Publications by authors named "Patrick Santens"

110 Publications

Evaluation of multi-feature auditory deviance detection in Parkinson's disease: a mismatch negativity study.

J Neural Transm (Vienna) 2021 May 24;128(5):645-657. Epub 2021 Apr 24.

Department of Rehabilitation Sciences, Faculty of Medicine and Health Sciences, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium.

Behavioral studies on auditory deviance detection in patients with Parkinson's disease (PD) have reported contradictory results. The primary aim of this study was to investigate auditory deviance detection of multiple auditory features in patients with PD by means of objective and reliable electroencephalographic (EEG) measurements. Twelve patients with early-stage PD and twelve age- and gender-matched healthy controls (HCs) were included in this study. Patients with PD participated without their regular dopaminergic medication. All subjects underwent an audiometric screening and performed a passive multi-feature mismatch negativity (MMN) paradigm. Repeated-measures analysis of variance (ANOVA) demonstrated no significant differences between patients with PD and HCs regarding MMN mean amplitude and latency for frequency, duration and gap deviants. Nevertheless, a trend towards increased MMN mean amplitude and latency was found in response to intensity deviants in patients with PD compared to HCs. Increased intensity MMN amplitude may indicate that more neural resources are allocated to the processing of intensity deviances in patients with PD compared to HCs. The interpretation of this intensity-specific MMN alteration is further discussed in the context of a compensatory mechanism for auditory intensity processing and involuntary attention switching in PD.
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http://dx.doi.org/10.1007/s00702-021-02341-zDOI Listing
May 2021

The Effect of Parkinson's Disease on Otoacoustic Emissions and Efferent Suppression of Transient Evoked Otoacoustic Emissions.

J Speech Lang Hear Res 2021 04 26;64(4):1354-1368. Epub 2021 Mar 26.

Department of Rehabilitation Sciences, Ghent University, Belgium.

Purpose Several studies have demonstrated increased auditory thresholds in patients with Parkinson's disease (PD) based on subjective tonal audiometry. However, the pathophysiological mechanisms underlying auditory dysfunction in PD remain elusive. The primary aim of this study was to investigate cochlear and olivocochlear function in PD using objective measurements and to assess the effect of dopaminergic medication on auditory function. Method Eighteen patients with PD and 18 gender- and age-matched healthy controls (HCs) were included. Patients with PD participated in medication on and off conditions. Linear mixed models were used to determine the effect of PD on tonal audiometry, transient evoked and distortion product otoacoustic emissions (OAEs), and efferent suppression (ES). Results Tonal audiometry revealed normal auditory thresholds in patients with PD for their age across all frequencies. OAE signal amplitudes demonstrated a significant interaction effect between group (PD vs. HC) and frequency, indicating decreased OAEs at low frequencies and increased OAEs at high frequencies in patients with PD. No significant differences were found between patients with PD and HCs regarding ES. In addition, no significant effect of medication status was found on auditory measurements in patients with PD. Conclusions Altered OAEs support the hypothesis of cochlear alterations in PD. No evidence was found for the involvement of the medial olivocochlear system. Altogether, OAEs may provide an objective early indicator of auditory alterations in PD and should complement subjective tonal audiometry when assessing and monitoring auditory function in PD.
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http://dx.doi.org/10.1044/2020_JSLHR-20-00594DOI Listing
April 2021

Hippocampal Sclerosis in Frontotemporal Dementia: When Vascular Pathology Meets Neurodegeneration.

J Neuropathol Exp Neurol 2021 Mar;80(4):313-324

Institute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of Antwerp, Antwerp, Belgium.

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified. We examined the relationship between HS, proteinopathies in frontotemporal cortices and hippocampus, Alzheimer disease, cerebrovascular changes, and age. We confirmed a strong association between HS and hippocampal TDP-43, whereas there was a weaker association between HS and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Nearly all of the FTLD-TDP cases had TDP-43 pathology in the hippocampus. HS was present in all FTLD-TDP type D cases, in 50% of the FTLD-TDP A cohort and in 6% of the FTLD-TDP B cohort. Our data also showed a significant association between HS and vascular changes. We reviewed the literature on HS and discuss possible pathophysiological mechanisms between TDP-43 pathology, cerebrovascular disease, and HS. Additionally, we introduced a quantitative neuronal cell count in CA1 to objectify the semiquantitative visual appreciation of HS.
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http://dx.doi.org/10.1093/jnen/nlab010DOI Listing
March 2021

Evidence of rehabilitation therapy in task-specific focal dystonia: a systematic review.

Eur J Phys Rehabil Med 2021 Feb 23. Epub 2021 Feb 23.

Physical and Rehabilitation Medicine, Ghent University Hospital, Ghent, Belgium.

Introduction: Task-specific dystonias are primary focal dystonias characterized by excessive muscle contractions producing abnormal postures during selective motor activities that often involve highly skilled, repetitive movements. Based on the idea of excessive motor excitability and aberrant sensorimotor integration in the pathophysiology of task-specific dystonia, sensorimotor retraining may hold promise. The purpose of this systematic review was to investigate the available evidence about the role of rehabilitation therapy as a treatment for task-specific dystonia.

