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Highlights: [•] C9orf72 repeat expansions are the most frequent cause of FTLD/ALS spectrum diseases. [•] Expanded C9orf72 repeats are associated with diverse neurological diseases. [•] Expanded C9orf72 repeats lead to diverse pathological inclusions in the CNS. [•] Not all families in the FTLD/ALS spectrum are genetically explained. [Copyright &y& Elsevier]

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative condition that predominantly affects behavior, social awareness, and language. It is characterized by extensive heterogeneity at the clinical, pathological, and genetic levels. Recognition of these levels of heterogeneity is important for proper disease management. The identification of progranulin and TDP-43 as key proteins in a significant proportion of FTLD patients has provided the impetus for a wealth of studies probing their role in neurodegeneration. This review highlights the most recent developments and future directions in this field and puts them in perspective of the novel insights into the neurodegenerative process, which have been gained from related disorders, e.g., the role of FUS in amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

Frontotemporal lobar degeneration (FTLD) represents a collection of neurodegenerative diseases of frontal and temporal brain regions. It has long been associated with mutations in microtubule-associated protein tau (MAPT), and more recently with loss-of-function mutations in progranulin (PGRN). Phenotypes of PGRN and MAPT mutation carriers overlap, although disease onset in PGRN carriers is a decade later. Mutations in PGRN might influence susceptibility to a wider range of neurodegenerative diseases including Alzheimer and Parkinson diseases. The recent demonstration that mutations in PGRN result in FTLD provided a novel entrance point to the molecular mechanisms leading to this disorder. The high variability in onset age and age-dependent penetrance suggests that the PGRN pathway is highly susceptible to modulating factors that might be exploited to delay the disease processes. [Copyright &y& Elsevier]

Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions (both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, we identified a mutation within the splice donor site of intron 0 (IVS0 + 5G > C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family. Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation (c.3G > A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis. [ABSTRACT FROM AUTHOR]

We obtained conclusive linkage of Alzheimer disease (AD) with a candidate region of 19.7 cM at 7q36 in an extended multiplex family, family 1270, ascertained in a population-based study of early-onset AD in the northern Netherlands. Single-nucleotide polymorphism and haplotype association analyses of a Dutch patient-control sample further supported the linkage at 7q36. In addition, we identified a shared haplotype at 7q36 between family 1270 and three of six multiplex AD-affected families from the same geographical region, which is indicative of a founder effect and defines a priority region of 9.3 cM. Mutation analysis of coding exons of 29 candidate genes identified one linked synonymous mutation, g.38030G→C in exon 10, that affected codon 626 of the PAX transactivation domain interacting protein gene (PAXIP1). It remains to be determined whether PAXIP1 has a functional role in the expression of AD in family 1270 or whether another mutation at this locus explains the observed linkage and sharing. Together, our linkage data from the informative family 1270 and the association data in the population- based early-onset AD patient-control sample strongly support the identification of a novel AD locus at 7q36 and re-emphasize the genetic heterogeneity of AD. [ABSTRACT FROM AUTHOR]

Genetic association has been reported between a di-allelic polymorphism in intron 8 of presenilin-1 (PSEN1) and Alzheimer's disease (AD) in some studies but not in others. In a population-based series of 102 patients with early onset AD and 118 community controls we examined whether polymorphisms in linkage disequilibrium with intron 8 of PSEN1 may explain the association. In addition to the intron 8 polymorphism (P = 0.05), a promoter polymorphism (P = 0.03) and the simple tandem repeat (STR) polymorphism D14S1028 located upstream of PSEN1 (P = 0.04) were found to be marginally significantly associated to AD. When excluding PSEN1 mutation cases (n = 6), the intron 8 association was explained by linkage disequilibrium to the dominant PSEN1 mutations. In the non-mutation cases, the weak associations between the polymorphisms in the regulatory region remained. Our study suggests that a polymorphism/mutation in the promoter or regulatory region of PSEN1 rather than the polymorphism in intron 8 of PSEN1 is associated with early onset AD. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor that focuses on Novel APP mutation V715A associated with presenile Alzheimer's disease in a German family.

Examines the mutations of apolipoprotein E polymorphism (APOE), the candidate gene for longetivity of humans in Rotterdam, Netherlands. Assessment on the limited role of APOE on the development of vascular and malignant disease; Influence of APOE on the prediction of mortality; Use of polymerase chain reaction to analyze the association between APOE and base-line age.

