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

Implante de tubo de silicone com e sem colágeno na regeneração de nervos em eqüinos Implant of silicone tube with or without collagen in nerve regeneration of horses

A reconstituição cirúrgica de nervos em humanos, em cães e em diversos animais de laboratório é bastante utilizada e tem indicações clínicas e experimentais importantes. No entanto, em eqüinos há poucas informações sobre esta prática. Há relatos sobre a excessiva proliferação de tecido conjuntivo e a formação de neuromas à neurorrafia experimental, mesmo quando se utilizam tubos de silicone para condução do crescimento axonal. O presente estudo teve o objetivo de acrescentar informações sobre o processo de reparação de nervos periféricos em eqüinos por meio de implante de tubo de silicone preenchido ou não com colágeno. Para tanto, foram utilizados oito eqüinos, alocados em dois grupos: GI-13 semanas e GII-26 semanas de observação. Foi realizada secção dos nervos ulnares (NUs) e dos ramos cutâneos laterais dos 17&deg; nervos torácicos (NTs), bilateralmente, seguindo tubulização, realizada em cada animal, alternando-se tubos de silicone vazios (TS), em um dos antímeros, ou preenchidos com solução de colágeno (TSC), no contralateral, deixando-se um espaço de 5mm entre os cotos. Nenhuma alteração foi encontrada ao exame do aparelho locomotor e as primeiras reações positivas ao teste de sensibilidade cutânea nos NUs e NTs com TS e TSC foram observadas a partir da 9&ordf; semana, em ambos os grupos. Ao final do período de observação, verificou-se, macroscopicamente, que os nervos encontravam-se envolvidos por tecido conjuntivo e o interior da câmara estava preenchido por tecido de coloração esbranquiçada, de forma cilíndrica, interligando os cotos proximal e distal. Microscopicamente, constatou-se a presença de axônios mielinizados interligando os cotos, as células de Schwann e o processo de remielinização do coto distal, principalmente no TSC. Em ambos os grupos, não houve formação de neuromas e o processo inflamatório limitou-se às áreas perineurais. Concluiu-se que o implante de tubo de silicone conduz à regeneração de NUs e NTs de eqüinos sem formação de neuromas e que a adição de colágeno promove aumento do número de fibras mielinizadas.<br>Surgical nerve repair in humans, dogs and laboratory animals is widely utilized for important clinical and experimental purposes. However, in horses there is scarce information. Neuroma and excessive conjunctive proliferation are reported. The aim of the present study was to add information about the repair process utilizing implant of silicone tubes with or without collagen in nerve regeneration of horses. Eight horses were allocated in two groups: GI-13 weeks and GII-26 weeks of observation. A complete section of the ulnar nerves (UNs) and of the lateral cutaneous branch of the 17th thoracic nerves (TNs), bilaterally, was followed by repair with silicone tubes alternately filled with (STC) or without collagen (ST), with a 5mm gap between stumps. Clinical evaluation was performed weekly, by cutaneous sensitivity testing of the region innervated by the respective operated nerves and physical examination of the thoracic limbs. No alterations were found in the locomotor apparatus. The first positive reactions to the cutaneous test occurred at the 9th week post-surgery. At the end of the observation period it was verified, grossly, that the nerves were involved by conjunctive tissue and the lumen of the tube was filled by a whitish tissue, in a cylindrical shape. The ends nerves were interconnected. Microscopically, myelinated axons and Schwann cells were present in the gap between the stumps. In the GII the number of myelinated fibers was greater. The distal nerve showed remyelination process. There was no presence of neuroma and the inflammatory process was limited to the perineural areas. It was concluded that the implant of silicone tubes results in regeneration of UNs and TNs of horses without formation of neuromas and that de addition of collagen promotes an increase in the number of myelinated fibers

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. © 2022, The Author(s)