Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease.

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal-lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is relatively rare, yet the economic and social burden is substantial. Having accurate incidence and prevalence estimates would facilitate efficient allocation of healthcare resources. OBJECTIVE: To provide a comprehensive and critical review of the epidemiological literature on ALS. METHODS: MEDLINE and EMBASE (1995-2011) databases of population-based studies on ALS incidence and prevalence reporting quantitative data were analyzed. Data extracted included study location and time, design and data sources, case ascertainment methods and incidence and/or prevalence rates. Medians and interquartile ranges (IQRs) were calculated, and ALS case estimates were derived using 2010 population estimates. RESULTS: In all, 37 articles met the inclusion criteria. In Europe, the median incidence rate (/100,000 population) was 2.08 (IQR 1.47-2.43), corresponding to an estimated 15,355 (10,852-17,938) cases. Median prevalence (/100,000 population) was 5.40 (IQR 4.06-7.89), or 39,863 (29,971-58,244) prevalent cases. CONCLUSIONS: Disparity in rates among ALS incidence and prevalence studies may be due to differences in study design or true variations in population demographics such as age and geography, including environmental factors and genetic predisposition. Additional large-scale studies that use standardized case ascertainment methods are needed to more accurately assess the true global burden of ALS.

Tau levels do not influence human ALS or motor neuron degeneration in the SOD1G93A mouse.

BACKGROUND: The microtubule-associated protein tau is thought to play a pivotal role in neurodegeneration. Mutations in the tau coding gene MAPT are a cause of frontotemporal dementia, and the H1/H1 genotype of MAPT, giving rise to higher tau expression levels, is associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson disease (PD). Furthermore, tau hyperphosphorylation and aggregation is a hallmark of Alzheimer disease (AD), and reducing endogenous tau has been reported to ameliorate cognitive impairment in a mouse model for AD. Tau hyperphosphorylation and aggregation have also been described in amyotrophic lateral sclerosis (ALS), both in human patients and in the mutant SOD1 mouse model for this disease. However, the precise role of tau in motor neuron degeneration remains uncertain. METHODS: The possible association between ALS and the MAPT H1/H2 polymorphism was studied in 3,540 patients with ALS and 8,753 controls. Furthermore, the role of tau in the SOD1(G93A) mouse model for ALS was studied by deleting Mapt in this model. RESULTS: The MAPT genotype of the H1/H2 polymorphism did not influence ALS susceptibility (odds ratio = 1.08 [95% confidence interval 0.99-1.18], p = 0.08) and did not affect the clinical phenotype. Lowering tau levels in the SOD1(G93A) mouse failed to delay disease onset (p = 0.302) or to increase survival (p = 0.557). CONCLUSION: These findings suggest that the H1/H2 polymorphism in MAPT is not associated with human amyotrophic lateral sclerosis, and that lowering tau levels in the mutant SOD1 mouse does not affect the motor neuron degeneration in these animals.

Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer's disease.

Large tracts of extended homozygosity are more prevalent in outbred populations than previously thought. With the advent of high-density genotyping platforms, regions of extended homozygosity can be accurately located allowing for the identification of rare recessive risk variants contributing to disease. We compared measures of extended homozygosity (greater than 1 Mb in length) in a population of 837 late-onset Alzheimer's disease (LOAD) cases and 550 controls. In our analyses, we identify one homozygous region on chromosome 8 that is significantly associated with LOAD after adjusting for multiple testing. This region contains seven genes from which the most biologically plausible candidates are STAR, EIF4EBP1, and ADRB3. We also compared the total numbers of homozygous runs and the total length of these runs between cases and controls, showing a suggestive difference in these measures (p-values 0.052-0.062). This research suggests a recessive component to the etiology of LOAD.

Prevalence of SOD1 mutations in the Italian ALS population.