This correction notice is for an article titled "Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins" published in Acta Neuropathologica. The correction addresses an error in Figure 3 of the article, where two images were found to be identical, with one being duplicated. The correct version of Figure 3 is provided in the notice. The publisher, Springer Nature, maintains a neutral stance on jurisdictional claims and institutional affiliations. The authors of the article are listed at the end of the notice. [Extracted from the article]

Patient carriers of a C9orf72 repeat expansion exhibit remarkable heterogeneous clinical and pathological characteristics suggesting the presence of modifying factors. In accordance with other repeat expansion diseases, repeat length is the prime candidate as a genetic modifier. Observations of earlier onset ages in younger generations of large families suggested a mechanism of disease anticipation. Yet, studies of repeat size and onset age have led to conflicting results. Also, the correlation between repeat size and diagnosis is poorly understood. We review what has been published regarding C9orf72 repeat size as modifier for phenotypic characteristics. Conclusive evidence is lacking, partly due to the difficulties in accurately defining the exact repeat size and the presence of repeat variability due to somatic mosaicism. [ABSTRACT FROM AUTHOR]

Presents several letters to the editor concerning human genetics. Efficacy of Glu318Gly on Alzheimer's disease; Characterization of human mitochondrial disorder; Measurement of immunocreative trypsinogen concentration.

Summary Here we describe NanoPack, a set of tools developed for visualization and processing of long-read sequencing data from Oxford Nanopore Technologies and Pacific Biosciences. Availability and implementation The NanoPack tools are written in Python3 and released under the GNU GPL3.0 License. The source code can be found at https://github.com/wdecoster/nanopack , together with links to separate scripts and their documentation. The scripts are compatible with Linux, Mac OS and the MS Windows 10 subsystem for Linux and are available as a graphical user interface, a web service at http://nanoplot.bioinf.be and command line tools. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Heterozygous loss-of-function (LOF) mutations in the human progranulin gene ( GRN ) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials. Multiple studies have demonstrated the heterogeneity in clinical presentation and wide variability in age of onset in patients carrying a GRN LOF mutation. Recently, this heterogeneity became an opportunity to identify disease modifiers, considering that these might constitute suitable targets for developing disease-modifying or disease-delaying therapies. [ABSTRACT FROM AUTHOR]

We identified in a cohort of patients with frontotemporal dementia (n = 481) or amyotrophic lateral sclerosis (n = 147), 10 index patients carrying a TBK1 loss of function mutation reducing TBK1 expression by 50%. Here, we describe the clinical and pathological characteristics of the 10 index patients and six of their affected relatives carrying a TBK1 mutation. Six TBK1 carriers were diagnosed with frontotemporal dementia, seven with amyotrophic lateral sclerosis, one with both clinical phenotypes and two with dementia unspecified. The mean age at onset of all 16 TBK1 carriers was 62.1 ± 8.9 years (range 41-73) with a mean disease duration of 4.7 ± 4.5 years (range 1-13). TBK1 carriers with amyotrophic lateral sclerosis had shorter disease duration than carriers with frontotemporal dementia. Six of seven TBK1 carriers were diagnosed with the behavioural variant of frontotemporal dementia, presenting predominantly as disinhibition. Memory loss was an important associated symptom in the initial phase of the disease in all but one of the carriers with frontotemporal dementia. Three of the patients with amyotrophic lateral sclerosis exhibited pronounced upper motor neuron symptoms. Overall, neuroimaging displayed widespread atrophy, both symmetric and asymmetric. Brain perfusion single-photon emission computed tomography or fluorodeoxyglucose-positron emission tomography showed asymmetric and predominantly frontotemporal involvement. Neuropathology in two patients demonstrated TDP-43 type B pathology. Further, we compared genotype-phenotype data of TBK1 carriers with frontotemporal dementia (n = 7), with those of frontotemporal dementia patients with a C9orf72 repeat expansion (n = 65) or a GRN mutation (n = 52) and with frontotemporal dementia patients (n = 259) negative for mutations in currently known causal genes. TBK1 carriers with frontotemporal dementia had a later age at onset (63.3 years) than C9orf72 carriers (54.3 years) (P = 0.019). In clear contrast with TBK1 carriers, GRN carriers were more often diagnosed with the language variant than the behavioural variant, and presented in case of the diagnosis of behavioural variant, more often than TBK1 carriers with apathy as the predominant characteristic (P = 0.004). Also, TBK1 carriers exhibited more often extrapyramidal symptoms than C9orf72 carriers (P = 0.038). In conclusion, our study identified clinical differences between the TBK1, C9orf72 and GRN carriers, which allows us to formulate guidelines for genetic diagnosis. After a negative result for C9orf72, patients with both frontotemporal dementia and amyotrophic lateral sclerosis should be tested first for mutations in TBK1. Specifically in frontotemporal dementia patients with early memory difficulties, a relatively late age at onset or extrapyramidal symptoms, screening for TBK1 mutations should be considered. [ABSTRACT FROM AUTHOR]