Evidence Acquisition: A systematic review was performed of studies identified through Pubmed and Embase in a structured search strategy by independent author screening. The JBI (Joanna Briggs Institute) Critical Appraisal Checklist and RoB 2 were used to evaluate their methodological quality.

Evidence Synthesis: 21 studies were included for qualitative synthesis. Most of the reports are small single group pre-/post-test study designs with a variability in the type of task-specific dystonia and the type of evaluated outcome measures. Rehabilitation interventions were grouped into six categories based upon the underlying theoretical basis of different approaches: 1) movement practice, 2) training with constraint, 3) sensory reorganization, 4) biofeedback training, 5) neuromodulation with training and 6) compensatory strategies.

Conclusions: Although it appears that a number of task-specific dystonia patients may improve with rehabilitation therapy, no definitive conclusions can be drawn. More research in this field is needed, using standardized approaches and clearly defined outcome measures in larger cohorts of task-specific dystonia patients that are clinically and diagnostically well characterized.
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http://dx.doi.org/10.23736/S1973-9087.21.06677-6DOI Listing
February 2021

Editorial: Prodromal Parkinson's Disease.

Front Neurol 2020 12;11:634490. Epub 2021 Jan 12.

Parkinson Foundation International Centre of Excellence, King's College Hospital and King's College, London, United Kingdom.

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http://dx.doi.org/10.3389/fneur.2020.634490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873967PMC
January 2021

Neurophysiological investigation of auditory intensity dependence in patients with Parkinson's disease.

J Neural Transm (Vienna) 2021 03 30;128(3):345-356. Epub 2021 Jan 30.

Department of Information Technology (INTEC), Acoustics Research Group, Ghent University, Technologiepark-Zwijnaarde 15, 9052, Ghent, Belgium.

There is accumulating evidence for auditory dysfunctions in patients with Parkinson's disease (PD). Moreover, a possible relationship has been suggested between altered auditory intensity processing and the hypophonic speech characteristics in PD. Nonetheless, further insight into the neurophysiological correlates of auditory intensity processing in patients with PD is needed primarily. In the present study, high-density EEG recordings were used to investigate intensity dependence of auditory evoked potentials (IDAEPs) in 14 patients with PD and 14 age- and gender-matched healthy control participants (HCs). Patients with PD were evaluated in both the on- and off-medication states. HCs were also evaluated twice. Significantly increased IDAEP of the N1/P2 was demonstrated in patients with PD evaluated in the on-medication state compared to HCs. Distinctive results were found for the N1 and P2 component. Regarding the N1 component, no differences in latency or amplitude were shown between patients with PD and HCs regardless of the medication state. In contrast, increased P2 amplitude was demonstrated in patients with PD evaluated in the on-medication state compared to the off-medication state and HCs. In addition to a dopaminergic deficiency, deficits in serotonergic neurotransmission in PD were shown based on increased IDAEP. Due to specific alterations of the N1-P2 complex, the current results suggest deficiencies in early-attentive inhibitory processing of auditory input in PD. This interpretation is consistent with the involvement of the basal ganglia and the role of dopaminergic and serotonergic neurotransmission in auditory gating.
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http://dx.doi.org/10.1007/s00702-021-02305-3DOI Listing
March 2021

Multicollector Inductively Coupled Plasma-Mass Spectrometry with 10 Ω Faraday Cup Amplifiers for Ultrasensitive Mg Isotopic Analysis of Cerebrospinal Fluid Microsamples.

Anal Chem 2020 12 23;92(24):15975-15981. Epub 2020 Nov 23.

Department of Chemistry, Atomic & Mass Spectrometry-A&MS Research Unit, Ghent University, Campus Sterre, Krijgslaan 281-S12, Ghent 9000, Belgium.

Magnesium isotopic analysis of cerebrospinal fluid (CSF) is a potentially interesting approach for studies on neurodegeneration. However, this type of analysis is challenging because of the invasiveness of the sampling and small sample volume. In this work, a novel analytical method was developed for ultrasensitive Mg isotopic analysis of CSF microsamples multicollector inductively coupled plasma-mass spectrometry (MC-ICP-MS) using high-gain 10 Ω Faraday cup amplifiers. The intermediate and internal errors on the δMg value were improved up to fourfold using 10 Ω resistors for the monitoring of both the Mg and Mg isotopes and up to twofold using a 10 Ω resistor for the most abundant Mg isotope and a 10 Ω resistor for the Mg isotope. Magnesium isotope ratios measured at a concentration level of 7-10 μg L were in good agreement with those obtained using the conventional method at a concentration level of 150 μg L. The expanded uncertainty for the quality control CSF material obtained at the ultratrace level was ±0.16‰. Ultrasensitive Mg isotopic analysis was carried out for CSF from hydrocephalus patients using only 5 μL of sample. δMg values thus obtained were not significantly different from those obtained using the conventional method using a sample volume of 400 μL instead ( ≤ 0.05). The Mg isotopic composition of the CSF from hydrocephalus patients ranged between -0.65 and 0.30‰, with a mean δMg value of -0.14 ± 0.27‰.
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http://dx.doi.org/10.1021/acs.analchem.0c03431DOI Listing
December 2020

Future Perspectives on the Relevance of Auditory Markers in Prodromal Parkinson's Disease.

