Lancet neurology
-
A growing need exists for reliable in-vivo measurement of neuroinflammation to better characterise the inflammatory processes underlying various diseases and to inform the development of novel therapeutics that target deleterious glial activity. PET is well suited to quantify neuroinflammation and has the potential to discriminate components of the neuroimmune response. However, there are several obstacles to the reliable quantification of neuroinflammation by PET imaging. ⋯ Tissue studies have also begun to clarify the meaning of changes in PET signal in some diseases. Furthermore, although PET imaging of neuroinflammation does not have an established clinical application, novel targets are under investigation and a small but growing number of studies have suggested that this imaging modality could have a role in drug development. Future studies are needed to further improve our knowledge of the cellular mechanisms that underlie changes in PET signal, how immune response contributes to neurological disease, and how it might be therapeutically modified.
-
Review Case Reports
Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias.
Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and 18F-fluorodeoxyglucose (18F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. ⋯ We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and 18F-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.
-
Multicenter Study
Monogenic variants in dystonia: an exome-wide sequencing study.
Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. ⋯ Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.
-
Prominent clinical symptoms of COVID-19 include CNS manifestations. However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, gains access to the CNS and whether it causes neuropathological changes. We investigated the brain tissue of patients who died from COVID-19 for glial responses, inflammatory changes, and the presence of SARS-CoV-2 in the CNS. ⋯ German Research Foundation, Federal State of Hamburg, EU (eRARE), German Center for Infection Research (DZIF).
-
Huntington's disease is a fatal neurodegenerative disorder that is caused by CAG-CAA repeat expansion, encoding polyglutamine, in the huntingtin (HTT) gene. Current age-of-clinical-onset prediction models for Huntington's disease are based on polyglutamine length and explain only a proportion of the variability in age of onset observed between patients. These length-based assays do not interrogate the underlying genetic variation, because known genetic variants in this region do not alter the protein coding sequence. Given that individuals with identical repeat lengths can present with Huntington's disease decades apart, the search for genetic modifiers of clinical age of onset has become an active area of research. ⋯ Results from three independent genetic studies of Huntington's disease have shown that glutamine-encoding CAA variants that interrupt DNA CAG repeat tracts, but do not alter polyglutamine length or polyglutamine homogeneity, are associated with substantial differences in age of onset of Huntington's disease in carriers. A variant that results in the loss of CAA interruption is associated with early onset and is particularly relevant to individuals that carry alleles in the reduced penetrance range (ie, CAG 36-39). Approximately a third of clinically manifesting carriers of reduced penetrance alleles, defined by current diagnostics, carry this variant. Somatic repeat instability, modified by interrupted CAG tracts, is the most probable cause mediating this effect. This relationship is supported by genome-wide screens for disease modifiers, which have revealed the importance of DNA-repair genes in Huntington's disease (ie, FAN1, LIG1, MLH1, MSH3, PMS1, and PMS2). WHERE NEXT?: Focus needs to be placed on refining our understanding of the effect of the loss-of-interruption and duplication-of-interruption variants and other interrupting sequence variants on age of onset, and assessing their effect in disease-relevant brain tissues, as well as in diverse population groups, such as individuals from Africa and Asia. Diagnostic tests should be augmented or updated, since current tests do not assess the underlying DNA sequence variation, especially when assessing individuals that carry alleles in the reduced penetrance range. Future studies should explore somatic repeat instability and DNA repair as new therapeutic targets to modify age of onset in Huntington's disease and in other repeat-mediated disorders. Disease-modifying therapies could potentially be developed by therapeutically targeting these processes. Promising approaches include therapeutically targeting the expanded repeat or directly perturbing key DNA-repair genes (eg, with antisense oligonucleotides or small molecules). Targeting the CAG repeat directly with naphthyridine-azaquinolone, a compound that induces contractions, and altering the expression of MSH3, represent two viable therapeutic strategies. However, as a first step, the capability of such novel therapeutic approaches to delay clinical onset in animal models should be assessed.