Background: The clusterin (CLU) gene has been identified as an important risk locus for Alzheimer's disease (AD). Although the actual risk-increasing polymorphisms at this locus remain to be identified, we previously observed an increased frequency of rare non-synonymous mutations and small insertion-deletions of CLU in AD patients, which specifically clustered in the β-chain domain of CLU. Nonetheless the pathogenic nature of these variants remained unclear. Here we report a novel non-synonymous CLU mutation (p.I360N) in a Belgian Alzheimer patient and have explored the pathogenic nature of this and 10 additional CLU mutations on protein localization and secretion in vitro using immunocytochemistry, immunodetection and ELISAs. Results: Three patient-specific CLU mutations in the β-chain (p.I303NfsX13, p.R338W and p.I360N) caused an alteration of the subcellular CLU localization and diminished CLU transport through the secretory pathway, indicative of possible degradation mechanisms. For these mutations, significantly reduced CLU intensity was observed in the Golgi while almost all CLU protein was exclusively present in the endoplasmic reticulum. This was further confirmed by diminished CLU secretion in HEK293T and HEK293 FLp-In cell lines. Conclusions: Our data lend further support to the contribution of rare coding CLU mutations in the pathogenesis of neurodegenerative diseases. Functional analyses suggest reduced secretion of the CLU protein as the mode of action for three of the examined CLU mutations. One of those is a frameshift mutation leading to a loss of secreted protein, and the other two mutations are amino acid substitutions in the disulfide bridge region, possibly interfering with heterodimerization of the α- and β-chain of CLU. [ABSTRACT FROM AUTHOR]

Massive GGGGCC repeat expansion in the first intron of the gene C9orf72 is the most common known cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Despite its intronic localization and lack of an ATG start codon, the repeat region is translated in all three reading frames into aggregating dipeptide-repeat (DPR) proteins, poly-(Gly-Ala), poly-(Gly-Pro) and poly-(Gly-Arg). We took an antibody-based approach to further validate the translation of DPR proteins. To test whether the antisense repeat RNA transcript is also translated, we raised antibodies against the predicted products, poly-(Ala-Pro) and poly-(Pro-Arg). Both antibodies stained p62-positive neuronal cytoplasmic inclusions throughout the cerebellum and hippocampus indicating that not only sense but also antisense strand repeats are translated into DPR proteins in the absence of ATG start codons. Protein products of both strands co-aggregate suggesting concurrent translation of both strands. Moreover, an antibody targeting the putative carboxyl terminus of DPR proteins can detect inclusion pathology in C9orf72 repeat expansion carriers suggesting that the non-ATG translation continues through the entire repeat and beyond. A highly sensitive monoclonal antibody against poly-(Gly-Arg), visualized abundant inclusion pathology in all cortical regions and some inclusions also in motoneurons. Together, our data show that the GGGGCC repeat is bidirectionally translated into five distinct DPR proteins that co-aggregate in the characteristic p62-positive TDP-43 negative inclusions found in FTLD/ALS cases with C9orf72 repeat expansion. Novel monoclonal antibodies against poly-(Gly-Arg) will facilitate pathological diagnosis of C9orf72 FTLD/ALS. [ABSTRACT FROM AUTHOR]

Mutations in the Tar DNA binding protein of 43 kDa (TDP-43; TARDBP) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43+ inclusions (FTLD-TDP). To determine the physiological function of TDP-43, we knocked out zebrafish Tardbp and its paralogue Tardbp (TAR DNA binding protein-like), which lacks the glycine-rich domain where ALS- and FTLD-TDP-associated mutations cluster. tardbp mutants show no phenotype, a result of compensation by a unique splice variant of tardbpl that additionally contains a C-terminal elongation highly homologous to the glycine-rich domain of tardbp. Double-homozygous mutants of tardbp and tardbpl show muscle degeneration, strongly reduced blood circulation, mispatterning of vessels, impaired spinal motor neuron axon outgrowth, and early death. In double mutants the muscle-specific actin binding protein Filamin Ca is up-regulated. Strikingly, Filamin C is similarly increased in the frontal cortex of FTLD-TDP patients, suggesting aberrant expression in smooth muscle cells and TDP-43 loss-of-function as one underlying disease mechanism. [ABSTRACT FROM AUTHOR]

The article explores the role of C9orf72 genetic code hexanucleotide repeat expansion mutations in the pathology of the neurodegenerative disorders frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Analysis of intracellular inclusions of misfolded proteins in the cerebellum, hippocampus, and frontotemporal neocortex of FTLD/ALS patients indicated the presence of dipeptide-repeat proteins (DPR) associated with repeat-associated non-ATG codon-initiated (RAN) translation. It is suggested that the repeat mutation causes the abnormal translation of DPR proteins in some FTLD/ALS variants.

