Understanding and Treating Neurological Conditions

In this issue, we delve into the exciting advancements in medical care for neurological diseases, focusing on cutting-edge research in biomarkers, genetics, and imaging. Our goal is to keep clinical scientists and clinicians abreast of these pivotal developments that are shaping the future of neurology.

Recent studies have spotlighted the role of biomarkers in early diagnosis and progression monitoring of neurological disorders. For instance, a breakthrough discovery in Alzheimer's disease research has identified specific protein levels in blood plasma that correlate with disease onset, offering a non-invasive diagnostic tool.

Genetic research continues to unveil the complexities of neurological diseases, paving the way for personalised medicine. A recent genetic study has identified new mutations linked to Parkinson's disease, providing insights into its pathogenesis and potential therapeutic targets.

Advancements in imaging technology are revolutionising our understanding and treatment of neurological conditions. The advent of high-resolution MRI has significantly improved the detection and characterisation of brain lesions in multiple sclerosis. This development not only aids in early diagnosis but also enhances treatment precision.

We invite you to explore a few selected key articles in depth to stay informed about these groundbreaking advancements. Click on the links provided to access the full articles and enhance your understanding of these critical topics in neurology.

Recent key publications

1) Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family. Neurol Sci 2024; Trinchillo A, Valente V, Esposito M et al. Link to full article

The authors explored a four-generation Italian family, revealing the complexity of SPG18. Researchers identified the common ERLIN2 gene mutation (p.V168M), linking it to a spectrum of conditions ranging from amyotrophic lateral sclerosis (ALS) to pure and complicated hereditary spastic paraplegia (HSP) with psychomotor delay and epilepsy. This groundbreaking study challenges previous notions about the relationship between inheritance patterns and phenotypes, underscoring the multifaceted nature of SPG18.

2) A method for the analysis of the oligomerization profile of the Huntington's disease-associated, aggregation-prone mutant huntingtin protein by isopycnic ultracentrifugation. Front Mol Biosci 2024; 11:1420691. Bonavita R, Di Martino R, Cortone G et al. Link to full article

A novel method utilising isopycnic ultracentrifugation has been developed to analyse the oligomerisation profiles of the Huntington's disease-associated mutant huntingtin protein. This cutting-edge technique allows researchers to characterise large and heterogeneous huntingtin (HTT) complexes, providing new insights into the molecular determinants responsible for HTT aggregation. The method demonstrated that mutant HTT tends to form high molecular weight oligomers compared to its wild-type counterpart. This ultracentrifugation-based approach is not only sensitive and versatile but also suitable for examining the effects of small molecules and bioactive compounds designed to inhibit HTT aggregation. Additionally, it offers potential applications in proteomics, interaction studies, and disease profiling. This innovative protocol opens new avenues for developing targeted therapeutic strategies for Huntington's disease.

3) The association between posterior resting-state EEG alpha rhythms and functional MRI connectivity in older adults with subjective memory complaint. Neurobiol Aging 2024; 137:62-77. Lopez S, Hampel H, Chiesa PA et al. Link to full article

A study in the journal "Neurobiology of Aging" explores the relationship between posterior resting-state EEG alpha rhythms and functional MRI connectivity in older adults with subjective memory complaints (SMC). Researchers analysed 161 SMC participants, focusing on the interaction between brain amyloid burden and cognitive reserve (CR), measured by educational attainment. They found that participants with low amyloid burden and high CR showed a positive association between thalamic and visual cortical network connectivity and posterior alpha rhythms. This suggests that early Alzheimer's amyloidosis may hinder the beneficial effects of CR on neurophysiological mechanisms.

4) Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease. Nat Rev Neurol 2024; 20:426-439. Schindler SE, Galasko D, Pereira AC et al. Link to full article

A consensus statement from the Global CEO Initiative on Alzheimer’s Disease (CEOi) addresses the pressing need for accurate blood biomarker (BBM) tests to diagnose amyloid pathology, which is crucial for the early treatment of Alzheimer's disease (AD). With the recent approval of anti-amyloid treatments such as aducanumab and lecanemab, biomarker testing has become indispensable. Traditional methods like amyloid PET and cerebrospinal fluid (CSF) tests are effective but less accessible and scalable.

The CEOi BBM Workgroup has set forth recommendations for the minimum acceptable performance of BBM tests. For triaging purposes in primary care, BBM tests should have a sensitivity of at least 90% and a specificity of at least 85%. In secondary care settings, where follow-up testing capacity may be higher, a specificity range of 75-85% is acceptable. For use as a confirmatory test without the need for follow-up, BBM tests should match the performance of CSF tests, with approximately 90% sensitivity and specificity. These standards aim to ensure that BBM tests can accurately identify individuals with amyloid pathology, enabling timely and appropriate treatment interventions. This initiative underscores the potential of BBM tests to significantly improve the diagnostic process for AD, making it more accessible and scalable, thus benefiting a larger patient population.

5) Tau, Glial Fibrillary Acidic Protein, and Neurofilament Light Chain as Brain Protein Biomarkers in Cerebrospinal Fluid and Blood for Diagnosis of Neurobiological Diseases. Int J Mol Sci 2024; 25. Park Y, Kc N, Paneque A, Cole PD. Link to full article

The International Journal of Molecular Sciences recently published a groundbreaking review on the role of Tau, Glial Fibrillary Acidic Protein (GFAP), and Neurofilament Light Chain (NfL) as biomarkers for neurobiological diseases. These biomarkers, detectable in cerebrospinal fluid (CSF) and blood, have shown promise in enhancing the diagnosis, monitoring, and prognosis of various neurological disorders. The study provides an in-depth analysis of how these brain protein biomarkers are released in response to neuron and astrocyte damage, and their proportional presence in CSF and blood can indicate the severity of conditions such as stroke, traumatic brain injury, multiple sclerosis, neurodegenerative dementia, and Parkinson’s disease. The detection of these biomarkers not only aids in early diagnosis but also helps in monitoring disease progression and evaluating treatment efficacy.

One of the key highlights of the review is the discussion on the biosensor approach, which allows for real-time detection of multiple biomarkers. This innovative technology could revolutionise the clinical tools available for diagnosing and managing neurodegenerative diseases, making it possible to identify the type and stage of these conditions with greater precision. This article provides essential insights and opens new avenues for enhancing patient care and outcomes. Clinicians and scientists are encouraged to read the full article to understand the detailed findings and explore the future directions in neurodegenerative disease diagnostics.

6) Mapping recurrent mosaic copy number variation in human neurons. Nat Commun 2024; 15:4220. Sun C, Kathuria K, Emery SB et al. Link to full article

A recent study in Nature Communications introduces SCOVAL, an innovative method to map recurrent mosaic copy number variations (CNVs) in human neurons. By analysing 2,125 frontal cortical neurons from a neurotypical brain, researchers identified 226 CNV neurons, including a subset with highly aberrant karyotypes. The study reveals a non-random distribution of CNVs, pinpointing specific genomic hotspots and cold spots. This research enhances our understanding of how somatic mutations in neurons contribute to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. The findings underscore the potential of SCOVAL in identifying critical genomic regions prone to rearrangement, offering new insights into neuronal genome dynamics. This approach could pave the way for targeted therapeutic strategies and further exploration of the genetic underpinnings of brain diseases.