BACKGROUND: Five to 10% of amyotrophic lateral sclerosis (ALS) cases are reported to be familial (FALS), and mutations of SOD1 account for 20% of these cases. However, estimates of SOD1 mutation prevalence have been exclusively based on case series and clinic referral cohorts. OBJECTIVE: To assess the frequency and nature of SOD1 mutations in a large population-based cohort of Italian patients diagnosed with ALS over a 6-year period. METHODS: All ALS cases incident in Piemonte and Valle d'Aosta, Italy, are collected through a prospective epidemiologic register. Almost all patients with ALS resident in the largest province of Piemonte (Turin) have been evaluated for SOD1 mutations in the 6-year period 2000 through 2005. RESULTS: During the study period, 386 residents of Turin province were diagnosed with ALS (mean crude incidence rate of 2.9/100,000/year). Twenty-two patients (5.7%) had a positive family history of ALS. SOD1 analysis was performed in 325 patients (84.2% of the whole cohort), including all FALS cases. Five patients carried a SOD1 coding mutation, three with a family history of ALS (13.6% of FALS) and two in sporadic cases (0.7% of sporadic ALS). CONCLUSIONS: In this population-based series, the frequency of familial amyotrophic lateral sclerosis (FALS) was lower than that reported in series from ALS referral centers. While the frequency of SOD1 mutations in FALS was similar to the data reported in the literature, only 0.7% of sporadic ALS cases had a SOD1 mutation. Our data indicate that studies from referral centers may overestimate the frequency of FALS and of SOD1 mutations in sporadic ALS.

Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues.

Amyotrophic lateral sclerosis (ALS) is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100,000 per year. Over the past 10 years, the design of ALS epidemiological studies has evolved to focus on a prospective, population based methodology, employing the El Escorial criteria and multiple sources of data to ensure complete case ascertainment. Five such studies, based in Europe and North America, have been published and show remarkably consistent incidence figures among their respective Caucasian populations. Population based studies have been useful in defining clinical characteristics and prognostic indicators in ALS. However, many epidemiological questions remain that cannot be resolved by any of the existing population based datasets. The working hypotheses is that ALS, like other chronic diseases, is a complex genetic condition, and the relative contributions of individual environmental and genetic factors are likely to be relatively small. Larger studies are required to characterise risks and identify subpopulations that might be suitable for further study. This current paper outlines the contribution of the various population based registers, identifies the limitations of the existing datasets and proposes a mechanism to improve the future design and output of descriptive epidemiological studies.

Epidemiology and clinical features of amyotrophic lateral sclerosis in Ireland between 1995 and 2004.

BACKGROUND: We conducted a prospective, population based study to examine trends in incidence and prevalence of amyotrophic lateral sclerosis (ALS) in Ireland from 1995 to 2004. METHODS: The Irish ALS Register was used to identify Irish residents diagnosed with ALS between the 3 year period from 1 January 1995 to 31 December 1997 and the 3 year period from 1 January 2002 to 31 December 2004. RESULTS: 465 Irish residents were diagnosed with ALS during the study periods. The annual incidence rate of ALS in Ireland remained stable over this time (2.0 cases per 100,000 person-years; 95% CI 1.9, 2.2). Median survival of Irish ALS patients was 16.4 months and did not change during the study period. Demographics and clinical features of the incident and prevalent Irish ALS cohorts were markedly different.

Genetics of sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is substantial evidence suggesting that ALS is a heritable disease, and a number of genes have been identified as being causative in familial ALS. In contrast, the genetics of the much commoner sporadic form of the disease is poorly understood and no single gene has been definitively shown to increase the risk of developing ALS. In this review, we discuss the genetic evidence for each candidate gene that has been putatively associated with increased risk of sporadic ALS. We also review whole genome association studies of ALS and discuss the potential of this methodology for identifying genes relevant to motor neuron degeneration.

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.

Neuroprotective agents for clinical trials in ALS: a systematic assessment.

BACKGROUND: Riluzole is currently the only Food and Drug Administration-approved treatment for ALS, but its effect on survival is modest. OBJECTIVE: To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug. METHODS: The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation. RESULTS: Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1-viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered. CONCLUSIONS: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS.

Functional outcome measures as clinical trial endpoints in ALS.

The topiramate study was a 12-month randomized placebo-controlled trial in patients with ALS. Follow-up evaluation of the placebo group (n = 97) constituted a well-described cohort of patients with ALS, in whom multiple outcome measures were assessed at 3-month intervals. During the 12-month study period, the decline of forced vital capacity (FVC%) and ALS functional rating scale (ALSFRS) was linear, whereas the decline of maximum voluntary isometric contraction-arm (MVIC-arm) and MVIC-grip Z scores was curvilinear. Rates of FVC% and ALFRS decline, but not of MVIC-arm or MVIC-grip, were independent predictors of survival.

A novel candidate region for ALS on chromosome 14q11.2.