Genetic analysis revealed the hexanucleotide repeat expansion GGGGCC within the regulatory region of the gene C9orf72 as the most common cause of familial amyotrophic lateral sclerosis and the second most common cause of frontotemporal lobar degeneration. Since repeat expansions might cause RNA toxicity via sequestration of RNA-binding proteins, we searched for proteins capable of binding to GGGGCC repeats. In vitro-transcribed biotinylated RNA containing hexanucleotide GGGGCC or, as control, AAAACC repeats were incubated with nuclear protein extracts. Using stringent filtering protocols 20 RNA-binding proteins with a variety of different functions in RNA metabolism, translation and transport were identified. A subset of these proteins was further investigated by immunohistochemistry in human autopsy brains. This revealed that hnRNP A3 formed neuronal cytoplasmic and intranuclear inclusions in the hippocampus of patients with C9orf72 repeat extensions. Confocal microcopy showed that these inclusions belong to the group of the so far enigmatic p62-positive/TDP-43 negative inclusions characteristically seen in autopsy cases of diseased C9orf72 repeat expansion carriers. Thus, we have identified one protein component of these pathognomonic inclusions. [ABSTRACT FROM AUTHOR]

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of disorders characterized by disturbances of behavior and personality and different types of language impairment with or without concomitant features of motor neuron disease or parkinsonism. FTLD is characterized by atrophy of the frontal and anterior temporal brain lobes. Detailed neuropathological studies have elicited proteinopathies defined by inclusions of hyperphosphorylated microtubule-associated protein tau, TAR DNA-binding protein TDP-43, fused-in-sarcoma or yet unidentified proteins in affected brain regions. Rather than the type of proteinopathy, the site of neurodegeneration correlates relatively well with the clinical presentation of FTLD. Molecular genetic studies identified five disease genes, of which the gene encoding the tau protein ( MAPT), the growth factor precursor gene granulin ( GRN), and C9orf72 with unknown function are most frequently mutated. Rare mutations were also identified in the genes encoding valosin-containing protein ( VCP) and charged multivesicular body protein 2B ( CHMP2B). These genes are good markers to distinguish underlying neuropathological phenotypes. Due to the complex landscape of FTLD diseases, combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis. Although major progress has been made in FTLD research in recent years, further studies are needed to completely map out and correlate the clinical, pathological and genetic entities, and to understand the underlying disease mechanisms. In this review, we summarize the current state of the rapidly progressing field of genetic, neuropathological and clinical research of this intriguing condition. [ABSTRACT FROM AUTHOR]

In a genome-wide association study of frontotemporal lobar degeneration with pathological inclusions of TAR DNA-binding protein, significant association was obtained with three single nucleotide polymorphisms at 7p21.3, in a region encompassing the gene TMEM106B. This study also suggested a potential modifying effect of TMEM106B on disease since the association was strongest in progranulin mutation carriers. Further, the risk effect seemed to correlate with increased TMEM106B expression in patients. In the present study, we sought to replicate these three findings using an independent Flanders–Belgian cohort of primarily clinically diagnosed patients with frontotemporal lobar degeneration (n = 288). We were able to confirm the association with TMEM106B with a P-value of 0.008 for rs1990622, the top marker from the genome-wide association study [odds ratio 0.75 (95% confidence interval 0.61–0.93)]. Further, high-density single nucleotide polymorphism mapping suggested that the association was solely driven by the gene TMEM106B. Homozygous carriers of the TMEM106B protective alleles had a 50% reduced risk of developing frontotemporal lobar degeneration. However, we were unable to detect a modifying effect of the TMEM106B single nucleotide polymorphisms on onset age in progranulin mutation carriers belonging to an extended, clinical and pathological well-documented founder family segregating a progranulin null mutation. Also, we could not observe significant differences in messenger RNA expression between patients and control individuals in lymphoblast cell lines and in brain frontal cortex. In conclusion, we replicated the genetic TMEM106B association in a primarily clinically diagnosed cohort of patients with frontotemporal lobar degeneration from Flanders–Belgium. Additional studies are needed to unravel the molecular role of TMEM106B in disease onset and pathogenesis. [ABSTRACT FROM AUTHOR]