Front Neurol 2020 16;11:689. Epub 2020 Jul 16.

Department of Rehabilitation Sciences, Ghent University, Ghent, Belgium.

Research on auditory processing in Parkinson's disease (PD) has recently made substantial progress. At present, evidence has been found for altered auditory processing in the clinical stage of PD. The auditory alterations in PD have been demonstrated with low-cost and non-invasive assessments that are already used in routine clinical practice. Since auditory alterations have been reported early in disease progression, it would be highly relevant to investigate whether auditory markers could be provided in the prodromal stage of PD. In addition, auditory alterations in early stage PD might be modulated by dopaminergic medication. Therefore, the aim of this review is (1) to summarize the literature on auditory processing in PD with a specific focus on the early disease stages, (2) to give future perspectives on which audiological and electrophysiological measurements could be useful in the prodromal stage of PD and (3) to assess the effect of dopaminergic medication on potential auditory markers in the prodromal stage of PD.
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http://dx.doi.org/10.3389/fneur.2020.00689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378374PMC
July 2020

Cognitive and Affective Theory of Mind in Healthy Aging.

Exp Aging Res 2020 Oct-Dec;46(5):382-395. Epub 2020 Aug 5.

Department of Experimental Psychology, Ghent University , Ghent, Belgium.

Background: Previous studies on the effect of healthy aging on Theory of Mind (ToM) have produced mixed results. A possible explanation may be that different ToM components and types of inference have not systematically been considered. This study examined the effect of aging on ToM by assessing both first and second order cognitive and affective components within a single task.

Methods: We compared performance of young ( = 18.3y) and older adults ( = 61.0y) on the Yoni task. This task allows for a within-subject assessment of both first and second order cognitive and affective ToM.

Results: We observed that older adults had longer reaction times than young adults across cognitive and affective first order items. For second order items, this age difference was larger for affective than cognitive items. Results showed no indications that these findings could be explained by age differences in speed/accuracy trade-offs.

Conclusion: Our findings suggest that decision processes underlying ToM are slower in older adults on both first and second order inferences, but that age differences in these processes between cognitive and affective ToM are selective to second order inferences. We propose that the observed age differences may be associated with cortical and mental changes that occur with aging.
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http://dx.doi.org/10.1080/0361073X.2020.1802980DOI Listing
January 2021

Oral appliances in the treatment of oromandibular dystonia: a systematic review.

Acta Neurol Belg 2020 Aug 27;120(4):831-836. Epub 2020 Jun 27.

Department of Neurology, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium.

Oromandibular dystonia (OMD) is a clinically and etiologically heterogeneous form of focal dystonia with variable social and functional implications. The results of pharmacological treatment and botulinum toxin infiltrations are often unsatisfactory. We performed a systematic review on the effects of oral and dental appliances in patients with OMD. Most of the reports in the literature are single subject descriptions or small case series with a considerable variability in the type of dystonia, the type of evaluated appliances and in the outcome measures. Only one report included a large group of unselected patients that were evaluated with a mixture of outcome measures. Although it appears that a number of OMD patients, especially those who benefit from sensory tricks, may sustain some improvement with the use of oral appliances, no definitive conclusions can be drawn about the type of patients that may benefit, nor about the preferred type or mode of appliance. More research in this field is needed, using standardized approaches and clearly defined outcome measures in larger cohorts of OMD patients that are clinically and diagnostically well characterized.
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http://dx.doi.org/10.1007/s13760-020-01404-4DOI Listing
August 2020

The sensitivity of event-related potentials/fields to logopedic interventions in patients with stroke-related aphasia.

Acta Neurol Belg 2020 Aug 30;120(4):805-817. Epub 2020 May 30.

Department of Rehabilitation Sciences, Ghent University, Corneel Heymanslaan 10, 2P1, 9000, Ghent, Belgium.

Recovery of stroke-related aphasia can be affected by language therapy in the early and chronic stage. Objectively monitoring therapy-induced neuroplasticity is possible by several measurement techniques including electro- and magneto-encephalography. The obtained event-related potentials (ERPs) and fields (ERFs) provide insights into the neural basis of intact or deficient language processing with milliseconds precision. In this literature review, we highlight the sensitivity of ERPs and ERFs to logopedic interventions by providing an overview of therapy-induced changes in the amplitude, latency and topography of early and mid-to-late components.
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http://dx.doi.org/10.1007/s13760-020-01378-3DOI Listing
August 2020

Articulation lost in space. The effects of local orobuccal anesthesia on articulation and intelligibility of phonemes.

Brain Lang 2020 08 20;207:104813. Epub 2020 May 20.