Sequence variations with biologic effect in ALS have been identified in the gene for vascular endothelial growth factor (VEGF). The gene for a related protein, angiogenin, lies on chromosome 14q11.2. Analysis of the angiogenin (ANG) gene in the authors' population has demonstrated a significant allelic association with the rs11701 single nucleotide polymorphism (SNP) and identified a novel mutation in two individuals with sporadic ALS that potentially inhibits angiogenin function. These observations propose a candidate region for ALS on chromosome 14q11.2 and suggest that other genes with similar function to VEGF may be important in the pathogenesis of ALS.

Access to health services in Ireland for people with Multiple Sclerosis and Motor Neurone Disease.

We conducted a telephone questionnaire to determine the utilisation of hospital and community based services by patients with Motor Neurone Disease and Multiple Sclerosis in Ireland. 94 MND and 188 MS patients participated in the study. MND patients were more likely to have free medical care than MS patients, despite legislation favouring the converse. Severely disabled MND patients were more successful at accessing free community-based services than were severely disabled MS patients. Private medical insurance conferred no advantage when obtaining services or purchasing equipment. Many patients were unaware of the specific roles of the various clinical professionals. There are significant deficiencies in patients' ability to access multidisciplinary services. Voluntary organisations often bridge the gap in service provision. An investment in services for people with chronic neurological disability is urgently required.

Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000.

BACKGROUND: In recent years, there has been a paradigm shift in the method of healthcare delivery to amyotrophic lateral sclerosis (ALS) patients with the emergence of multidisciplinary ALS clinics that cater exclusively for patients with this condition. The impact of multidisciplinary management has not been previously evaluated. METHODS: Using data from the Irish ALS Register, we conducted a prospective, population based study of all ALS cases diagnosed in Ireland over a five year period to evaluate the effectiveness of a multidisciplinary clinic on ALS survival. RESULTS: Eighty two (24%) patients attended the multidisciplinary ALS clinic, with the remaining 262 (76%) cases followed in a general neurology clinic. The ALS clinic cohort was an average of five years younger (60.1 v 65.6 years) and were more likely to receive riluzole than the general neurology cohort (99% v 61%). The median survival of the ALS clinic cohort was 7.5 months longer than for patients in the general neurology cohort (logrank = 15.4, p < 0.0001). Overall, one year mortality was decreased by 29.7%. Prognosis of bulbar onset patients was extended by 9.6 months if they attended the ALS clinic. Using multivariate analysis, attendance at the ALS clinic was an independent covariate of survival (HR = 1.47, p = 0.02). CONCLUSIONS: ALS patients who received their care at a multidisciplinary clinic had a better prognosis than patients attending a general neurology clinic. The data suggest that active and aggressive management enhances survival, particularly among ALS patients with bulbar dysfunction. The effect of clinic type must be considered in future clinical trials design.

Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: A population-based study.

BACKGROUND: The El Escorial and the revised Airlie House diagnostic criteria for amyotrophic lateral sclerosis (ALS) classify patients into categories reflecting different levels of diagnostic certainty. We conducted a prospective, population-based study of the natural course of ALS in the Republic of Ireland during a 6-year period to examine the utility of these ALS diagnostic criteria. METHODS: Using data from the Irish ALS Register, we studied the clinical features of all patients diagnosed as having ALS in Ireland throughout their illness. RESULTS: Between 1993 and 1998, 388 patients were diagnosed as having ALS. Forty percent of patients reported bulbar-onset symptoms. Disease progression occurred over time: at last follow-up, 75% of all patients had bulbar signs, compared with 59% at diagnosis. When the El Escorial criteria were applied, more than half of patients (218 [56%]) had definite or probable ALS at diagnosis. Of the 165 possible and suspected ALS cases at diagnosis (trial ineligible), 110 (67%) were trial eligible at last follow-up. Of the 254 patients who had died, 229 (90%) had definite or probable ALS, whereas 25 patients (10%) remained trial ineligible at death. El Escorial category at diagnosis was not a significant prognostic indicator. Use of the Airlie House criteria had no effect on the median time from symptom onset to trial eligibility (12.9 vs 12.8 months). CONCLUSIONS: The El Escorial and Airlie House diagnostic criteria are excessively restrictive. Furthermore, levels of diagnostic certainty cannot be used as prognostic indicators. Arch Neurol. 2000;57:1171-1176

Amyotrophic lateral sclerosis mimic syndromes: a population-based study.

