Heterozygous and Homozygous Variants in SORL1 Gene in Alzheimer's Disease Patients: Clinical, Neuroimaging and Neuropathological Findings.

In the last few years, the SORL1 gene has been strongly implicated in the development of Alzheimer's disease (AD). We performed whole-exome sequencing on 37 patients with early-onset dementia or family history suggestive of autosomal dominant dementia. Data analysis was based on a custom panel that included 46 genes related to AD and dementia. SORL1 variants were present in a high proportion of patients with candidate variants (15%, 3/20). We expand the clinical manifestations associated with the SORL1 gene by reporting detailed clinical and neuroimaging findings of six unrelated patients with AD and SORL1 mutations. We also present for the first time a patient with the homozygous truncating variant c.364C>T (p.R122*) in SORL1, who also had severe cerebral amyloid angiopathy. Furthermore, we report neuropathological findings and immunochemistry assays from one patient with the splicing variant c.4519+5G>A in the SORL1 gene, in which AD was confirmed by neuropathological examination. Our results highlight the heterogeneity of clinical presentation and familial dementia background of SORL1-associated AD and suggest that SORL1 might be contributing to AD development as a risk factor gene rather than as a major autosomal dominant gene.

Home calligraphic exercises as manual dexterity training in patients with Parkinson's disease: a pilot feasibility study.

PURPOSE: To assess the feasibility and effects on manual dexterity and the quality of life (QoL) of a 12-week home calligraphic training program in patients with Parkinson's disease (PD). METHODS: A pilot study with participants recruited from the Movement Disorders consultation at the Hospital 12 de Octubre (Madrid). The main outcome, manual dexterity, was assessed using the Purdue Pegboard Test (PPT). Secondary outcomes included clinical rating scales that contemplate aspects related to manual dexterity (DextQ-24, UPDRSII, UPDRSIII), and QoL (PDQ-39 and EuroQoL-5D). RESULTS: Thirty PD patients (57% males) with a mean age of 66.11 (9.76) years and 93% adherence rate. The PPT scores improved significantly (p < 0.0001) from T0 (start of the study) to T1 (after 24 weeks). No statistically significant change was found in DextQ-24, UPDRS-II and UPDRS-III, but a clear improvement was observed in the QoL measurement: EuroQoL-5D (p < 0.0001), PDQ-39 (p < 0.0001) and modified PDQ-39 (p = 0.022). CONCLUSIONS: This is the first study to demonstrate the feasibility and improvement in hand dexterity assessed by the PPT for patients diagnosed with PD after a 12-week home calligraphic training program. A significant improvement was noted in the QoL measurements, such as the PDQ-39, modified PDQ-39, and EuroQoL-5D.Implications for RehabilitationMost patients with Parkinson's disease suffer from impaired manual dexterity, making it difficult to perform activities of daily living such as eating, buttoning, or shaving.A 12-week home calligraphic training program could improve hand dexterity in these patients.The advantage of this home calligraphic trainingis is that it is an easy-to-perform, low-cost and no side effects.This training also improves their quality of life.

Does Your Loved One With Cognitive Symptoms Need to See a Doctor? Check It Online.

Widespread access to emerging information and communication technologies (ICT) allows its use for the screening of diseases in the general population. At the initiative of the Spanish Confederation of Associations of Families of People with Alzheimer's disease and other dementias (CEAFA), a website (http://www.problemasmemoria.com) has been created that provides information about Alzheimer's disease and includes questionnaires to be completed by family or friends concerned about memory problems of a relative. A cross-sectional, randomized, multicenter study was performed to evaluate feasibility, validity, and user satisfaction with an electronic method of completion vs. the current method of paper-based questionnaires for clinically dementia screening completed by the informants: the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and the Alzheimer's disease-8 screening test (AD8). A total of 111 pairs were recruited by seven memory clinics. Informants completed IQCODE and AD8 questionnaires both in their paper and electronic versions. The correlation between paper and electronic versions was significantly positive for IQCODE (r = 0.98; p < 0.001) and AD8 (r = 0.96; p < 0.001). The execution time did not differ significantly, and participants considered their use equally easy. This study shows that an electronic version of the IQCODE and AD8 questionnaires is suitable for its online use via the internet and achieves the same results as the traditional paper versions.

Expanding the clinical and genetic spectrum of SQSTM1-related disorders in family with personality disorder and frontotemporal dementia.

Objective:SQSTM1-variants associated with frontotemporal lobar degeneration have been described recently. In this study, we investigated a heterozygous in-frame duplication c.436_462dup p. (Pro146_Cys154dup) in the SQSTM1 gene in a family with a new phenotype characterized by a personality disorder and behavioral variant frontotemporal dementia (bvFTD). We review the literature on frontotemporal dementia (FTD) associated with SQSTM1. Methods: The index case and relatives were described, and a genetic study through Whole Exome Sequencing was performed. The literature was reviewed using Medline and Web of Science. Case reports, case series, and cohort studies were included if they provided information on SQSTM1 mutations associated with FTD. Results: Our patient is a 70-year-old man with a personality disorder since youth, familial history of dementia, and personality disorders with a 10-year history of cognitive decline and behavioral disturbances. A diagnosis of probable bvFTD was established, and the in-frame duplication c.436_462dup in the SQSTM1 gene was identified. Segregation analysis in the family confirmed that both affected sons with personality disorder were heterozygous carriers, but not his healthy 65-year-old brother. A total of 14 publications about 57 patients with SQSTM1-related FTD were reviewed, in which the bvFTD subtype was the main phenotype described (66.6%), with a predominance in men (63%) and positive family history in 61.4% of the cases. Conclusions: We describe a heterozygous in-frame duplication c.436_462dup p.(Pro146_Cys154dup) in the SQSTM1 gene, which affects the zinc-finger domain of p62, in a family with a personality disorder and bvFTD, expanding the genetics and clinical phenotype related to SQSTM1.

Kynurenic Acid Levels are Increased in the CSF of Alzheimer's Disease Patients.

Kynurenic acid (KYNA) is a product of the tryptophan (TRP) metabolism via the kynurenine pathway (KP). This pathway is activated in neurodegenerative disorders, such as Alzheimer´s disease (AD). KYNA is primarily produced by astrocytes and is considered neuroprotective. Thus, altered KYNA levels may suggest an inflammatory response. Very recently, significant increases in KYNA levels were reported in cerebrospinal fluid (CSF) from AD patients compared with normal controls. In this study, we assessed the accuracy of KYNA in CSF for the classification of patients with AD, cognitively healthy controls, and patients with a variety of other neurodegenerative diseases, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy (PSP). Averaged KYNA concentration in CSF was higher in patients with AD when compared with healthy subjects and with all the other differentially diagnosed groups. There were no significant differences in KYNA levels in CSF between any other neurodegenerative groups and controls. These results suggest a specific increase in KYNA concentration in CSF from AD patients not seen in other neurodegenerative diseases.