Department of Neurology, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address:

Motor speech requires numerous neural computations including feedforward and feedback control mechanisms. A reduction of auditory or somatosensory feedback may be implicated in disorders of speech, as predicted by various models of speech control. In this paper the effects of reduced somatosensory feedback on articulation and intelligibility of individual phonemes was evaluated by using topical anesthesia of orobuccal structures in 24 healthy subjects. The evaluation was done using a combination of perceptual intelligibility estimation of consonants and vowels and acoustic analysis of motor speech. A significantly reduced intelligibility was found, with a major impact on consonant formation. Acoustic analysis demonstrated disturbed diadochokinesis. These results underscore the clinical importance of somatosensory feedback in speech control. The interpretation of these findings in the context of speech control models, neuro-anatomy and clinical neurology may have implications for subtyping of dysarthria.
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http://dx.doi.org/10.1016/j.bandl.2020.104813DOI Listing
August 2020

Phenotypic characterization of paroxysmal dyskinesia in Maltese dogs.

J Vet Intern Med 2020 Jul 16;34(4):1541-1546. Epub 2020 May 16.

Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.

Background: Paroxysmal dyskinesias (PDs) are a group of central nervous system diseases characterized by episodes of abnormal involuntary hyperkinetic movement without altered consciousness that increasingly have been recognized in dogs.

Objectives: To present the phenotypical characterization, treatment, and outcome of a PD observed in Maltese dogs.

Animals: Client-owned Maltese dogs (n = 19) with presumed diagnosis of PD.

Methods: Data were collected retrospectively from medical records (2014-2019), and supporting information was added prospectively by using a questionnaire directed to the owners of the affected dogs.

Results: The episodes were characterized mainly by sudden dystonia of ≥1 limbs and generalized body tremors with preserved consciousness. The mean age of clinical onset was 5.4 years. Episode frequency varied widely both among and within individuals. Median episode duration was 4.5 minutes. Most episodes were stress- or exercise-induced. Acetazolamide was administered to 6 dogs, and 4 dogs experienced a decrease in episode frequency. In 7 dogs that received a gluten-free diet, 6 dogs became episode-free. In 4 dogs, the episodes stopped spontaneously and in 2 dogs no medication or specific diet was given and the episodes continued at the same frequency.

Conclusions And Clinical Importance: Given the breed predisposition and regional distribution of the disease, additional research should focus on elucidating the underlying genetic cause doing so might advance both our understanding of the pathophysiology and treatment of this disease, not only in dogs, but also in humans. Regardless of the treatment protocol selected, prognosis appears fair to good.
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http://dx.doi.org/10.1111/jvim.15804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379016PMC
July 2020

Central auditory processing in parkinsonian disorders: A systematic review.

Neurosci Biobehav Rev 2020 06 4;113:111-132. Epub 2020 Mar 4.

Department of Rehabilitation Sciences, Ghent University, C. Heymanslaan 10, B-9000, Ghent, Belgium.

Altered auditory processing has been increasingly recognized as a non-motor feature in parkinsonian disorders. This systematic review provides an overview of behavioral and electrophysiological literature on central auditory processing in patients with Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A systematic database search was conducted and yielded 88 studies that met the intelligibility criteria. The collected data revealed distinct impairments in a range of central auditory processes in PD, including altered deviance detection of basic auditory features, auditory brainstem processing, auditory gating and selective auditory attention. In contrast to PD, literature on central auditory processing in atypical parkinsonian disorders was relatively scarce, but provided some evidence for impaired central auditory processing in MSA and PSP. The interpretation of these findings is discussed and suggestions for further research are offered.
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http://dx.doi.org/10.1016/j.neubiorev.2020.03.001DOI Listing
June 2020

Systematic Audiological Assessment of Auditory Functioning in Patients With Parkinson's Disease.

J Speech Lang Hear Res 2019 12 26;62(12):4564-4577. Epub 2019 Nov 26.

Ecole d'Orthophonie et d'Audiologie, Université de Montréal, Quebec, Canada.

Purpose Alterations in primary auditory functioning have been reported in patients with Parkinson's disease (PD). Despite the current findings, the pathophysiological mechanisms underlying these alterations remain unclear, and the effect of dopaminergic medication on auditory functioning in PD has been explored insufficiently. Therefore, this study aimed to systematically investigate primary auditory functioning in patients with PD by using both subjective and objective audiological measurements. Method In this case-control study, 25 patients with PD and 25 age-, gender-, and education-matched healthy controls underwent an audiological test battery consisting of tonal audiometry, short increment sensitivity index, otoacoustic emissions (OAEs), and speech audiometry. Patients with PD were tested in the on- and off-medication states. Results Increased OAE amplitudes were found when patients with PD were tested without dopaminergic medication. In addition, speech audiometry in silence and multitalker babble noise demonstrated higher phoneme scores for patients with PD in the off-medication condition. The results showed no differences in auditory functioning between patients with PD in the on-medication condition and healthy controls. No effect of disease stage or motor score was evident. Conclusions This study provides evidence for a top-down involvement in auditory processing in PD at both central and peripheral levels. Most important, the increase in OAE amplitude in the off-medication condition in PD is hypothesized to be linked to a dysfunction of the olivocochlear efferent system, which is known to have an inhibitory effect on outer hair cell functioning. Future studies may clarify whether OAEs may facilitate an early diagnosis of PD.
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http://dx.doi.org/10.1044/2019_JSLHR-H-19-0097DOI Listing
December 2019

Myoclonus-dystonia: Distinctive motor and non-motor phenotype from other dystonia syndromes.