Numerous loss-of-function mutations in the progranulin (GRN) gene cause frontotemporal lobar degeneration with ubiquitin and TAR-DNAbinding protein 43-positive inclusions by reduced production and secretion of GRN. Consistent with the observation that GRN has neurotrophic properties, pharmacological stimulation of GRN production is a promising approach to rescue GRN haploinsufficiency and prevent disease progression. We therefore searched for compounds capable of selectively increasing GRN levels. Here, we demonstrate that four independent and highly selective inhibitors of vacuolar ATPase (bafilomycin A1, concanamycin A, archazolid B, and apicularen A) significantly elevate intracellular and secreted GRN. Furthermore, clinically used alkalizing drugs, including chloroquine, bepridil, and amiodarone, similarly stimulate GRN production. Elevation of GRN levels occurs via a translational mechanism independent of lysosomal degradation, autophagy, or endocytosis. Importantly, alkalizing reagents rescue GRN deficiency in organotypic cortical slice cultures from a mouse model for GRN deficiency and in primary cells derived from human patients with GRN loss-of-function mutations. Thus, alkalizing reagents, specifically those already used in humans for other applications, and vacuolar ATPase inhibitors may be therapeutically used to prevent GRN-dependent neurodegeneration. [ABSTRACT FROM AUTHOR]

The nuclear transactive response (TAR) DNA binding protein-43, TDP-43, is a major constituent of the ubiquitinated neuronal inclusions in patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Missense mutations in TDP-43 have been associated with familial and sporadic ALS. Since TDP-43 immunoreactivity was also frequently observed in Alzheimer's disease (AD) brains and elevated TDP-43 plasma levels were detected in a subset of AD patients, we sequenced the TDP-43 gene, TARDBP, in a well-documented group of AD patients (n=485). We observed one mutation in exon 3 (c.269C>T) predicting a p.Ala90Val substitution in two patients. One extra p.Ala90Val carrier was observed by sequencing exon 3 of an additional set of 254 AD patients. The mutation was absent from 604 control individuals. Allele and haplotype analysis using microsatellite markers suggested that the three patients might share a common founder. However, co-segregation of p.Ala90Val with AD could not be realized leaving its pathogenic unclear at this moment. Also, sequencing in 190 additional AD patients of TARDBP exon 6 in which pathogenic mutations have been reported in FTLD and ALS was negative. Further, genetic association analyses using five single nucleotide polymorphisms did not detect significant differences between AD patients and control individuals. In conclusion, the genetic contribution of TARDBP to AD was restricted to the rare mutation p.Ala90Val (3/739, 0.4%) of unclear pathogenic nature that affects the nuclear localization signal in TDP-43. [ABSTRACT FROM AUTHOR]

The recent discoveries in genome-wide association studies (GWAS) of novel susceptibility loci (CLU, CR1 and PICALM) for Alzheimer''s disease (AD) have elicited considerable interest in the AD community. But what are the implications of these purely epidemiological findings for our understanding of disease etiology and patient care? In this review, we attempt to place these findings in the context of current and future AD genetics research. CLU, CR1 and PICALM support existing hypotheses about the amyloid, lipid, chaperone and chronic inflammatory pathways in AD pathogenesis. We discuss how these and future findings can be translated into efforts to ameliorate patient care by genetic profiling for risk prediction and pharmacogenetics and by guiding drug development. [Copyright &y& Elsevier]

Objective Mutations that lead to a loss of progranulin (PGRN) explain a considerable portion of the occurrence of frontotemporal lobar degeneration. We tested a biomarker allowing rapid detection of a loss of PGRN. Methods We used an enzyme-linked immunosorbent assay to measure in serum the PGRN protein levels of six affected and eight unaffected carriers from within an extended Belgian founder family segregating the null mutation IVS1+5G>C. Further, we measured serum PGRN levels in 2 patients with another null mutation (a Met1 and a frameshift mutation), in 4 patients carrying a predicted pathogenic missense mutation and in 5 patients carrying a benign missense polymorphism, in 9 unaffected noncarrier relatives, and in 22 community controls. Results Serum PGRN levels were reduced in both affected and unaffected null mutation carriers compared with noncarrier relatives ( pexact < 0.0001), and allowed perfect discrimination between carriers and noncarriers (sensitivity: 1.0; 1 − specificity: 0.0). Serum PGRN levels in Cys139Arg and Arg564Cys mutation carriers were significantly lower than in controls, but greater than in null mutation carriers, fitting the hypothesis of partial loss of function caused by these missense mutations. As expected, levels for carriers of benign missense polymorphisms were not significantly different from controls. Interpretation Our results indicate that the serum PGRN level is a reliable biomarker for diagnosing and early detection of frontotemporal lobar degeneration caused by PGRN null mutations, and provided the first in vivo evidence that at least some missense mutations in PGRN may lead to a (partial) loss of PGRN. Ann Neurol 2009 [ABSTRACT FROM AUTHOR]

