Anne Sieben

Additional file 1. Supplementary materials and methods. Detailed protocols and references. Supplementary results. Phasing compound heterozygous variants in the Belgian cohorts. Effect of VPS13C splice site variants on mRNA splicing. Supplementary tables. Table S1: Clinical and demographic characteristics of study cohorts. Table S2. Clinical data of patient carriers of rare homozygous or trans compound heterozygous VPS13C mutations. Table S3: Candidate genes and mutations identified in WGS data of family A. Table S4: VPS13C rare coding and splice site variants in DLB and PD patients and in controls. Table S5: Major genes associated with neurodegenerative brain diseases. Table S6: LBD patient carriers of cis compound heterozygous coding and splice site variants in VPS13C. Table S7: Control carriers of compound heterozygous coding and splice site variants in VPS13C. Table S8: Primer sequences. Table S9: In-silico predictions on VPS13C mRNA splicing of splice site variants in compound h...

The current study investigated the effects of bilingualism on the clinical manifestation of Alzheimer's disease (AD) in a European sample of patients. We assessed all incoming AD patients in two university hospitals within a specified timeframe. Sixty-nine monolinguals and 65 bilinguals diagnosed with probable AD were compared for time of clinical AD manifestation and diagnosis. The influence of other potentially interacting variables was also examined. Results indicated a significant delay for bilinguals of 4.6 years in manifestation and 4.8 years in diagnosis. Our study therefore strengthens the claim that bilingualism contributes to cognitive reserve and postpones the symptoms of dementia.

Aims: This study aimed to investigate phoneme perception in patients with primary progressive aphasia (PPA) by using the event-related potential (ERP) technique. These ERP components might contribute to the diagnostic process of PPA and its clinical variants (NFV: nonfluent variant, SV: semantic variant, LV: logopenic variant) and reveal insights about phoneme perception processes in these patients. Method: Phoneme discrimination and categorization processes were investigated by the mismatch negativity (MMN) and P300 in eight persons with early- and late-stage PPA (3 NFV, 2 LV, 2 SV, and 1 PPA-NOS; not otherwise specified) and 30 age-matched healthy adults. The mean amplitude, the onset latency, and the topographic distribution of both components in each patient were compared to the results of the control group. Results: The MMN was absent or the onset latency of the MMN was delayed in the patients with the NFV, LV, and PPA-NOS in comparison to the control group. In contrast, no dif...

Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (

Background Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically overlapping disorders. They are included in the Lewy body disease (LBD) continuum characterized by α-synuclein-positive Lewy body pathology in neurons. Homozygous PTC mutations in Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset PD. Methods Whole genome sequencing of two affected siblings and healthy parents of family A with onset age below 50 years and DLB pathology confirmed at autopsy. Targeted resequencing of the VPS13C coding region in 844 LBD patients and 664 control individuals. Phasing cis-trans location of the compound heterozygous VPS13C variants. Analysis of VPS13C protein expression in lymphoblast cells and brain lysates. Immunohistochemistry and live cell labeling in HeLa and SH-SY5Y cells overexpressing wild type or mutant VPS13C. Results In the two affected siblings of family A, we identified compound heterozygous ...

Background Alzheimer’s disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ1–43 is more prone to aggregation and has higher toxic properties than the long-known Aβ1–42. However, a direct effect on Aβ1–43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined. Methods N = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ1–43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ1–42 and Aβ1–40 CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers. Results A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6%...

Introduction: Distinguishing between two of the most common causes of dementia, Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD), on clinical diagnostic criteria alone has poor diagnostic accuracy. Promising tools to increase the diagnostic accuracy of AD are the use of cerebrospinal fluid (CSF) biomarkers and electroencephalography (EEG), which is being investigated as a diagnostic tool for neurodegenerative brain disorders. In this study, we investigated the utility of EEG-based biomarkers in comparison and in addition to established neurochemical biomarkers in the AD versus FTLD differential diagnosis. Methods: Our study cohort comprised 37 AD and 32 FTLD patients, of which 19 AD and 11 FTLD had definite diagnoses. All these participants had CSF biomarker analyses resulting in four neurochemical (NCM) biomarkers (Aβ1-42, T-tau, P-tau181 and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks (DFP) were extracted in f...

We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead...

TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13-1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p...