Parkinsonism Relat Disord 2019 12 22;69:85-90. Epub 2019 Oct 22.

Department of Neurology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands. Electronic address:

Background: Myoclonus-dystonia (M-D) due to a pathogenic variant of SGCE is an autosomal dominant inherited movement disorder. Apart from motor symptoms, psychiatric disorders are highly prevalent in patients with M-D. Previous studies suggest, but never tested directly, that the type of psychiatric disorder differs between dystonia syndromes, probably related to disease specific pathology. Little is known about other non-motor symptoms (NMS) in M-D. Here, we systematically study NMS in M-D in direct comparison to other types of dystonia and healthy controls.

Methods: Standardized questionnaires were used to assess type and severity of psychiatric co-morbidity, sleep problems, fatigue and quality of life. Results of M-D patients with a pathogenic variant of SGCE were compared to results of idiopathic cervical dystonia (CD) patients, dopa-responsive dystonia (DRD) patients with a pathogenic variant of GCH1 and controls.

Results: We included 164 participants: 41 M-D, 51 CD, 19 DRD patients, 53 controls. Dystonia patients (M-D, CD and DRD) had an increased prevalence of psychiatric disorders compared to controls (56-74% vs. 29%). In M-D we found a significantly increased prevalence of obsessive-compulsive disorder (OCD) and psychosis compared to CD and DRD. All dystonia patients had more sleep problems (49-68% vs. 36%) and fatigue (42-73% vs. 15%) than controls. Compared to other dystonia subtypes, M-D patients reported less excessive daytime sleepiness and fatigue.

Conclusion: Psychiatric comorbidity is frequent in all dystonia types, but OCD and psychosis are more common in M-D patients. Further research is necessary to elucidate underlying pathways.
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http://dx.doi.org/10.1016/j.parkreldis.2019.10.015DOI Listing
December 2019

Category specific recall in acute stroke: a case with letter speech.

Neurocase 2019 12 1;25(6):251-258. Epub 2019 Oct 1.

Department of Neurology, Ghent University Hospital , Ghent , Belgium.

Category selective recall in spontaneous speech after stroke has been reported only rarely. We recently described three cases demonstrating transient number speech in the acute stage of left hemispheric stroke and hypothesized a link with multilingualism and mathematical proficiency. In this report, we describe a similar case with a transient episode of utterances of randomly selected letters. Like in the three previous cases, this episode was preceded by a brief stage of mutism and ultimately evolved to Wernicke's aphasia over a period of days. This phenomenon is reviewed with reference to linguistic models and neuroanatomic and neurophysiological correlates.
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http://dx.doi.org/10.1080/13554794.2019.1673440DOI Listing
December 2019

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.

Acta Neuropathol 2019 06 14;137(6):901-918. Epub 2019 Mar 14.

Center for Molecular Neurology, VIB, Antwerp, Belgium.

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frameshift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.
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http://dx.doi.org/10.1007/s00401-019-01976-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531610PMC
June 2019

The moral brain and moral behaviour in patients with Parkinson's disease: a review of the literature.

Acta Neurol Belg 2018 Sep 16;118(3):387-393. Epub 2018 Jul 16.

Department of Speech, Language and Hearing Sciences, Ghent University, Corneel Heymanslaan 10, 2P1, 9000, Ghent, Belgium.

Morality is a complex and versatile concept that necessitates the integrated activity of multiple interacting networks in the brain. Numerous cortical and subcortical areas, many of which are implicated in either emotional and cognitive control or Theory of Mind, are involved in the processing of moral behaviour. Different methods have been used to investigate various aspects of morality, which has lead to confusing and sometimes opposing results. Emotional, cognitive and personality changes have long been recognized in Parkinson's disease (PD) patients, suggesting a potential impact on moral aspects of behaviour in daily living situations. Alterations in social cognition have been described in all stages of PD but these are rather directly related to PD pathology and not to dopaminergic or DBS treatment. There are no convincing data supporting the hypothesis that dopaminergic treatment or deep brain stimulation of the STN per se interfere with morality in PD patients, although subgroups of patients may display socially unacceptable behaviour. Research in social cognition in PD patients is a fascinating topic that needs further attention in view of the impact on quality of life for PD patients and their caregivers.
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http://dx.doi.org/10.1007/s13760-018-0986-9DOI Listing
September 2018

Clinical variability and onset age modifiers in an extended Belgian GRN founder family.

Neurobiol Aging 2018 07 10;67:84-94. Epub 2018 Mar 10.

Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge and University of Antwerp, Antwerp, Belgium. Electronic address:

We previously reported a granulin (GRN) null mutation, originating from a common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of a 10-year follow-up study to describe in detail the clinical heterogeneity observed in this extended founder pedigree. We identified 85 patients and 40 unaffected mutation carriers, belonging to 29 branches of the founder pedigree. Most patients (74.4%) were diagnosed with frontotemporal dementia, while others had a clinical diagnosis of unspecified dementia, Alzheimer's dementia or Parkinson's disease. The observed clinical heterogeneity can guide clinical diagnosis, genetic testing, and counseling of mutation carriers. Onset of initial symptomatology is highly variable, ranging from age 45 to 80 years. Analysis of known modifiers, suggested effects of GRN rs5848, microtubule-associated protein tau H1/H2, and chromosome 9 open reading frame 72 GC repeat length on onset age but explained only a minor fraction of the variability. Contrary, the extended GRN founder family is a valuable source for identifying other onset age modifiers based on exome or genome sequences. These modifiers might be interesting targets for developing disease-modifying therapies.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.03.007DOI Listing
July 2018

Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family.

