Severe infantile-onset cardiomyopathy associated with a homozygous deletion in desmin

Desminopathy is a genetically heterogeneous disorder with autosomal dominant pattern of inheritance in most affected families; the age of disease onset is on average 30 years. We studied a patient with a history of recurrent episodes of syncope from infancy who later developed second-degree AV block and restrictive cardiomyopathy; she subsequently suffered several episodes of ventricular tachyarrhythmia requiring implantation of bicameral defibrillator. Neurological examination revealed rapidly progressive bilateral facial weakness, winging of the scapulae, symmetric weakness and atrophy of the trunk muscles, shoulder girdle and distal muscles of both upper and lower extremities. Muscle biopsy demonstrated signs of myofibrillar myopathy with prominent subsarcolemmal desmin-reactive aggregates. Molecular analysis identified a homozygous deletion in DES resulting in a predicted in-frame obliteration of seven amino acids (p.R173_E179del) in the 1B domain of desmin. We describe the youngest known desminopathy patient with severe cardiomyopathy and aggressive course leading to the devastation of cardiac, skeletal and smooth musculature at an early age

Decrease in sleep depth is associated with higher cerebrospinal fluid neurofilament light levels in patients with Alzheimer's disease

STUDY OBJECTIVES: The majority of studies investigating the association between sleep and Alzheimer's disease (AD) biomarkers have been performed in healthy participants. Our objective was to investigate the association between sleep and several biomarkers that reflect distinct aspects of AD physiopathology. METHODS: The cohort included 104 individuals with mild-moderate AD. The participants were submitted to one-night polysomnography, and cerebrospinal fluid was collected in the following morning to measure the selected biomarkers associated with amyloid deposition, tau pathology, neurodegeneration, axonal damage, synaptic integrity, neuroinflammation, and oxidative damage. RESULTS: There was a positive correlation between neurofilament light (NF-L) and the time spent in stage 1 of non-rapid eyes movement (NREM) (N1) sleep and a negative correlation between this marker and the time spent in stage 3 of NREM (N3) sleep. Accordingly, we observed that deep sleep was associated with lower levels of NF-L, whereas light sleep increased the probability of having higher levels of this marker. Furthermore, chitinase-3-like-1 (YKL-40) was negatively correlated with sleep efficiency, the time spent in stage 2 of NREM (N2) sleep, and the time spent in N3 sleep. Conversely, there was a positive correlation between N3 sleep and the oxidative protein damage markers N-ε-(carboxyethyl)lysine and N-ε-(malondialdehyde)lysine. CONCLUSIONS: There were significant correlations between sleep parameters and AD biomarkers related to axonal damage and neuroinflammation, such as NF-L and YKL-40. A lack of deep sleep was associated with higher levels of NF-L. This highlights a potential role for NF-L as a biomarker of sleep disruption in patients with mild-moderate AD in addition to its role in predicting neurodegeneration and cognitive decline

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Ecological assessment of mild cognitive impairment and Alzheimer disease using the Rivermead Behavioural Memory Test

Introduction: The Rivermead Behavioural Memory Test (RBMT) is a short, ecologically valid memory test battery that can provide data about a subject's memory function in daily life. We used RBMT to examine daily memory function in patients with mild cognitive impairment (MCI), Alzheimer disease (AD), and in healthy controls. We also evaluated differences between the memory profiles of subjects whose MCI remained stable after 1 year and those with conversion to AD. Patients and methods: Sample of 91 subjects older than 60 years: 30 controls, 27 MCI subjects and 34 AD patients. Subjects were assessed using MMSE and RBMT. Results: The 40 men and 51 women in the sample had a mean age of 74.29 ± 6.71 and 5.87 ± 2.93 years of education. For the total profile, screening RBMT scores (P < .001) and total MMSE scores (P < .05), control subjects scored significantly higher than those with MCI, who in turn scored higher than AD patients. In all subtests, the control group (P < .001) and MCI group (P < .05) were distinguishable from the AD group. Prospective, retrospective, and orientation subtests found differences between the MCI and control groups (P < .05). MCI subjects who progressed to AD scored lower at baseline on the total RBMT and MMSE, and on name recall, belongings recall, story immediate recall, route delayed recall, orientation (P < .05), face recognition, story delayed recall, and messages delayed recall sections (P < .01). Conclusions: RBMT is an ecologically valid episodic memory test that can be used to differentiate between controls, MCI subjects, and AD subjects. It can also be used to detect patients with MCI who will experience progression to AD. Resumen: Objetivos: El Rivermead Behavioural Memory Test (RBMT) es una batería ecológica breve que permite predecir el funcionamiento mnésico del sujeto en la vida diaria. Evaluamos mediante el RBMT el funcionamiento mnésico en la vida diaria, de pacientes con deterioro cognitivo leve (DCL), enfermedad de Alzheimer (EA) y sujetos sanos, así como las diferencias entre perfiles mnésicos de los sujetos DCL estables al año y los que progresarán a EA. Pacientes y métodos: Muestra de 91 sujetos con 60 o más años, 30 controles, 27 DCL y 34 pacientes con EA. Se evalúa a los sujetos mediante MMSE y RBMT. Resultados: Cuarenta hombres y 51 mujeres, con edad y escolaridad media de 74,29 ± 6,71 y 5,87 ± 2,93 años, respectivamente. En las puntuaciones totales, perfil y global del RBMT (p < 0,001) y del MMSE (p < 0,05), los sujetos control puntúan significativamente más alto que los DCL y estos que los EA. En todos los subtest, los controles (p < 0,001) y DCL (p < 0,05) se diferencian de la EA. Subtest prospectivos, retrospectivos y de orientación diferencian al grupo control del DCL (p < 0,05). Los sujetos DCL que progresan a EA puntúan más bajo en la exploración inicial en las puntuaciones totales del RBMT, MMSE y en el recuerdo del nombre, objeto personal, recuerdo inmediato de la historia, recuerdo diferido del recorrido y orientación (p < 0,05), reconocimiento de dibujos, recuerdo diferido de la historia y del mensaje (p < 0,01). Conclusiones: RBMT es una prueba ecológica de memoria episódica útil para diferenciar entre sí sujetos controles/DCL/EA, que además permite detectar a los pacientes con DCL que progresan a EA. Keywords: Mild cognitive impairment, Dementia, Alzheimer disease, Neuropsychology, Rivermead, Ecologically valid tests, Palabras clave: Deterioro cognitivo leve, Demencia, Enfermedad de Alzheimer, Neuropsicología, Rivermead, Test ecológico

