Mathieu Vandenbulcke

A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats

We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan‐European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early‐Onset Dementia (EOD) consortium. Next, we performed a meta‐analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7–24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss‐of‐function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC‐rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.

A European multicentre PET study of fibrillar amyloid in Alzheimer’s disease

PurposeAmyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer’s disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies.MethodsIn this study 238 [11C]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [11C]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69u2009±u20098xa0years), 72 patients with mild cognitive impairment (MCI; mean age 67.5u2009±u20098xa0years) and 51 healthy controls (mean age 67.4u2009±u20096xa0years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28u2009±u200915xa0months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype.Results[11C]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [11C]PIB retention was observed in MCI patients, with a bimodal distribution (64xa0% MCI PIB-positive and 36xa0% MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [11C]PIB retention was observed in MCI ApoE ε4 carriers compared to non-ApoE ε4 carriers (pu2009<u20090.005). Of the MCI PIB-positive patients, 67xa0% had converted to AD at follow-up while none of the MCI PIB-negative patients converted.ConclusionThis study demonstrated the robustness of [11C]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25xa0% per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100xa0% negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.

Distinct Clinical Characteristics of C9orf72 Expansion Carriers Compared With GRN, MAPT, and Nonmutation Carriers in a Flanders-Belgian FTLD Cohort

OBJECTIVEnTo characterize patients with frontotemporal lobar degeneration (FTLD) with a repeat expansion mutation in the gene C9orf72, and to determine whether there are differences in the clinical presentation compared with FTLD carriers of a mutation in GRN or MAPT or with patients with FTLD without mutation.nnnDESIGNnPatient series.nnnSETTINGnDementia clinics in Flanders, Belgium.nnnPATIENTSnTwo hundred seventy-five genetically and phenotypically thoroughly characterized patients with FTLD.nnnMAIN OUTCOME MEASURESnClinical and demographic characteristics of 26 C9orf72 expansion carriers compared with patients with a GRN or MAPT mutation, as well as patients with familial and sporadic FTLD without mutation.nnnRESULTSnC9orf72 expansion carriers developed FTLD at an early age (average, 55.3 years; range, 42-69 years), significantly earlier than in GRN mutation carriers or patients with FTLD without mutation. Mean survival (6.2 years; range, 1.5-17.0 years) was similar to other patient groups. Most developed behavioral variant frontotemporal dementia (85%), with disinhibited behavior as the prominent feature. Concomitant amyotrophic lateral sclerosis is a strong distinguishing feature for C9orf72 -associated FTLD. However, in most patients (73%), amyotrophic lateral sclerosis symptoms were absent. Compared with C9orf72 expansion carriers, nonfluent aphasia and limb apraxia were significantly more common in GRN mutation carriers.nnnCONCLUSIONSnC9orf72 -associated FTLD most often presents with early-onset behavioral variant frontotemporal dementia with disinhibition as the prominent feature, with or without amyotrophic lateral sclerosis. Based on the observed genotype-phenotype correlations between the different FTLD syndromes and different genetic causes, we propose a decision tree to guide clinical genetic testing in patients clinically diagnosed as having FTLD.

C9orf72 G4C2 repeat expansions in Alzheimer's disease and mild cognitive impairment.

C9orf72 G4C2 repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimers disease (AD) is less clear. We assessed the prevalence of G4C2 pathogenic repeat expansions in Flanders-Belgian patients with clinical AD or mild cognitive impairment (MCI). In addition, we studied the effect of non-pathogenic G4C2 repeat length variability on susceptibility to AD, and on AD cerebrospinal fluid (CSF) biomarker levels. A pathogenic repeat expansion was identified in 5 of 1217 AD patients (frequency <1%). No pathogenic expansions were observed in patients with MCI (n = 200) or control individuals (n = 1119). Nonpathogenic repeat length variability was not associated with AD, risk of conversion to AD in MCI individuals, or CSF biomarker levels. We conclude that pathogenic C9orf72 G4C2 repeat expansions can be detected in clinical AD patients and could act as a contributor to AD pathogenesis. Non-pathogenic repeat length variability did not affect risk of AD or MCI, nor AD biomarker levels in CSF, indicating that C9orf72 is not a direct AD risk factor.

Measuring Extrastriatal Dopamine Release During a Reward Learning Task

Objectives: Reward learning is critical for survival. Animal research emphasizes the role of dopaminergic (DA) mesocorticolimbic pathways in reward learning, but few studies have evaluated extrastriatal DA functioning in humans. The purpose of this study was to examine presynaptic DA release in extrastriatal regions of the reward circuit by measuring displacement of the high affinity D2/D3 radioligand [18F]Fallypride during a reward task. Design: Ten healthy volunteers underwent a [18F]Fallypride positron emission tomography protocol while performing a reward task, allowing us to assess participants ability to modulate behavior as a function of reward. DA receptor ligand displacement was correlated with task performance and self‐reported anhedonia. Observations: Parametric t‐maps revealed significant decrease in [18F]Fallypride binding in the medial orbitofrontal cortex (mOFC), ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC), indicating endogenous DA release in these regions. Increasing anhedonic symptoms correlated with DA release in the left vmPFC, left dACC, and right dACC emerged (all rs > 0.65, Ps < 0.05). Similarly, reduced reward learning correlated with higher DA release in left vmPFC, right vmPFC, and left dACC (all rs < −0.64, Ps < 0.05). Left dACC (r = 0.66, P = 0.04) and left vmPFC (r = 0.74, P = 0.01) DA release showed a significant positive correlation with impaired tendency to modulate behavior as a function of prior positive reinforcements. Conclusions: These findings support the hypothesis that DA release in mOFC, vmPFC, and dACC regions plays an important role in reinforcement learning in the human brain. Hum Brain Mapp, 2013.

