDS in PD are very limited; it thus remains to be determined whether decreasing pain and BMI in association with the treatment of sleep apnea syndrome would decrease significantly daytime sleepiness in PD.

Decreased sAβPPβ, Aβ38, and Aβ40 cerebrospinal fluid levels in frontotemporal dementia.

To improve the etiological diagnosis of neurodegenerative dementias like Alzheimers disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aβ42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAβPPβ, Aβ38, and Aβ40 levels. Aβ38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aβ38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aβ38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AβPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia.

Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.

Next‐generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini‐exome coupled to read‐depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini‐exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini‐exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.

IMU based detection of freezing of gait and festination in Parkinson's disease

Freezing of gait (FOG) and festination are common symptoms in Parkinson Disease. They affect gait pattern and are associated to fall risks. We aim at early detection of FOG and festination episodes in order to trigger FES assistance. In this paper we present preliminary experimental results of FOG and festination detection including frequency analysis and gait parameters changes. The proposed solution is based on one wireless inertial sensor placed on the patient shank.

On the Use of Fixed‐Intensity Functional Electrical Stimulation for Attenuating Essential Tremor

A great proportion of essential tremor (ET) patients have not so far been able to receive functional benefits from traditional therapies. In this regard, the use of functional electrical stimulation (FES) has been proposed for reducing tremor amplitude by stimulating muscles in antiphase with respect to the trembling motion. Although some studies have reported success in terms of tremor attenuation, drawbacks still exist that prevent the method from being used in real-life applications. In this article, we explore an alternative approach: a strategy based on the hypothesis that FES-induced constant muscle contraction may provide functional benefit for tremor patients. To evaluate the proposed strategy, experiments were conducted in which stimulation was intermittently turned on and off while the subjects performed a static motor task. The results of the proposed experimental protocol indicate that tremor attenuation using this strategy is feasible, as consistent tremor attenuation levels were obtained in eight out of 10 ET patients. Nonetheless, tremor reduction was not instantaneous for all successful trials, indicating that prior training with FES may improve the overall response. Furthermore, although simpler assistive devices may potentially be designed based on this technique, some experimental difficulties still exist, which suggests that further studies are necessary.

Rhythmic abilities and musical training in Parkinson’s disease: do they help?

Rhythmic auditory cues can immediately improve gait in Parkinson’s disease. However, this effect varies considerably across patients. The factors associated with this individual variability are not known to date. Patients’ rhythmic abilities and musicality (e.g., perceptual and singing abilities, emotional response to music, and musical training) may foster a positive response to rhythmic cues. To examine this hypothesis, we measured gait at baseline and with rhythmic cues in 39 non-demented patients with Parkinson’s disease and 39 matched healthy controls. Cognition, rhythmic abilities and general musicality were assessed. A response to cueing was qualified as positive when the stimulation led to a clinically meaningful increase in gait speed. We observed that patients with positive response to cueing (n = 17) were more musically trained, aligned more often their steps to the rhythmic cues while walking, and showed better music perception as well as poorer cognitive flexibility than patients with non-positive response (n = 22). Gait performance with rhythmic cues worsened in six patients. We concluded that rhythmic and musical skills, which can be modulated by musical training, may increase beneficial effects of rhythmic auditory cueing in Parkinson’s disease. Screening patients in terms of musical/rhythmic abilities and musical training may allow teasing apart patients who are likely to benefit from cueing from those who may worsen their performance due to the stimulation.Musicality in Parkinson’s disease: Trained to follow the beatListening to rhythmic auditory cues improves the ability to walk in patients with Parkinson’s disease (PD). Previous studies have shown that music can help patients with neurological disorders synchronize their movements to a beat. An international study led by Valérie Cochen De Cock at Clinique Beau Soleil in Montpellier (France) and Simone Dalla Bella at the International Laboratory For Brain, Music and Sound Research (BRAMS) in Montreal (Canada), measured gait speed in 39 patients with PD without dementia in response to rhythmic stimulation. Twenty-two patients increased their gait speed by spontaneously synchronizing their steps to the beat. The remaining 17 patients showed no effect or significant worsening of gait performance (e.g., smaller step length). The patients who benefited the most from rhythmic cues exhibited better rhythmic skills and were more musical than the others. Assessing musical abilities may serve to identify patients who are likely to benefit from this music-based intervention and may foster individualization of the treatment.

Diffusion tensor imaging differentiates vascular parkinsonism from parkinsonian syndromes of degenerative origin in elderly subjects

BACKGROUND AND PURPOSE The etiologic diagnosis of parkinsonian syndromes is of particular importance when considering syndromes of vascular or degenerative origin. The purpose of this study is to find differences in the white-matter architecture between those two groups in elderly patients. MATERIALS AND METHODS Thirty-five patients were prospectively included (multiple-system atrophy, n=5; Parkinsons disease, n=15; progressive supranuclear palsy, n=9; vascular parkinsonism, n=6), with a mean age of 76 years. Patients with multiple-system atrophy, progressive supranuclear palsy and Parkinsons disease were grouped as having parkinsonian syndromes of degenerative origin. Brain MRIs included diffusion tensor imaging. Fractional anisotropy and mean-diffusivity maps were spatially normalized, and group analyses between parkinsonian syndromes of degenerative origin and vascular parkinsonism were performed using a voxel-based approach. RESULTS Statistical parametric-mapping analysis of diffusion tensor imaging data showed decreased fractional anisotropy value in internal capsules bilaterally in patients with vascular parkinsonism compared to parkinsonian syndromes of degenerative origin (p=0.001) and showed a lower mean diffusivity in the white matter of the left superior parietal lobule (p=0.01). Fractional anisotropy values were found decreased in the middle cerebellar peduncles in multiple-system atrophy compared to Parkinsons disease and progressive supranuclear palsy. The mean diffusivity was increased in those regions for these subgroups. CONCLUSION Clinically defined vascular parkinsonism was associated with decreased fractional anisotropy in the deep white matter (internal capsules) compared to parkinsonian syndromes of degenerative origin. These findings are consistent with previously published neuropathological data.