The process of ovarian aging: it is not just about oocytes and granulosa cells.

Ovarian age is classically considered the main cause of female reproductive infertility. In women, the process proceeds as an ongoing decline in the primordial follicle stockpile and it is associated with reduced fertility in the mid-thirties, irregular menstruation from the mid-forties, cessation of fertility, and, eventually, menopause in the early fifties. Reproductive aging is historically associated with changes in oocyte quantity and quality. However, besides the oocyte, other cellular as well as environmental factors have been the focus of more recent investigations suggesting that ovarian decay is a complex and multifaceted process. Among these factors, we will consider mitochondria and oxidative stress as related to nutrition, changes in extracellular matrix molecules, and the associated ovarian stromal compartment where immune cells of both the native and adaptive systems seem to play an important role. Understanding such processes is crucial to design treatment strategies to  slow down ovarian aging and consequently prolong reproductive lifespan and, more to this, alleviaingt side effects of menopause on the musculoskeletal, cardiovascular, and nervous systems.

King's college progression rate at first clinical evaluation: A new measure of disease progression in amyotrophic lateral sclerosis.

BACKGROUND: To estimate King's college clinical stage progression rate (ΔKC) at first clinical evaluation in order to define its predictive and prognostic role on survival in a large cohort of Amyotrophic Lateral Sclerosis (ALS) patients. METHODS: The ΔKC was calculated with the following formula: 0 - KC clinical stage at first clinical evaluation/disease duration from onset to first evaluation, and each result was reported as absolute value. All the evaluations were performed in two cohorts: one from our tertiary centre for motor neuron disease and the other one from a pooled resource open-access ALS clinical trials (PRO-ACT) database. C-statistic was used to evaluate the model discrimination of survival at different time points (1-3 years). Cox proportional hazard model was used to identify factors associated with survival. RESULTS: ΔKC predicted survival at three years in our centre and in the PRO-ACT cohort (C-statistic 0.83, 95% CI 0.8-0.86, p < 0.0001; 0.7, 95% CI 0.68-0.73, p < 0.0001, respectively). At multivariate analysis, ΔKC was independently associated with survival both in our cohort (HR 3.62 95% CI 2.71-4.83 p = 0.001) and in the PRO-ACT cohort (HR 2.75 95% CI 2.1-3.6 p = 0.001). CONCLUSIONS: Based on our results, ΔKC could be used as a novel measure of disease progression, hence as an accurate predictor of survival in ALS patients. Indeed, greater values of ΔKC were associated with a 3.5-fold higher risk to experience the event, confirming its robust prognostic value.

Guillain-Barré syndrome after AstraZeneca COVID-19-vaccination: A causal or casual association?

We report a case of Guillain-Barré syndrome (GBS) following the first dose of Oxford/AstraZeneca COVID-19 vaccine with papilledema as atypical onset. As the COVID-19 vaccination campaign progresses worldwide, GBSs vaccine-related have been increasingly reported. After reviewing the available literature, considering the annual incidence of GBS, in this historical moment, the public health systems cannot afford an unjustified distrust in vaccines, caused by misinterpretation of epidemiological data. Nonetheless, it is important for clinicians to promptly recognize neurological complications potentially associated with COVID-19 vaccinations and report them to pharmacovigilance agencies.

Cerebrospinal Fluid and Clinical Profiles in Adult Type 2-3 Spinal Muscular Atrophy Patients Treated with Nusinersen: An 18-Month Single-Centre Experience.

BACKGROUND AND OBJECTIVES: Nusinersen was approved as the first disease-modifying therapy in spinal muscular atrophy (SMA). Our aim was to analyse therapy-related changes in cerebrospinal fluid (CSF) and serum parameters of adult type 2-3 SMA and to correlate biochemical data with motor functional status. METHODS: Nine adult SMA type 2-3 patients and ten control subjects without neurodegenerative diseases were included in our single-centre study. Cross-sectional analysis of CSF routine parameters, CSF neurofilament light chain, CSF Tau, CSF phospho-Tau and serum creatinine was performed between SMA patients at baseline (T0) and control subjects. The above-mentioned fluid parameters were longitudinally analysed in the SMA cohort after loading dose (T1) and after four maintenance doses (T2, T3, T4, T5). Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and the 6-minute walking test (6MWT) were used to evaluate motor outcomes. RESULTS: Improvements in HFMSE, RULM and 6MWT were observed only after the loading dose of nusinersen. No significant differences in routine CSF parameters and CSF markers of neurodegeneration were found between SMA patients and control subjects. Serum creatinine levels were significantly lower in SMA patients than in control subjects. CSF/serum albumin ratio (Qalb) significantly increased from T0 to each time point, without any further increase after the maintenance doses. Persistent systemic oligoclonal bands (OCBs) were found in five patients from baseline. Three more patients developed persistent systemic OCBs from T1; one patient showed intrathecal OCBSs from baseline to T5. Markers of neurodegeneration did not change during the follow-up and did not correlate with motor scores at baseline and at each timepoint. Serum creatinine levels significantly correlated with HFMSE and RULM at each time point. CONCLUSIONS: The increase of the Qalb values and the development of systemic OCBs in some SMA patients could be due to repeated lumbar puncture and to the immunogenic effect of nusinersen. On the other hand, the presence of OCBs in serum and/or CSF at baseline should be further investigated. Furthermore, biomarkers of neurodegeneration did not play a prognostic role in our cohort of adult SMA patients.

Is cerebrospinal fluid amyloid-ß42 a promising biomarker of response to nusinersen in adult spinal muscular atrophy patients?

INTRODUCTION: Nusinersen was approved as the first treatment for all types of spinal muscular atrophy (SMA), including adults with SMA types 2 and 3. Robust biomarkers of treatment response in SMA adults are lacking. Our aim was to examine cerebrospinal fluid (CSF) amyloid-ß40 (Aß40) and amyloid-ß42 (Aß42) peptides as biomarkers of treatment response. METHODS: Eight patients with SMA types 2 and 3 were recruited consecutively in a single-center study. CSF was sampled at baseline, after a loading dose, and after three maintenance doses. Levels of Aß42 and Aß40 were evaluated for each CSF sampling. Wilcoxon matched-pairs signed-rank test was used to detect longitudinal changes. RESULTS: CSF levels of Aß42 increased from baseline to day 420 (95% confidence interval, P = .018), with a significant increase at days 180 and 420 compared with days 0 and 300, respectively (95% confidence interval, P = .012 and P = .018). DISCUSSION: The maintenance and promotion of wellness of residual motor neurons mediated by the restored level of SMN protein due to nusinersen could result in an increased level of amyloid peptides.