How affective information from faces and scenes interacts in the brain

Facial expression perception can be influenced by the natural visual context in which the face is perceived. We performed an fMRI experiment presenting participants with fearful or neutral faces against threatening or neutral background scenes. Triangles and scrambled scenes served as control stimuli. The results showed that the valence of the background influences face selective activity in the right anterior parahippocampal place area (PPA) and subgenual anterior cingulate cortex (sgACC) with higher activation for neutral backgrounds compared to threatening backgrounds (controlled for isolated background effects) and that this effect correlated with trait empathy in the sgACC. In addition, the left fusiform gyrus (FG) responds to the affective congruence between face and background scene. The results show that valence of the background modulates face processing and support the hypothesis that empathic processing in sgACC is inhibited when affective information is present in the background. In addition, the findings reveal a pattern of complex scene perception showing a gradient of functional specialization along the posterior-anterior axis: from sensitivity to the affective content of scenes (extrastriate body area: EBA and posterior PPA), over scene emotion-face emotion interaction (left FG) via category-scene interaction (anterior PPA) to scene-category-personality interaction (sgACC).

APP Processing in Human Pluripotent Stem Cell-Derived Neurons Is Resistant to NSAID-Based γ-Secretase Modulation

Summary Increasing evidence suggests that elevated Aβ42 fractions in the brain cause Alzheimer’s disease (AD). Although γ-secretase modulators (GSMs), including a set of nonsteroidal anti-inflammatory drugs (NSAIDs), were found to lower Aβ42 in various model systems, NSAID-based GSMs proved to be surprisingly inefficient in human clinical trials. Reasoning that the nonhuman and nonneuronal cells typically used in pharmaceutical compound validation might not adequately reflect the drug responses of human neurons, we used human pluripotent stem cell-derived neurons from AD patients and unaffected donors to explore the efficacy of NSAID-based γ-secretase modulation. We found that pharmaceutically relevant concentrations of these GSMs that are clearly efficacious in conventional nonneuronal cell models fail to elicit any effect on Aβ42/Aß40 ratios in human neurons. Our work reveals resistance of human neurons to NSAID-based γ-secretase modulation, highlighting the need to validate compound efficacy directly in the human cell type affected by the respective disease.

The associative-semantic network for words and pictures: Effective connectivity and graph analysis

Explicit associative-semantic processing of words and pictures activates a distributed set of brain areas that has been replicated across a wide range of studies. We applied graph analysis to examine the structure of this network. We determined how the left ventral occipitotemporal transition zone (vOT) was connected to word-specific areas. A modularity analysis discerned four communities: one corresponded to the classical perisylvian language system, including superior temporal sulcus (STS), middle temporal gyrus (GTm) and pars triangularis of the inferior frontal gyrus (GFi), among other nodes. A second subsystem consisted of vOT and anterior fusiform gyrus along with hippocampus and intraparietal sulcus. The two subsystems were linked through a unique connection between vOT and GTm, which were hubs with a high betweenness centrality compared to STS and GFi which had a high local clustering coefficient. Graph analysis reveals novel insights into the structure of the network for associative-semantic processing.

Explorative genetic study of UBQLN2 and PFN1 in an extended Flanders-Belgian cohort of frontotemporal lobar degeneration patients.

UBQLN2 and PFN1 were recently associated with amyotrophic lateral sclerosis (ALS). We investigated a role for these ALS genes in frontotemporal lobar degeneration (FTLD). We screened 328 FTLD, 17 FTLD-ALS, and 157 ALS patients. Patients originated from Flanders-Belgium except for 26 Bulgarian ALS patients. The frequency of UBQLN2 and PFN1 genetic variants in the FTLD patients was low at 0.30% and 0.91% respectively. Moreover, the biological relevance to disease of the variants was questionable. In UBQLN2, we identified p.S346C outside of the PXX domain in 1 FTLD patient. Yet, a closely located serine substitution, p.S340I, was observed in a neurologically healthy control individual. In PFN1, we observed the previously reported p.E117G mutation in 3 FTLD patients and in 3 control individuals. In the ALS patient cohort, we detected UBQLN2 variants in 1.27% of patients. These involved 2 novel UBQLN2 missense mutations, p.S400G and p.P440L, that were also present in unaffected relatives (i.e., the p.S400G carriers son [70 years] and daughter [65 years]) and the p.P440L carriers mother (67 years). No mutations were observed in PFN1. In summary, we conclude that genetic variations in UBQLN2 and PFN1 in a predominantly Flanders-Belgian cohort of FTLD and ALS patients are extremely rare.

Polymorphism of brain derived neurotrophic factor influences β amyloid load in cognitively intact apolipoprotein E ε4 carriers

Aside from apolipoprotein E (APOE), genetic risk factors for β amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimers disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects β amyloid burden and the relationship between β amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was measured by means of 18F-flutemetamol PET in 64 community-recruited cognitively intact individuals (mean age 66, S.D. 5.1). Recruitment was stratified according to a factorial design with APOE (ε4 allele present vs absent) and BDNF (met allele at codon 66 present vs absent) as factors. Individuals in the four resulting cells were matched by the number of cases, age, and gender. Among the APOE ε4 carriers, BDNF met positive subjects had a significantly higher amyloid load than BDNF met negative subjects, while BDNF met carrier status did not have an effect in APOE ε4 noncarriers. This interaction effect was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. In the APOE ε4/BDNF met carriers, a significant inverse relationship existed between episodic memory scores and amyloid burden but not in any of the other groups. This hypothesis-generating experiment highlights a potential role of BDNF polymorphisms in the preclinical phase of β amyloid deposition and also suggests that BDNF codon 66 polymorphisms may influence resilience against β amyloid-related effects on cognition.