Screening over Speech in Unselected Populations for Clinical Trials in AD (PROSPECT-AD): Study Design and Protocol.

BACKGROUND: Speech impairments are an early feature of Alzheimer's disease (AD) and consequently, analysing speech performance is a promising new digital biomarker for AD screening. Future clinical AD trials on disease modifying drugs will require a shift to very early identification of individuals at risk of dementia. Hence, digital markers of language and speech may offer a method for screening of at-risk populations that are at the earliest stages of AD, eventually in combination with advanced machine learning. To this end, we developed a screening battery consisting of speech-based neurocognitive tests. The automated test performs a remote primary screening using a simple telephone. OBJECTIVES: PROSPECT-AD aims to validate speech biomarkers for identification of individuals with early signs of AD and monitor their longitudinal course through access to well-phenotyped cohorts. DESIGN: PROSPECT-AD leverages ongoing cohorts such as EPAD (UK), DESCRIBE and DELCODE (Germany), and BioFINDER Primary Care (Sweden) and Beta-AARC (Spain) by adding a collection of speech data over the telephone to existing longitudinal follow-ups. Participants at risk of dementia are recruited from existing parent cohorts across Europe to form an AD 'probability-spectrum', i.e., individuals with a low risk to high risk of developing AD dementia. The characterization of cognition, biomarker and risk factor (genetic and environmental) status of each research participants over time combined with audio recordings of speech samples will provide a well-phenotyped population for comparing novel speech markers with current gold standard biomarkers and cognitive scores. PARTICIPANTS: N= 1000 participants aged 50 or older will be included in total, with a clinical dementia rating scale (CDR) score of 0 or 0.5. The study protocol is planned to run according to sites between 12 and 18 months. MEASUREMENTS: The speech protocol includes the following neurocognitive tests which will be administered remotely: Word List [Memory Function], Verbal Fluency [Executive Functions] and spontaneous free speech [Psychological and/ or behavioral symptoms]. Speech features on the linguistic and paralinguistic level will be extracted from the recordings and compared to data from CSF and blood biomarkers, neuroimaging, neuropsychological evaluations, genetic profiles, and family history. Primary candidate marker from speech will be a combination of most significant features in comparison to biomarkers as reference measure. Machine learning and computational techniques will be employed to identify the most significant speech biomarkers that could represent an early indicator of AD pathology. Furthermore, based on the analysis of speech performances, models will be trained to predict cognitive decline and disease progression across the AD continuum. CONCLUSION: The outcome of PROSPECT-AD may support AD drug development research as well as primary or tertiary prevention of dementia by providing a validated tool using a remote approach for identifying individuals at risk of dementia and monitoring individuals over time, either in a screening context or in clinical trials.

Multimodal MRI cerebral correlates of verbal fluency switching and its impairment in women with depression.

BACKGROUND: The search of biomarkers in the field of depression requires easy implementable tests that are biologically rooted. Qualitative analysis of verbal fluency tests (VFT) are good candidates, but its cerebral correlates are unknown. METHODS: We collected qualitative semantic and phonemic VFT scores along with grey and white matter anatomical MRI of depressed (n = 26) and healthy controls (HC, n = 25) women. Qualitative VFT variables are the "clustering score" (i.e. the ability to produce words within subcategories) and the "switching score" (i.e. the ability to switch between clusters). The clustering and switching scores were automatically calculated using a data-driven approach. Brain measures were cortical thickness (CT) and fractional anisotropy (FA). We tested for associations between CT, FA and qualitative VFT variables within each group. RESULTS: Patients had reduced switching VFT scores compared to HC. Thicker cortex was associated with better switching score in semantic VFT bilaterally in the frontal (superior, rostral middle and inferior gyri), parietal (inferior parietal lobule including the supramarginal gyri), temporal (transverse and fusiform gyri) and occipital (lingual gyri) lobes in the depressed group. Positive association between FA and the switching score in semantic VFT was retrieved in depressed patients within the corpus callosum, right inferior fronto-occipital fasciculus, right superior longitudinal fasciculus extending to the anterior thalamic radiation (all p < 0.05, corrected). CONCLUSION: Together, these results suggest that automatic qualitative VFT scores are associated with brain anatomy and reinforce its potential use as a surrogate for depression cerebral bases.

Sensitivity and specificity of ultrasound in spinal trauma in 29 consecutive patients.

PURPOSE: Indication for surgery in spine trauma patients depends on the extent of destruction of the spine. Computer-assisted tomography scan (CAT scan) is not suitable to diagnose type B-injuries. Aim of the study was to investigate whether ultrasound is able to detect destruction of the posterior ligament complex (PLC). METHODS: Twenty-nine patients were included. The results of ultrasound were compared with magnetic resonance imaging (MRI), CAT scan, X-ray, intraoperative findings. Statistical analysis was carried out by an independent observer. RESULTS: In 27 cases both ultrasound and MRI had the same result. In two cases, ultrasound failed to detect ligamentous injury. The sensitivity of ultrasound was 0.82 (CI 0.48-0.98), its specificity: 1. MRI and Ultrasound findings had a strong positive correlation (phi = 0.85, Cohen's kappa: 0.85, with 95 % confidence interval 0.65-1) and a high significance (Fischer's exact test: p < 0.0001). CONCLUSION: Ultrasound may indicate rupture or integrity of PLC in cases where MRI is missing.

[Alternatives to femtosecond laser technology: subnanosecond UV pulse and ring foci for creation of LASIK flaps]. / Alternativen zur Femtosekundentechnologie: UV-Subnanosekundenpulse und Ringfoki für LASIK-Flaperzeugung.

BACKGROUND: In refractive corneal surgery femtosecond (fs) lasers are used for creating LASIK flaps, dissecting lenticules and for astigmatism correction by limbal incisions. OBJECTIVES: Femtosecond laser systems are complex and expensive and cutting precision is compromised by the large focal length associated with the commonly used infrared (IR) wavelengths. Based on investigations of the cutting dynamics, novel approaches for corneal dissection using ultraviolet A (UVA) picosecond (ps) pulses and ring foci from vortex beams are presented. METHODS: Laser-induced bubble formation in corneal stroma was investigated by high-speed photography at 1-50 million frames/s. Using Gaussian and vortex beams of UVA pulses with durations between 200 and 850 ps the laser energy needed for easy removal of flaps created in porcine corneas was determined and the quality of the cuts by scanning electron microscopy was documented. Cutting parameters for 850 ps are reported also for rabbit eyes. The UV-induced and mechanical stress were evaluated for Gaussian and vortex beams. RESULTS: The results show that UVA picosecond lasers provide better cutting precision than IR femtosecond lasers, with similar processing times. Cutting energy decreases by >50 % when the laser pulse duration is reduced to 200 ps. Vortex beams produce a short, donut-shaped focus allowing efficient and precise dissection along the corneal lamellae which results in a dramatic reduction of the absorbed energy needed for cutting and of mechanical side effects as well as in less bubble formation in the cutting plane. CONCLUSION: A combination of novel approaches for corneal dissection provides the option to replace femtosecond lasers by compact UVA microchip laser technology. Ring foci are also of interest for femtosecond laser surgery, especially for improved lenticule excision.