BACKGROUND: The Irish ALS Register is a population-based register of the epidemiological characteristics of amyotrophic lateral sclerosis (ALS) in the republic of Ireland. OBJECTIVE: To describe the clinical and demographic details of those patients included in the Irish ALS Register who were incorrectly diagnosed as having ALS (patients who were ultimately rediagnosed as having an "ALS mimic syndrome"). METHODS: The medical records of each patient referred to the register are routinely reviewed and, where possible, patients are examined by our group during their illness. RESULTS: Between January 1, 1993, and December 31, 1997, 32 patients (representing 7.3% of 437 referrals) were rediagnosed as having a condition other than ALS. The median age at onset for these 32 patients was 56.0 years (range, 19.5-85.8 years) for men and 53.5 years (range, 39.5-70.4 years) for women. Twenty-nine patients (91%) presented with symptoms referable to the limbs, and the remainder presented with symptoms involving the bulbar musculature. Multifocal motor neuropathy was the most common condition mistaken for ALS, accounting for 7 cases (22%), followed closely by Kennedy disease (4 cases [13%]). Factors leading to diagnostic revision included evolution of atypical symptoms, results of specific investigations, and failure of symptoms to progress. Twenty-seven (84%) of the patients with an ALS mimic syndrome fulfilled the El Escorial criteria for either "suspected" or "possible" ALS, 4 (13%) met the criteria for probable ALS, and 1 (3%) had definite ALS. CONCLUSIONS: The application of the El Escorial diagnostic criteria may facilitate early recognition of non-ALS cases. Misdiagnosis of ALS remains a common clinical problem despite the increased availability of investigations and a greater awareness among neurologists of potential diagnostic pitfalls.

Incidence and prevalence of ALS in Ireland, 1995-1997: a population-based study.

BACKGROUND: We conducted a prospective, population-based study of ALS in the Republic of Ireland for the 3-year period 1995 to 1997. METHODS: To ensure complete case ascertainment, multiple sources of information were used, including consultant neurologists, neurophysiologists, primary care physicians, and the Irish Motor Neuron Disease Association. The El Escorial diagnostic criteria for ALS were applied to all cases enrolled on the register and each patient was regularly followed up during his or her illness. RESULTS: Between January 1, 1995, and December 31, 1997, 231 patients were diagnosed with possible, probable, or definite ALS, including 133 men (57.6%) and 98 women (42.4%). The average annual incidence rate was 2.1 per 100,000 person-years (95% CI, 1.8 to 2.4), and 2.8 per 100,000 person-years for the population older than 15 years (95% CI, 2.4 to 3.1). The incidence rate was higher for men, being 2.5 per 100,000 person-years (95% CI, 2.0 to 2.9), than for women, at 1.8 per 100,000 person-years (95% CI, 1.5 to 2.2), and increased with age for both sexes. The median age at onset was 64.2 years for men and 67.8 years for women. On December 31, 1996, the crude prevalence was 4.7 per 100,000 of the total population (95% CI, 4.0 to 5.5), and 6.2 per 100,000 for the population older than 15 years (95% CI, 5.3 to 7.1). Adjusting to the 1996 Irish population as standard, the incidence of ALS in Ireland during the 3-year study period is the third highest reported to date. CONCLUSIONS: There was a trend toward a higher incidence of ALS in the northwestern region of Ireland, although the numbers of cases involved were small and further study is required.

Service provision for patients with ALS/MND: a cost-effective multidisciplinary approach.

Optimal management of patients with ALS/MND requires a team approach, with early referral to paramedical services for clinical assessment and prompt intervention. As the condition progresses, a flexible approach to management must be adopted by the medical team, with an ability to intervene at very short notice. We have developed an efficient multi-disciplinary clinic that services the ALS/MND population of Ireland by combining the existing infrastructure of community services with a hospital-based specialist clinic. The clinic operates on a weekly basis, and is staffed by a core team including a neurologist, a liaison nurse, and the director of the ALS/MND Association. On-site and same-day physiotherapy, occupational therapy and speech therapy is available, as is pulmonary evaluation. All patients utilising the clinical services are automatically included on the Irish Register of Motor Neurone Disease, and are tracked by the liaison nurse. The core members of the clinic interact regularly with paramedical staff within the community, ensuring that necessary community services are made available within 1-2 weeks of the clinic visit. Equipment necessary for the patient's well being is made available free of charge by the Irish Motor Neurone Disease Association, following an appropriate request from the regional para-medical staff. We have thus demonstrated that an effective multi- disciplinary care service for ALS/MND can be developed at modest cost by close personal liaison between the existing health care structures and core members of a multidisciplinary team.