Alzheimers Res Ther 2018 01 22;10(1). Epub 2018 Jan 22.

Institute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of Antwerp, Universiteitsplein 1, B-2160, Antwerp, Belgium.

Background: In this paper, we describe the clinical and neuropathological findings of nine members of the Belgian progranulin gene (GRN) founder family. In this family, the loss-of-function mutation IVS1 + 5G > C was identified in 2006. In 2007, a clinical description of the mutation carriers was published that revealed the clinical heterogeneity among IVS1 + 5G > C carriers. We report our comparison of our data with the published clinical and neuropathological characteristics of other GRN mutations as well as other frontotemporal lobar degeneration (FTLD) syndromes, and we present a review of the literature.

Methods: For each case, standardized sampling and staining were performed to identify proteinopathies, cerebrovascular disease, and hippocampal sclerosis.

Results: The neuropathological substrate in the studied family was compatible in all cases with transactive response DNA-binding protein (TDP) proteinopathy type A, as expected. Additionally, most of the cases presented also with primary age-related tauopathy (PART) or mild Alzheimer's disease (AD) neuropathological changes, and one case had extensive Lewy body pathology. An additional finding was the presence of cerebral small vessel changes in every patient in this family.

Conclusions: Our data show not only that the IVS1 + 5G > C mutation has an exclusive association with FTLD-TDP type A proteinopathy but also that other proteinopathies can occur and should be looked for. Because the penetrance rate of the clinical phenotype of carriers of GRN mutations is age-dependent, further research is required to investigate the role of co-occurring age-related pathologies such as AD, PART, and cerebral small vessel disease.
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http://dx.doi.org/10.1186/s13195-017-0334-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389176PMC
January 2018

Teenage-onset progressive myoclonic epilepsy due to a familial repeat expansion.

Neurology 2018 02 19;90(8):e658-e663. Epub 2018 Jan 19.

From the Department of Neurology (J.v.d.A., A.S., A.M., P.S., B.D.) and Center for Medical Genetics (B.D.), Ghent University Hospital, Belgium; Institute for Inherited Metabolic Disorders (I.J., A.P., H.H., S.K.), Prague, First Faculty of Medicine, Charles University in Prague, Czech Republic; Neurodegenerative Brain Diseases Group (A.S., S.V.M., C.V.B.), Center for Molecular Neurology, VIB; Neuropathology and Laboratory of Neurochemistry and Behavior (A.S.), Laboratory of Neurogenetics (S.V.M., C.V.B.), and Laboratory of Neuromuscular Pathology and Translational Neurosciences (C.C.-d.G.), Institute Born-Bunge, University of Antwerp, Belgium; Institute of Pathology, First Faculty of Medicine (H.H., R.M.), Charles University and General University Hospital; Department of Pathology and Molecular Medicine (R.M.), National Reference Laboratory for Diagnostics of Human Prion Diseases, Thomayer Hospital, Prague, Czech Republic; Epilepsy Research Centre, Department of Medicine (S.F.B.), University of Melbourne, Austin Health, Heidelberg, Australia; and Inserm U1167 (B.D.), Laboratoire d'Excellence Distalz, Institut Pasteur de Lille, Longevity Research Center, Université de Lille, France. J.v.d.A. is currently affiliated with the Department of Clinical Neurosciences and WT/CRUK Gurdon Institute, University of Cambridge, UK.

Background: The progressive myoclonic epilepsies (PME) are a heterogeneous group of disorders in which a specific diagnosis cannot be made in a subset of patients, despite exhaustive investigation. repeat expansions are emerging as an important causal factor in several adult-onset neurodegenerative disorders, in particular frontotemporal lobar degeneration and amyotrophic lateral sclerosis. An association with PME has not been reported previously.

Objective: To identify the causative mutation in a Belgian family where the proband had genetically unexplained PME.

Results: We report a 33-year old woman who had epilepsy since the age of 15 and then developed progressive cognitive deterioration and multifocal myoclonus at the age of 18. The family history suggested autosomal dominant inheritance of psychiatric disorders, epilepsy, and dementia. Thorough workup for PME including whole exome sequencing did not reveal an underlying cause, but a repeat expansion was found in our patient and affected relatives. Brain biopsy confirmed the presence of characteristic p62-positive neuronal cytoplasmic inclusions.

Conclusion: mutation analysis should be considered in patients with PME and psychiatric disorders or dementia, even when the onset is in late childhood or adolescence.
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http://dx.doi.org/10.1212/WNL.0000000000004999DOI Listing
February 2018

Cognate effects and cognitive control in patients with parallel and differential bilingual aphasia.