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically and genetically highly complex disorder. In the last few years enormous progress has been made in dissecting the genetic etiology of FTLD. Mutations have been identified in the progranulin gene (PGRN), the charged multivesicular body protein 2B gene (CHMP2B) and the valosin-containing protein gene (VCP). Mutations in these genes all lead to FTLD pathology characterized by ubiquitin-immunoreactive neuronal cytoplasmic and intranuclear lentiform inclusions (FTLD-U). The similar pathology suggests that these genes may be connected trough a common disease pathway leading to neurodegeneration and the formation of these pathognomic inclusions. This review focuses on the molecular genetic processes underlying FTLD-U pathology. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We used data from the Betula Study to examine associations between total cholesterol, triglycerides, and apolipoprotein E on 10-year changes in cognitive performance. Tests assessing episodic memory (recall and recognition), semantic memory (knowledge and fluency), and visuospatial ability (block design) were administered to 524 nondemented adults (initial age of 55-80 years); multilevel modeling was applied to the data. Higher triglyceride levels were associated with a decline in verbal knowledge. Lipid levels moderated the influence of apolipoprotein E on episodic memory, such that among ~4 allele carriers, decline in recognition was noted for individuals with higher cholesterol levels. Cholesterol and triglyceride levels are pharmacologically modifiable risk factors that account for variation in normal cognitive aging. [ABSTRACT FROM AUTHOR]

Abstract: Apolipoprotein E ɛ4 (APOE ɛ4) is the main known genetic risk factor for Alzheimer''s disease (AD). Some previous studies have reported structural brain changes as well as cognitive deficits in non-demented APOE ɛ4 carriers, but the pattern of results is inconsistent and studies with larger sample sizes have been called for. Here we compared hippocampal volume and recognition–memory performance between AD-symptom-free carriers (N =30) and non-carriers (N =30) of the APOE ɛ4 (age range: 49–79 years). We observed reduced right hippocampal volume in APOE ɛ4 carriers, and found that the difference was most pronounced before the age of 65. Further, the APOE ɛ4 carriers made significantly more false alarms in the recognition–memory test, and the number of false alarms correlated significantly with right hippocampus volume. These results indicate that relatively young individuals at genetic risk for AD have smaller hippocampal volume and lower performance on hippocampal-dependent cognitive tasks. A question for the future is whether smaller hippocampal volume represents early-onset hippocampal volume reduction or an inherent trait. [Copyright &y& Elsevier]

Abstract: To determine whether apolipoprotein alleles (APOE) influence behavioral and psychological signs and symptoms of dementia (BPSD), we initiated a prospective, longitudinal study. Patients with Alzheimer''s disease (AD) (N =186), frontotemporal dementia (FTD) (N =29), mixed dementia (MXD) (N =28), dementia with Lewy bodies (DLB) (N =11) and Parkinson''s disease dementia (PDD) (N =7) were included. Blood was collected for DNA extraction and APOE genotyping. Behavioral assessments were performed at baseline and semi-annually thereafter, using behavioral assessment scales (Middelheim frontality score, behavioral pathology in Alzheimer''s disease rating scale (Behave-AD)). In FTD patients, we identified dose dependent effects of APOE ɛ4 on the Behave-AD total and cluster aggressiveness scores. APOE ɛ2 was associated with a higher score on the Behave-AD cluster delusions in PDD/DLB patients. No APOE effects on frequency or severity of BPSD in AD and MXD patients were found. In conclusion, APOE has disease-specific effects on BPSD in FTD and PDD/DLB patients, given the reported associations of APOE ɛ4 with aggression (FTD) and of APOE ɛ2 with delusions (PDD/DLB). [Copyright &y& Elsevier]

In contrast to the common and genetically complex senile form of Alzheimer''s disease (AD), the molecular genetic dissection of inherited presenile dementias has given important mechanistic insights into the pathogenesis of degenerative brain disease. Here, we focus on recent genotype–phenotype correlative studies in presenile AD and the frontotemporal dementia (FTD) complex of disorders. Together, these studies suggest that AD and FTD are linked in a genetic spectrum of presenile degenerative brain disorders in which tau appears to be the central player. [Copyright &y& Elsevier]