Objective: We aim to describe the phenotypical characteristics of Belgian TBK1 mutation carriers and identify differences with C9orf72, GRN and nonmutation carriers. Background: In cohorts of FTD (n=481) and ALS (n=147) patients, we identified 10 patients carrying a TBK1 loss-of-function mutation. Additionally, 6 affected relatives were identified as TBK1 carriers.(Gijselinck I. et al., Neurology 2015) Methods: A descriptive study was performed of 6 FTD, 7 ALS, 1 FTD-ALS and 2 unspecified dementia patients carrying a TBK1 mutation. Further, we compared the phenotypic characteristics of FTD patients with a TBK1 mutation (n=7), with those of FTD patients with a C9orf72 repeat expansion (n=65), a GRN mutation (n=52) or without mutations in currently known causal genes (n=259). Results: The mean onset age of all 16 TBK1 carriers was 62.1 years (SD 8.9, range 41-73) with a mean disease duration of 4.7 years (SD 4.5, range 1-13). Among the TBK1 carriers, most FTD patients had the behavior...

Genetic screening of our Belgian Alzheimer’s Disease (AD) cohort (n = 1478) observed in 69 patients, 15 different premature termination codon (PTC) mutations in the gene coding ATP‐Binding Cassette Subfamily A Member 7 (ABCA7) leading to loss of ABCA7 protein. We aimed to delineate the clinicopathological AD phenotype of the ABCA7 mutation carriers. The ABCA7 gene was initially identified as a risk gene in genome wide association studies of large AD patient cohorts.

BACKGROUND The semantic variant of primary progressive aphasia (PPA) is typically associated with a loss of semantic knowledge. Research on the semantic processing in the other clinical variants of PPA is, however, rather sparse and limited to off-line behavioural studies. AIMS This study aimed to investigate verbal semantic processing in patients with the three variants of PPA by the event-related potential technique. The presence, latency, amplitude and/or topographic distribution of the N400 effect may be helpful in the diagnosis of PPA and its clinical variants and it provides temporal information about semantic processing (disturbances) in the three variants of PPA. METHODS & PROCEDURES The N400 effect was studied by a categorical word-priming paradigm and a semantic-anomaly paradigm at sentence level in eight persons with PPA(-plus) and 30 age-matched healthy controls. The mean amplitudes and onset latencies of the N400 effect were compared between each patient and the control group by two methods that are applicable in clinical practice, namely visual inspection and Z-scores. OUTCOMES & RESULTS The N400 effect elicited by the categorical-priming paradigm was only present in the two patients with the non-fluent variant of PPA. This effect was absent in the two patients with the semantic variant(-plus), two patients with the logopenic variant(-plus), one patient with the non-fluent variant-plus, and the patient with PPA not otherwise specified. The results of the N400 effect elicited by the semantic-anomaly task at the sentence level were variable, but differences in the presence, mean amplitudes, onset latencies and/or topographic distributions of the effect were found in all patients with PPA(-plus) in comparison with the control group. CONCLUSIONS & IMPLICATIONS The results of our study showed that the evaluation of the N400 effect might have an added value in the diagnostic process of PPA in general and in the differentiation of patients with the non-fluent variant from patients with the logopenic and semantic variants. Furthermore, our results indicate the presence of difficulties with retrieving stored semantic knowledge or semantic integration of a word in the preceding context in patients with the three variants of PPA. These findings might help the speech-language pathologist in determining individualized therapy goals and indicate that it might be helpful to focus on verbal semantic processing in language therapy in patients with the three variants of PPA and not only in patients with the semantic variant. WHAT THIS PAPER ADDS What is already known on the subject The semantic variant of PPA is characterized by an impaired object knowledge and single-word comprehension and these functions are relatively spared in the non-fluent and logopenic variants following the guidelines of Gorno-Tempini et al. (2011). Research on the semantic processing in patients with the non-fluent and logopenic variant is, however, rather sparse and limited to off-line behavioural studies. Only four group studies investigated verbal semantic processing by the N400 effect, and these studies indicate disturbances in the three variants of PPA. What this paper adds to existing knowledge Our results indicate the presence of difficulties with retrieving stored semantic knowledge or semantic integration of a word in the preceding context during a semantic-priming paradigm in patients with the semantic and logopenic variants of PPA and during a semantic-anomaly task at the sentence level in patients with the three variants of PPA. What are the potential or actual clinical implications of this work? The results of our study showed that the evaluation of the N400 effect might have an added value in the diagnostic process of PPA in general and in the differentiation of patients with the non-fluent variant from patients with the logopenic and semantic variants. The evaluation of the N400 effect might also help the speech-language pathologist in determining individualized therapy goals and indicate that it might be helpful to focus on verbal semantic processing in language therapy in patients with the three variants of PPA and not only in patients with the semantic variant.

