Rare variants in LRRK1 and Parkinson's disease

Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow- up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance

Structural and functional neural correlates of visuospatial information processing in normal aging and amnestic mild cognitive impairment

Our understanding of cognitive changes related to human aging and their underlying neural processes is challenged by the distinction between normal and pathological aging. In our study, the neural correlates of visuospatial working memory (VSWM) in young persons (YC), healthy older adults (HC) and patients with amnestic mild cognitive impairment (aMCI) were investigated. Effects of the genetic risk factor apolipoprotein E (ApoE) ε4 on a VSWM task were analyzed for HC and aMCI patients. Higher cortical activation in extrastriate occipital regions and significantly decreased brain volumes in frontoparietal areas were observed in HC compared with young persons. Also, reduced cortical activation in the right middle frontal gyrus and superior frontal gyrus was observed in aMCI-patients compared with HC. Thus, attenuated cortical activation during VSWM tasks is related to the formation of aMCI and may serve as an early marker for cognitive decline. In contrast to previous studies, no significant apolipoprotein E-linked differences were found between HC and aMCI groups

Differential Impact of ApoE ε4 on Cortical Activation During Famous Face Recognition in Cognitively Intact Individuals and Patients With Amnestic Mild Cognitive Impairment

This study explores the neurofunctional correlates of the recognition of famous faces in patients with amnestic mild cognitive impairment (aMCI) and healthy controls depending on the genetic risk factor, Apolipoprotein E (ApoE) e4. An eventrelated functional magnetic resonance imaging experiment was conducted while participants discriminated between famous and nonfamous faces. We compared the results of 32 healthy controls [17 ApoE e4 carriers (E4+); 15 noncarriers (E4�)] with those of 30 patients with aMCI (16 E4+; 14 E4�). Despite comparable task performance, patients with aMCI, E4+ showed significantly less activation in a large cortical network including the left parahippocampal gyrus than patients with aMCI E4�. Furthermore, in the aMCI group, we found significantly reduced activation in the left parahippocampal gyrus and posterior cingulate cortex compared with the control group. Our results show that critical regions of the brain show functional decline associated with major risk factors, such as ApoE e4 allele and neuropsychological signs of aMCI for the development of Alzheimer disease. Importantly, the ApoE genotype seems to influence cortical activation in patients with aMCI and to a lesser degree in healthy controls as well, who are without any cognitive symptoms

Consensus clinical management guidelines for Niemann-Pick disease type C.

Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy.NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location