Advances in understanding the molecular basis of frontotemporal dementia

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. Until recently, the underlying cause was known in only a minority of cases that were associated with abnormalities of the tau protein or gene. In 2006, however, mutations in the progranulin gene were discovered as another important cause of familial FTD. That same year, TAR DNA-binding protein 43 (TDP-43) was identified as the pathological protein in the most common subtypes of FTD and amyotrophic lateral sclerosis (ALS). Since then, substantial efforts have been made to understand the functions and regulation of progranulin and TDP-43, as well as their roles in neurodegeneration. More recently, other DNA/RNA binding proteins (FET family proteins) have been identified as the pathological proteins in most of the remaining cases of FTD. In 2011, abnormal expansion of a hexanucleotide repeat in the gene C9orf72 was found to be the most common genetic cause of both FTD and ALS. All common FTD-causing genes have seemingly now been discovered and the main pathological proteins identified. In this Review, we highlight recent advances in understanding the molecular aspects of FTD, which will provide the basis for improved patient care through the development of more-targeted diagnostic tests and therapies.     

Chromosome 9 ALS and FTD locus is probably derived from a single founder

We and others have recently reported an association between amyotrophic lateral sclerosis (ALS) and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data are that there is a single founder for this form of disease.     

Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes

Objective

Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS–FTD.

Methods

The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS–FTD.

Results

Missense changes were identified in an ALS–FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear.

Conclusion

PGRN mutations are not a common cause of ALS phenotypes.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder predominantly involving motor neurons leading to paralysis and death within 3–5 years from symptom onset. The pathogenic mechanism leading to motor neuron degeneration is unknown in the majority of cases. Frontotemporal dementia (FTD) is a degenerative disorder of the frontal and anterior temporal lobes.¹ Clinical, pathological and genetic data suggest that ALS and FTD form a spectrum of disease.² Approximately 5% of ALS patients have FTD (ALS–FTD)³ and approximately half of patients with “classical” ALS have subtle frontal and temporal lobe cognitive impairment.⁴ Many FTD cases similarly develop symptoms of motor neuron involvement during the course of their illness⁵ and up to one third of FTD patients without overt motor symptoms have loss of anterior horn cells with characteristic ubiquitin inclusions in surviving motor neurons on autopsy.⁶Recently, mutations in the progranulin (PGRN) gene have been described as the cause of ubiquitin positive FTD.^7,8 The overlap between ALS and FTD prompted us to screen 272 cases of sporadic ALS, 40 familial ALS cases and 49 patients diagnosed with ALS–FTD for mutations in this gene.     

Quantification of regional left and right ventricular radial and longitudinal function in healthy children using ultrasound-based strain rate and strain imaging.

BACKGROUND: Noninvasive assessment of left (LV) and right (RV) ventricular function in children could benefit from a technique that would characterize local myocardial deformation. Color Doppler myocardial imaging (CDMI) allows the calculation of either local longitudinal or radial Strain Rate (SR) and Strain (epsilon). To determine the clinical feasibility and reproducibility of longitudinal and radial SR and epsilon, the following study was carried out. METHODS: CDMI data were obtained from 33 healthy children (4-16 years). To quantify regional longitudinal and radial function SR and epsilon data were obtained from apical and parasternal views respectively. From the extracted SR curves, peak values for systole, early diastole, and late diastole were calculated. From the extracted epsilon curves the systolic, early and late diastolic epsilon values were calculated. RESULTS: LV longitudinal deformation were homogeneous for LV basal, mid and apical segments (peak systolic SR: -1.9 +/- 0.7 s(-1), systolic epsilon -25% +/- 7%). Longitudinal SR and epsilon values were significantly higher and heterogeneous in the RV (compared with LV walls) and were maximal in the mid part of the RV free wall (peak systolic SR: -2.8 +/- 0.7 s(-1), systolic epsilon -45% +/- 13%). The RV inferior wall showed homogeneous but lower longitudinal SR and epsilon values. The LV systolic and diastolic SR and epsilon values were higher for deformation in the radial direction compared with the longitudinal direction (radial peak systolic SR: 3.7 +/- 0.9 s(-1), radial systolic epsilon 57% +/- 11%; P <.0001). The interobserver variability for radial systolic epsilon and SR was 10.3% and 13.1%, respectively. CONCLUSION: Ultrasound-based Strain SR/epsilon imaging is a practical, reproducible clinical technique, which allows the calculation of regional longitudinal and radial deformation from both LV and RV segments. The combination of regional SR/epsilon indices and the timing of specific systolic or diastolic regional events may offer a new noninvasive approach to quantifying regional myocardial function in congenital and acquired heart disease in children.     

Ataxin-2 repeat-length variation and neurodegeneration

Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.     

Molecular detection of Campylobacter jejuni as a cause of culture-negative spondylodiscitis

Spondylodiscitis caused by Campylobacter species is a rare disease which is most often caused by Campylobacter fetus. We report a case of culture-negative spondylodiscitis and a psoas abscess due to Campylobacter jejuni in a 68-year-old woman, as revealed by 16S rRNA gene and Campylobacter-specific PCRs from biopsied tissue.     

Corticobasal degeneration: a pathologically distinct 4R tauopathy

Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disorder with onset in the 5(th) to 7(th) decade of life. It is associated with heterogeneous motor, sensory, behavioral and cognitive symptoms, which make its diagnosis difficult in a living patient. The etiology of CBD is unknown; however, neuropathological and genetic evidence supports a pathogenetic role for microtubule-associated protein tau. CBD pathology is characterized by circumscribed cortical atrophy with spongiosis and ballooned neurons; the distribution of these changes dictates the patient's clinical presentation. Neuronal and glial tau pathology is extensive in gray and white matter of the cortex, basal ganglia, diencephalon and rostral brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques. The classic clinical presentation, termed corticobasal syndrome (CBS), comprises asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus. CBS also occurs in conjunction with other diseases, including Alzheimer disease and progressive supranuclear palsy. Moreover, the pathology of CBD is associated with clinical presentations other than CBS, including Richardson syndrome, behavioral variant frontotemporal dementia, primary progressive aphasia and posterior cortical syndrome. Progress in biomarker development to differentiate CBD from other disorders has been slow, but is essential in improving diagnosis and in development of disease-modifying therapies.