Evaluación ecológica en el deterioro cognitivo leve y enfermedad de Alzheimer mediante el Rivermead Behavioural Memory Test

Resumen: Objetivos: El Rivermead Behavioural Memory Test (RBMT) es una batería ecológica breve que permite predecir el funcionamiento mnésico del sujeto en la vida diaria. Evaluamos mediante el RBMT el funcionamiento mnésico en la vida diaria, de pacientes con deterioro cognitivo leve (DCL), enfermedad de Alzheimer (EA) y sujetos sanos, así como las diferencias entre perfiles mnésicos de los sujetos DCL estables al año y los que progresarán a EA. Pacientes y métodos: Muestra de 91 sujetos con 60 o más años, 30 controles, 27 DCL y 34 pacientes con EA. Se evalúa a los sujetos mediante MMSE y RBMT. Resultados: Cuarenta hombres y 51 mujeres, con edad y escolaridad media de 74,29 ± 6,71 y 5,87 ± 2,93 años, respectivamente. En las puntuaciones totales, perfil y global del RBMT (p < 0,001) y del MMSE (p < 0,05), los sujetos control puntúan significativamente más alto que los DCL y estos que los EA. En todos los subtest, los controles (p < 0,001) y DCL (p < 0,05) se diferencian de la EA. Subtest prospectivos, retrospectivos y de orientación diferencian al grupo control del DCL (p < 0,05). Los sujetos DCL que progresan a EA puntúan más bajo en la exploración inicial en las puntuaciones totales del RBMT, MMSE y en el recuerdo del nombre, objeto personal, recuerdo inmediato de la historia, recuerdo diferido del recorrido y orientación (p < 0,05), reconocimiento de dibujos, recuerdo diferido de la historia y del mensaje (p < 0,01). Conclusiones: RBMT es una prueba ecológica de memoria episódica útil para diferenciar entre sí sujetos controles/DCL/EA, que además permite detectar a los pacientes con DCL que progresan a EA. Abstract: Introduction: The Rivermead Behavioural Memory Test (RBMT) is a short, ecologically-valid memory test battery that can provide data about a subject's memory function in daily life. We used RBMT to examine daily memory function in patients with mild cognitive impairment (MCI), Alzheimer disease (AD), and in healthy controls. We also evaluated differences between the memory profiles of subjects whose MCI remained stable after 1 year and those with conversion to AD. Patients and methods: Sample of 91 subjects older than 60 years: 30 controls, 27 MCI subjects and 34 AD patients. Subjects were assessed using MMSE and RBMT. Results: The 40 men and 51 women in the sample had a mean age of 74.29 ± 6.71 and 5.87 ± 2.93 years of education. For the total profile and screening RBMT scores (P<.001) and total MMSE scores (P<.05), control subjects scored significantly higher than those with MCI, who in turn scored higher than AD patients. In all subtests, the control group (P<.001) and MCI group (P<.05) were distinguishable from the AD group. Prospective, retrospective, and orientation subtests found differences between the MCI and control groups (P<.05). MCI subjects who progressed to AD scored lower at baseline on the total RBMT and MMSE, and on name recall, belongings, story − immediate recall, route − delayed recall, orientation (P<.05), face recognition, story − delayed recall, and messages − delayed recall sections (P<.01). Conclusions: RBMT is an ecologically-valid episodic memory test that can be used to differentiate between controls, MCI subjects, and AD subjects. It can also be used to detect patients with MCI who will experience progression to AD. Palabras clave: Deterioro cognitivo leve, Demencia, Enfermedad de Alzheimer, Neuropsicología, Rivermead, Test ecológicos, Keywords: Mild cognitive impairment, Dementia, Alzheimer disease, Neuropsychology, Rivermead, Ecologically-valid test