Primary progressive aphasia (PPA) is an overarching term for a heterogeneous group of neurodegenerative diseases which affect language processing. Impaired picture naming has been linked to atrophy of the anterior temporal lobe in the semantic variant of PPA. Although atrophy of the anterior temporal lobe proposedly impairs picture naming by undermining access to semantic knowledge, picture naming also entails object recognition and lexical retrieval. Using multivariate analysis, we investigated whether cortical atrophy relates to different types of naming errors generated during picture naming in 43 PPA patients (13 semantic, 9 logopenic, 11 nonfluent, and 10 mixed variant). Omissions were associated with atrophy of the anterior temporal lobes. Semantic errors, for example, mistaking a rhinoceros for a hippopotamus, were associated with atrophy of the left mid and posterior fusiform cortex and the posterior middle and inferior temporal gyrus. Semantic errors and atrophy in these regions occurred in each PPA subtype, without major between-subtype differences. We propose that pathological changes to neural mechanisms associated with semantic errors occur across the PPA spectrum.

The first case of iatrogenic Creutzfeldt–Jakob disease (iCJD), due to a contaminated corneal transplant, was described in 1974. Between 1974 and 2012, an additional 469 iCJD cases were reported [1]. Most of these have been attributed to the use of contaminated human growth hormone or human cadaveric dura mater grafts in the 1970’s and 80’s, when screening procedures and sterilization processes were insufficient to prevent transmission of prions of the donor to the receptor [1]. Approximately 228 cases of dura mater graftassociated iCJD (dCJD) have been reported, and almost all of them have been associated with the use of Lyodura®, lyophilized human cadaveric dura mater grafts produced by German manufacturer B. Braun Melsungen AG [1]. Here, we present the case of a 48-year-old man with a history of traumatic brain injury with right frontal epidural hematoma and contusion, who, according to his medical file, underwent craniotomy and transplantation of a human cadaveric Lyodura® [B. Braun Melsungen AG, Melsungen, Germany] dura mater graft in the right frontoparietal region in July 1985. In October 2015, he was admitted to our hospital after developing progressive apraxia, a sense of malaise and aphasia over a period of 2–3 weeks. Clinical examination revealed global aphasia, pseudobulbar affect, ideomotor apraxia, increased reflexes in the left arm and leg, gait ataxia and fluctuating consciousness. EEG showed right frontotemporal slowing and lateralized periodic discharges (LPD’s) (Fig. 1a). Brain MRI showed right frontal posttraumatic gliosis, surrounded by hyperintense signal in the right frontal cortex and right (more than left) striatum on diffusion-weighted imaging (DWI) and T2 images (Fig. 1b, c). Initial cerebrospinal fluid (CSF) and serum analysis were normal. While awaiting further tests, he was treated with multiple anti-epileptic drugs and barbiturate coma for a possible non-convulsive status epilepticus (NCSE), which did not result in clinical or electrographical improvement. Subsequently, CSF analysis showed elevated 14-3-3 protein. Serology of neuronal receptor antibodies in plasma and CSF was negative. Given the relatively low specificity of elevated 14-3-3 protein, a brain biopsy of the right frontal cortex was performed. Histological analysis showed spongiform changes and misfolded prion protein (PrPsc) deposits, confirming the diagnosis of CJD. The real-time quakinginduced (RT-QuIC) test on CSF was also positive for prion proteins. Anti-epileptic therapy was gradually reduced. The patient died of pneumonia 2 months after admission. Autopsy revealed severe spongiosis (Fig. 1d) and synapticlike prion immunoreactivity throughout the entire cortex, cerebellum and midbrain compatible with a synaptic-like non-plaque type of CJD. Additionally, there were moderate Alzheimer’s disease neuropathological changes; neuropil threads and neurofibrillary tangles in the mesotemporal structures (Braak stage II) and beta-amyloid pathology in the frontal, temporal, occipital neocortex, parahippocampal gyrus, thalamus, neostriatum and colliculus superior (Thal phase 3) as well as amyloid angiopathy without significant predominance for the region of previous brain trauma. No mutation was found in the PRNP-gene; a Met/Val genotype was present at codon 129. This case illustrates the diagnostic pitfalls in CJD. Our initial diagnosis of NCSE was based on clinical presentation, the presence of a potentially epileptogenic posttraumatic lesion in the right frontal lobe, and on the presence—in the * Vincent Van Iseghem Vincent.vaniseghem@icloud.com