Int J Lang Commun Disord 2018 05 4;53(3):515-525. Epub 2018 Jan 4.

Department of Experimental Psychology, Ghent University, Ghent, Belgium.

Background: Until today, there is no satisfying explanation for why one language may recover worse than another in differential bilingual aphasia. One potential explanation that has been largely unexplored is that differential aphasia is the consequence of a loss of language control rather than a loss of linguistic representations. Language control is part of a general control mechanism that also manages non-linguistic cognitive control. If this system is impaired, patients with differential aphasia could still show bilingual language activation, but they may be unable to manage activation in non-target languages, so that performance in another language is hindered.

Aims: To investigate whether a loss of cognitive control, rather than the loss of word representations in a particular language, might underlie differential aphasia symptoms.

Methods & Procedures: We compared the performance of seven bilinguals with differential and eight bilinguals with parallel aphasia with 19 control bilinguals in a lexical decision and a flanker task to assess bilingual language co-activation and non-linguistic control respectively.

Outcomes & Results: We found similar cognate effects in the three groups, indicating similar lexical processing across groups. Additionally, we found a larger non-linguistic control congruency effect only for the patients with differential aphasia.

Conclusions & Implications: The present data indicate preserved language co-activation for patients with parallel as well as differential aphasia. Furthermore, the results suggest a general cognitive control dysfunction, specifically for differential aphasia. Taken together, the results of the current study provide further support for the hypothesis of impaired cognitive control abilities in patients with differential aphasia, which has both theoretical and practical implications.
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http://dx.doi.org/10.1111/1460-6984.12365DOI Listing
May 2018

Neuromodulatory procedures for gait disorders in Parkinson's disease.

Authors:
Patrick Santens

Acta Neurol Belg 2018 Mar 14;118(1):13-19. Epub 2017 Nov 14.

Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium.

The neurophysiology of gait is complex and involves numerous structures in the central nervous system. Gait disorders occur frequently in Parkinson's disease (PD), and their management may become cumbersome, especially in the more advanced stages. Neuromodulatory treatments, including deep brain stimulation, cortical stimulation and spinal cord stimulation, are reviewed with respect to their effectiveness to improve gait in PD patients. Although positive effects have been reported for all of these procedures, many issues remain in view of methodological heterogeneity, variability in outcome measures and sample size. Gait in PD remains a difficult issue with a tremendous impact on quality of life, for which future research is badly needed.
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http://dx.doi.org/10.1007/s13760-017-0862-zDOI Listing
March 2018

Anti-NMDA receptor encephalitis: still unknown and underdiagnosed by physicians and especially by psychiatrists?

Acta Clin Belg 2018 Oct 19;73(5):364-367. Epub 2017 Oct 19.

a Department of Psychiatry , Ghent University Hospital , Ghent , Belgium.

Anti-NMDA receptor encephalitis is an autoimmune disorder confirmed by the presence of antibodies against the NMDA-receptor in serum or CSF. This case report describes a young woman with anti-NMDA receptor encephalitis, who presented with prominent psychiatric symptoms. There was a crucial delay in diagnosis and necessary treatment due to the fact that the clinical presentation was diagnosed and treated as a first psychotic episode. Physicians and especially psychiatrists, should consider the possibility of an autoimmune encephalitis in their differential diagnosis in every new onset psychotic episode with rapid progression, the presence of pathognomonic orofacial dyskinesia, the lack of psychiatric history, and the non-responding to psychopharmacological treatment. Early diagnosis and treatment is essential for recovery and may improve the prognosis.
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http://dx.doi.org/10.1080/17843286.2017.1392077DOI Listing
October 2018

Bilingualism and Cognitive Decline: A Story of Pride and Prejudice.

J Alzheimers Dis 2017 ;60(4):1237-1239

Department of Experimental Psychology, Ghent University, Ghent, Belgium.

In a recent review, Mukadam, Sommerlad, and Livingston (2017) argue that bilingualism offers no protection against cognitive decline. The authors examined the results of 13 studies (five prospective, eight retrospective) in which monolinguals and bilinguals were compared for cognitive decline and onset of dementia symptoms. Analysis of four of the five prospective studies resulted in the conclusion that there was no difference between monolinguals and bilinguals, whereas seven of the eight retrospective studies actually showed bilingualism to result in a four-to-five year delay of symptom onset. The authors decided to ignore the results from the retrospective studies in favor of those from the prospective studies, reasoning that the former may be confounded by participants' cultural background and education levels. In this commentary, we argue that most of these studies actually controlled for these two variables and still found a positive effect of bilingualism. Furthermore, we argue that the meta-analysis of the prospective studies is not complete, lacking the results of two crucial reports. We conclude that the literature offers substantial evidence for a bilingual effect on the development of cognitive decline and dementia.
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http://dx.doi.org/10.3233/JAD-170759DOI Listing
March 2019

Verbal monitoring in Parkinson's disease: A comparison between internal and external monitoring.

PLoS One 2017 23;12(8):e0182159. Epub 2017 Aug 23.

Department of Experimental Psychology, Ghent University, Ghent, Belgium.