Technological improvements shifted sequencing from low-throughput, work-intensive, gel-based systems to high-throughput capillary systems. This resulted in a broad use of genomic resequencing to identify sequence variations in genes and regulatory, as well as extended genomic regions. We describe a software package, novoSNP, that conscientiously discovers single nucleotide polymorphisms (SNPs) and insertion-deletion polymorphisms (INDELs) in sequence trace files in a fast, reliable, and user-friendly way. We compared the performance of novoSNP with that of PolyPhred and PolyBayes on two data sets. The first data set comprised 1028 sequence trace files obtained from diagnostic mutation analyses of SCNL4 (neuronal voltage-gated sodium channel a-subunit type I gene). The second data set comprised 9062 sequence trace files from a genomic resequencing project aiming at the construction of a high-density SNP map of MAPT (microtubule-associated protein tau gene). Visual inspection of these data sets had identified 38 sequence variations for SCNIA and 488 for MAPT. novoSNP automatically identified all 38 SCNIA variations including five INDELs, while for MAPT only 15 of the 488 variations were not correctly marked. PolyPhred detected far fewer SNPs as compared to novoSNP and missed nearly all INDELs. PolyBayes, designed for the sequence analysis of cloned templates, detected only a limited number of the variations present in the data set. Besides the significant improvement in the automated detection of sequence variations both in diagnostic mutation analyses and in SNP discovery projects, novoSNP also offers a user-friendly interface for inspecting possible genetic variations. [ABSTRACT FROM AUTHOR]

The challenges inherent in diagnosing and treating patients with Alzheimer's disease are increasing. Early diagnosis and modification of risk factors have received growing attention from the media in recent years. As a result, the general public, and patients and family members, are increasingly better informed about the disease, its genetic background, and the possibilities for treatment. The physician is often faced with questions about hereditary patterns within the family and with requests to perform genetic testing. Children, with increasing frequency, ask for a separate appointment with the treating physician, during the patient's life or after the patient has died, to discuss whether they are likely to get the disease and whether genetic tests should be performed. In this paper, some of the clinical and ethical questions that physicians face are explored. Arguments as to why we think routine genetic assessment should not be part of the diagnostic examination of the patient suspected of Alzheimer's disease are given. [ABSTRACT FROM AUTHOR]

Presents a study on the role of the gene encoding nicastrin (NCSTN), a major gamma -secretase component, in modifying the risk for familial early-onset Alzheimer disease (EOAD) in a Dutch population-based sample. Genomic organization of NCSTN; Contribution of genetic variations in NCSTN in patients with EOAD; Results.

The aim of the study was to investigate the course of objective memory impairment in non-demented subjects who attended a memory clinic and to test predictors of outcome. Non-demented subjects (N =74) were included when they were older than 40 years and had a baseline score on the delayed recall of a word learning test below the tenth percentile. Subjects with memory impairment due to known somatic or neurological causes were excluded. The subjects were reassessed after 2 and 5 years. At the 5-year follow-up, 42% of the subjects had no memory impairment, 19% of the subjects had memory impairment without dementia, and 39% of the subjects had Alzheimer type dementia (AD). Predictors at baseline of reversible memory impairment in a multivariate analysis were age, scores on the MMSE and delayed recall, and the degree of functional impairment. Predictors at baseline of AD in a multivariate analysis were age and the score on the MMSE. The apolipoprotein E genotype and the presence of depression at baseline were not predictors of outcome. The positive predictive value was 72% for reversible memory impairment and 81% for AD. Memory impairment is often reversible and therefore its presence alone is not sufficient to consider subjects as preclinically demented. Predictive accuracy can be increased by including simple measures such as age, the scores on the MMSE and delayed recall, and the degree of functional impairment. Copyright © 2000 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: The nuclear TAR DNA binding protein (TDP-43) is deposited in ubiquitin-positive inclusions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two clinicopathologically overlapping neurodegenerative diseases. In this study we excluded mutations and copy number variations in the gene encoding TDP-43 (TARDBP) from an extended series of 173 FTD and 237 ALS patients. Further, we did not identify association of common genetic variants in these patients. Our data implicate that TDP-43 has no primary genetic role in the pathophysiological mechanisms underlying central nervous system neurodegeneration in these diseases. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Progranulin (GRN) is a secreted growth factor involved in various cellular functions, and loss-of-function mutations are a major cause of frontotemporal lobar degeneration (FTLD) with TDP-43 positive pathology. Most FTLD-related GRN mutations are nonsense mutations resulting in reduced GRN expression. Nonsynonymous GRN missense mutations have been described as risk factor for neurodegenerative brain diseases, but their pathogenic nature remains largely elusive. We identified a double missense mutation in GRN leading to amino acid changes p.D33E and p.G35R in an FTLD patient from Turkish origin. Biochemical and cell biological analysis of the double-mutation together with 2 so-far uncharacterized GRN missense mutations (p.C105R and p.V514M) revealed a reduced secretion efficiency of the GRN p.D33E/p.G35R and p.C105R proteins. Furthermore, loss of the conserved cysteine residue affects protein folding and altered proteolytic processing by neutrophil elastase and proteinase 3. Our data indicate that the described variants may cause a loss-of-function, albeit to a lesser extent than GRN null mutations, and hence could be considered as low-penetrant risk factors for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract: Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOEε4. We systematically screened the TREM2 coding region within a Belgian study on neurodegenerative brain diseases (1216 AD patients, 357 FTD patients, and 1094 controls). We observed an enrichment of rare variants across TREM2 in both AD and FTD patients compared to controls, most notably in the extracellular IgV-set domain (relative risk = 3.84 [95% confidence interval = 1.29–11.44]; p = 0.009 for AD; relative risk = 6.19 [95% confidence interval = 1.86–20.61]; p = 0.0007 for FTD). None of the rare variants individually reached significant association, but the frequency of p.R47H was increased ∼3-fold in both AD and FTD patients compared to controls, in line with previous reports. Meta-analysis including 11 previously screened AD cohorts confirmed the association of p.R47H with AD (p = 2.93×10−17). Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general. [Copyright &y& Elsevier]