Background:Variants in APP, PSEN1 or PSEN2 presented a majority of cases of autosomal dominant early-onset Alzheimer disease (EOAD), which just accounted for less than 5% of AD cases. Clusterin (CLU), as an apolipoprotein, was suggested as the second highest genetic risk factor for AD. It was strongly suggested that molecular effects from the mutations in CLU promoted AD pathology. No study so far has screened the variants in CLU among EOAD patients. Methods: We analyzed the all exons of 50 genes from 92 EOAD patients using next-generation sequencing (NGS) with high depth of coverage. Given the absence of PSEN1, PSEN2 and APP causative variants in patients, we continuously investigated whether these patients might be burdened with protein-modifying variants in CLU gene. The phenotypic consequences associated with CLU mutations were characterized, based on clinical reviews of medical records. Functional studies from PolyPhen2, SIFT and 3D modeling were performed to evaluate the effect to protein stability from the mutation. Results: Sequence analysis of the entire coding region of CLU was performed, identifying three novel non-synonymous changes in three EOAD patients: Arg127His, Arg182His and Pro428Arg. In silico structural analyses suggested the disruption of the local protein structure around Arginine 127. A possible destabilization of the hydrophobic interior of the molecule in Histamine 128 and that Arginine 428 could be structurally and functionally importance. The fact that all three novel variants were not present in healthy individuals in both the Korea Centers for Disease Control and Prevention and the Exome Aggregation Consortium datasets. The results suggested that these mutations were probably novel pathogenic variants with stronger pathogenicity. Conclusions: The findings from this study suggested an important role for CLUmutations in AD pathogenesis. In addition, the presence of strongly clinical features among select individuals with AD and CLU mutations would call for further functional investigation. P4-069 A PROSPECTIVE NEUROGENETIC STUDY ON EARLY-ONSET DEMENTIA IN PATIENTS WITH UNCLEAR INITIAL DIAGNOSIS OF DEGENERATIVE DEMENTIA Federica Perrone, Rita Cacace, Sara VanMossevelde, Tobi Van den Bossche, Anne Sieben, Sebastiaan Engelborghs, Patrick Cras, Peter Paul De Deyn, Jean-Jacques Martin, Julie van der Zee, Christine Van Broeckhoven, Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Wilrijk, Belgium. Contact e-mail: federica.perrone@molgen.vib-ua.be

A subset of patients with the nonfluent variant of primary progressive aphasia (PPA) exhibit concomitant single-word comprehension problems, constituting a 'mixed variant' phenotype. This phenotype is rare and currently not fully characterized. The aim of this study was twofold: to assess the prevalence and nature of single-word comprehension problems in the nonfluent variant and to study multimodal imaging characteristics of atrophy, tau, and amyloid burden associated with this mixed phenotype. A consecutive memory-clinic recruited series of 20 PPA patients (12 nonfluent, five semantic, and three logopenic variants) were studied on neurolinguistic and neuropsychological domains relative to 64 cognitively intact healthy older control subjects. The neuroimaging battery included high-resolution volumetric magnetic resonance imaging processed with voxel-based morphometry, and positron emission tomography with the tau-tracer [F]-THK5351 and amyloid-tracer [C]-Pittsburgh Compound...

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

People with Down syndrome (DS) are at high risk for Alzheimer's disease (AD). Defects in monoamine neurotransmitter systems are implicated in DS and AD but have not been comprehensively studied in DS. Noradrenaline, adrenaline, and their metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; and serotonin and its metabolite 5-hydroxyindoleacetic acid were quantified in 15 brain regions of DS without AD (DS, n = 4), DS with AD (DS+AD, n = 17), early-onset AD (EOAD, n = 11) patients, and healthy non-DS controls (n = 10) in the general population. Moreover, monoaminergic concentrations were determined in cerebrospinal fluid (CSF)/plasma samples of DS (n = 37/149), DS with prodromal AD (DS+pAD, n = 13/36), and DS+AD (n = 18/40). In brain, noradrenergic and serotonergic compounds were overall reduced in DS+AD versus EOAD, while the dopaminergic system showed a bidirectional change. For DS versus no...

Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD). We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available. The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical dia...

To assess the binding of the PET tracer [F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology. The study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [F]T...

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 fracti...