Patients with Parkinson's disease (PD) display a variety of impairments in motor and non-motor language processes; speech is decreased on motor aspects such as amplitude, prosody and speed and on linguistic aspects including grammar and fluency. Here we investigated whether verbal monitoring is impaired and what the relative contributions of the internal and external monitoring route are on verbal monitoring in patients with PD relative to controls. Furthermore, the data were used to investigate whether internal monitoring performance could be predicted by internal speech perception tasks, as perception based monitoring theories assume. Performance of 18 patients with Parkinson's disease was measured on two cognitive performance tasks and a battery of 11 linguistic tasks, including tasks that measured performance on internal and external monitoring. Results were compared with those of 16 age-matched healthy controls. PD patients and controls generally performed similarly on the linguistic and monitoring measures. However, we observed qualitative differences in the effects of noise masking on monitoring and disfluencies and in the extent to which the linguistic tasks predicted monitoring behavior. We suggest that the patients differ from healthy subjects in their recruitment of monitoring channels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182159PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568285PMC
October 2017

Impaired Processing of Serial Order Determines Working Memory Impairments in Alzheimer's Disease.

J Alzheimers Dis 2017 ;59(4):1171-1186

Ghent University, Ghent, Belgium.

Background: Working memory (WM) problems are commonly observed in Alzheimer's disease (AD), but the affected mechanisms leading to impaired WM are still insufficiently understood. The ability to efficiently process serial order in WM has been demonstrated to be fundamental to fluent daily life functioning. The decreased capability to mentally process serial position in WM has been put forward as the underlying explanation for generally compromised WM performance.

Objective: Determine which mechanisms, such as order processing, are responsible for deficient WM functioning in AD.

Method: A group of AD patients (n = 32) and their partners (n = 25), assigned to the control group, were submitted to an extensive battery of neuropsychological and experimental tasks, assessing general cognitive state and functioning of several aspects related to serial order WM.

Results: The results revealed an impaired ability to bind item information to serial position within WM in AD patients compared to controls. It was additionally observed that AD patients experienced specific difficulties with directing spatial attention when searching for item information stored in WM.

Conclusion: The processing of serial order and the allocation of attentional resources are both disrupted, explaining the generally reduced WM functioning in AD patients. Further studies should now clarify whether this observation could explain disease-related problems for other cognitive functions such as verbal expression, auditory comprehension, or planning.
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http://dx.doi.org/10.3233/JAD-170193DOI Listing
April 2018

The effect of dopaminergic medication on conflict adaptation in Parkinson's disease.

J Neuropsychol 2019 03 16;13(1):121-135. Epub 2017 Jul 16.

Department of Experimental Psychology, Faculty of Psychology and Educational Sciences, Ghent University, Belgium.

Parkinson's disease (PD) is a neurological disorder associated primarily with motor symptoms such as tremor, slowness of movement, and difficulties with gait and balance. Most patients take dopaminergic medication to improve their motor functions. Previous studies reported indications that such medication can impair higher cognitive functions (cf. dopamine overdose hypothesis). In the present study, we examined the effect of medication status on conflict adaptation. PD patients performed a Stroop task in which we manipulated the proportion of congruent and incongruent items, thereby allowing us to explore conflict adaptation. The use of mouse movements allowed us to examine the action dynamics of conflict adaptation in PD, and their sensitivity to dopaminergic medication. Each patient performed the same task twice: once without making changes to their regular medication regime, and once after overnight withdrawal from their medication. Results showed that medication improved mouse movements and alleviated motor symptoms. Moreover, patients' mouse movements were modulated as a function of the proportion congruency manipulation, revealing conflict adaptation in PD, which was unaffected by medication status. The present study extends earlier work on conflict adaptation in PD where reduced transient (trial-by-trial) conflict adaptation was observed ON compared to OFF medication (Duthoo et al., 2013, Neuropsychology, 27, 556). Our findings suggest that more sustained cognitive control processes may not be sensitive to dopamine overdose effects.
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http://dx.doi.org/10.1111/jnp.12131DOI Listing
March 2019

Facial nerve regeneration after facial allotransplantation: A longitudinal clinical and electromyographic follow-up of lip movements during speech.

J Plast Reconstr Aesthet Surg 2017 Jun 10;70(6):729-733. Epub 2017 Mar 10.

Department of Speech, Language and Hearing Sciences, Ghent University, Belgium.

Introduction: Facial allotransplantation constitutes a reconstructive option after extensive damage to facial structures. Functional recovery has been reported but remains an issue.

Case Report - Methods: A patient underwent facial allotransplantation after a ballistic injury with extensive facial tissue damage. Speech motor function was sequentially assessed clinically, along with repeated electromyography of lip movements during a follow-up of 3 years.

Results: Facial nerve recovery could be demonstrated within the first month, followed by a gradual increase in electromyographic amplitude and decrease in reaction times. These were accompanied by gradual improvement of clinical assessments.

Conclusions: Axonal recovery starts early after transplantation. Electromyographic testing is sensitive in demonstrating this early recovery, which ultimately results in clinical improvements.
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http://dx.doi.org/10.1016/j.bjps.2017.02.025DOI Listing
June 2017
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