Abstract: 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 carrier’s son [70 years] and daughter [65 years]) and the p.P440L carrier''s 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. [Copyright &y& Elsevier]

Abstract: C9orf72 G4C2 repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimer''s 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. [Copyright &y& Elsevier]

Abstract: CR1 is a novel Alzheimer''s disease (AD) gene identified by genome-wide association studies (GWAS). Recently, we showed that AD risk could be explained by an 18-kilobase insertion responsible for the complement component (3b/4b) receptor 1 (CR1)-S isoform. We investigated the relevance of the CR1 isoforms to AD in a Canadian dataset. Also, we genotyped rs4844610 tagging the GWAS-significant CR1 single nucleotide polymorphisms. Individuals with F/S genotype had a 1.8 times increased risk for AD compared with F/F genotype (p-adjusted = 0.003), while rs4844610 was only marginally significant (p-adjusted = 0.024). The analyses of brain samples demonstrated that the CR1-S isoform is expressed at lower protein levels than CR1-F (p < 0.0001) hence likely associated with increased complement activation. Intriguingly, our neuropathological results show that the pattern of CR1 expression in neurons is different between the F/F and F/S genotypes (filiform vs. vesicular-like profiles). Furthermore, double labeling studies supported a differential distribution of CR1 in neurons (endoplasmic reticulum intermediate compartment vs. lysosomes). These observations indicate that the CR1-S and CR1-F isoforms could be processed in different ways in neurons. In conclusion, our results support that the CR1-S isoform explains the GWAS signals and open a novel prospect for the investigation of CR1-related disease mechanisms. [Copyright &y& Elsevier]

Abstract: There exists considerable clinical and pathological overlap between frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), which implies that these 2 neurodegenerative conditions share common pathogenic mechanisms. Recently, intermediate-length (27-33) polyglutamine (polyQ) expansions in ataxin-2 (ATXN2) have been associated with increased risk for ALS, while expansions of > 34 repeats are known to cause spinocerebellar ataxia type 2 (Sca-2). We identified in 72 ALS patients one patient with a 33 polyQ expansion that was absent in 810 control individuals. This allele was also found in one patient with concomitant ALS-Sca-2. In contrast, in a Flanders-Belgian series of 270 FTLD and 22 FTLD-ALS patients, we found no association with intermediate-length polyQ expansions nor did we observe patient-specific long expansions in agreement with the recent observation in a screening of a substantial sized cohort of patients with diverse neurodegenerative brain diseases. Our results provide further support to the notion that ATXN2 associated polyglutamine amplification is specific to the ALS-end of the FTLD-ALS disease spectrum. [Copyright &y& Elsevier]

The goals of the human genome project did not include sequencing of the heterochromatic regions. We describe here an initial sequence of 1.1 Mb of the short arm of human chromosome 21 (HSA21p), estimated to be 10% of 21p. This region contains extensive euchromatic-like sequence and includes on average one transcript every 100 kb. These transcripts show multiple inter- and intrachromosomal copies, and extensive copy number and sequence variability. The sequencing of the "heterochromatic" regions of the human genome is likely to reveal many additional functional elements and provide important evolutionary information. [ABSTRACT FROM AUTHOR]