We explored the diagnostic performance of cerebrospinal fluid (CSF) biomarkers in allowing differentiation between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD), as well as between FTLD pathological subtypes. CSF levels of routine AD biomarkers (phosphorylated tau (p-tau), total tau (t-tau), and amyloid-beta (Aβ)) and neurofilament proteins, as well as progranulin levels in both CSF and serum were quantified in definite FTLD (n = 46), clinical AD (n = 45), and cognitively healthy controls (n = 20). FTLD subgroups were defined by genetic carrier status and/or postmortem neuropathological confirmation (FTLD-TDP: n = 34, including FTLD-C9orf72: n = 19 and FTLD-GRN: n = 9; FTLD-tau: n = 10). GRN mutation carriers had significantly lower progranulin levels compared to other FTLD patients, AD, and controls. Both t-tau and p-tau were normal in FTLD patients, even in FTLD-tau. Aβ levels were very variable in FTLD. Neurofilament light chain (Nf-L) was significantl...

We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynon...

Alzheimer's disease (AD) is a highly prevalent condition and its prevalence is expected to further increase due to the aging of the general population. It is obvious that the diagnosis of AD has implications for driving. Finally, driving discussions are also emotionally charged because driving is associated with independence and personal identity. However, it is not clear how to implement this in clinical practice and the Belgian law on driving is rather vague in its referral to neurodegenerative brain diseases in general nor does it provide clear-cut instructions for dementia or AD compared to for example driving for patients with epilepsy and as such does not prove to be very helpful. The present article reviews what is known from both literature and existing guidelines and proposes a consensus recommendation tailored to the Belgian situation agreed by both AD experts and the Belgian Road Safety Institute endorsed by the Belgian Medical Association. It is concluded that the de...

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

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

The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ1-42, t-tau, and p-tau181 overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-taurel), may improve differential dementia diagnosis. The goal of this study is to investigate if p-taurel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis. The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ1-42, t-tau, p-tau181, and p-taurel were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compare...

Patients carrying a C9orf72 repeat expansion leading to frontotemporal dementia and/or amyotrophic lateral sclerosis have highly variable ages at onset of disease, suggesting the presence of modifying factors. To provide clinical-based evidence for disease anticipation in families carrying a C9orf72 repeat expansion by analyzing age at onset, disease duration, and age at death in successive generations. This cohort study was performed from June 16, 2000, to June 1, 2016, in 36 extended Belgian families in which a C9orf72 repeat expansion was segregating. The generational effect on age at onset, disease duration, and age at death was estimated using a mixed effects Cox proportional hazards regression model, including random-effects terms for within-family correlation and kinship. Time until disease onset or last examination, time from disease onset until death or last examination, or age at death was collected for for 244 individuals (132 proven or obligate C9orf72 carriers), of whom...

Mutation screening and phenotypic profiling of 2 amyotrophic lateral sclerosis-(ALS) and frontotemporal dementia-(FTD) associated genes, CHCHD10 and TUBA4A, were performed in a Belgian cohort of 459 FTD, 28 FTD-ALS, and 429 ALS patients. In CHCHD10, we identified a novel nonsense mutation (p.Gln108*) in a patient with atypical clinical FTD and pathology-confirmed Parkinson's disease (1/459, 0.22%) leading to loss of transcript. We further observed 3 previously described missense variants (p.Pro34Ser, p.Pro80Leu, and p.Pro96Thr) that were also present in the matched control series. In TUBA4A, we detected a novel frameshift mutation (p.Arg64Glyfs*90) leading to a truncated protein in 1 FTD patient (1/459 of 0.22%) with family history of Parkinson's disease and cognitive impairment, and a novel missense mutation (p.Thr381Met) in 2 sibs with familial ALS and memory problems (1 index patient/429, 0.23%) in whom we previously identified a pathogenic Chromosome 9 open reading frame...

P1-176 CSF EXPLORATORY BIOMARKER STUDY FOR (DIFFERENTIAL) DIAGNOSIS OF FRONTOTEMPORAL LOBAR DEGENERATION Joery Goossens, Julie van der Zee, Sara Van Mossevelde, Eugeen Vanmechelen, Tobi Van den Bossche, Bart De Vil, Anne Sieben, Jean-Jacques Martin, Patrick Cras, Johan Goeman, Peter Paul de Deyn, Christine Van Broeckhoven, Sebastiaan Engelborghs, Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; 2 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Antwerp, Belgium; 5 Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium; ADx NeuroSciences, Ghent, Belgium; Laboratory of Neurobiology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; 8 Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Contact e-mail: joery.goossens@uantwerpen.be