Introduction: Many studies demonstrate positive associations between infections and Alzheimer disease (AD), suggesting that brain and/or systemic inflammation may impact AD pathogenesis. However, studies of meningitis and AD risk have been limited to animal models or small human cohorts in the USA. The objective of this study was to examine the relationship between incident AD and three different types of infections (meningitis, pneumonia, and urinary tract infections [UTIs]) using a population-based sample of US Medicare beneficiaries. Methods: We created a case-control dataset by frequency matching 4:1 (control:case) by age group, sex, and month/year of the date of AD diagnosis or control selection date. We identified 52,628 newly diagnosed AD cases and 210,512 population-based controls ≥67 years of age using comprehensive Medicare claims data from 2016 to 2018. We classified infections using ICD-9-CM and ICD-10-CM diagnosis codes. We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between AD and each infection separately. We lagged exposures up to 18 months and examined hospitalization or comorbid sepsis as a proxy for infection severity. Covariates included age, sex, race/ethnicity, and health care utilization. Results: AD was positively associated with meningitis in individuals hospitalized without superimposed sepsis with a 6-month lag (OR = 2.713, 95% CI: 1.277–5.764), and UTIs without superimposed sepsis with an 18-month lag (OR = 1.231, 95% CI: 1.101–1.376), and with superimposed sepsis with an 18-month lag (OR = 1.388, 95% CI: 1.050–1.835). There was no association between AD and pneumonia in individuals hospitalized with or without superimposed sepsis. When examining infections that occurred in the outpatient setting, the association between AD and UTI remained positive yet attenuated at all time points, however, the association became inverse between AD and pneumonia. Conclusion: More severe infections, particularly meningitis, may be associated with a higher risk of AD, due to either unmasking of prodromal AD or acceleration of AD pathogenesis in susceptible individuals.

Background: Alzheimer’s disease (AD), the most common cause of dementia, affects twice as many women as men. Moreover, sex is increasingly recognised as an important factor for AD, influencing symptom presentation, progression, disease biology, and treatment responses. In parallel, AD biomarkers are becoming more accessible with the discovery of specific and accurate blood-based biomarkers and their incorporation in AD diagnostic frameworks. This narrative review aimed to summarise sex differences in the concentration and interpretation of biofluid biomarkers for AD. Summary: Biological sex may influence both the concentration and interpretation of biofluid biomarkers for AD pathology such as amyloid-β aggregation, tau neurofibrillary tangles, neurodegeneration, or neuroinflammation. While some biofluid biomarkers display consistent sex differences in absolute levels, most biomarker levels have not been found to differ consistently by sex. Nonetheless, even biomarkers that do not differ in absolute levels display sex-specific associations with clinically relevant variables such as brain atrophy, cognitive impairment, and disease progression. Key Message: Sex may influence the interpretation of AD biomarkers depending on their context of use, and more research is required to develop sex-specific guidelines. Future research should aim to study sex differences and sex-specific associations with variables of interest, as well as the underlying factors driving sex differences in AD.

Background: Parkinson’s disease (PD), although widely heterogeneous and manifesting with numerous motor and non-motor symptoms, presents clinically as a single entity worldwide. Its genetic causes are also heterogeneous and include highly penetrant variants in a single gene representing rare monogenic forms, and rare or common variants conferring a relative disease risk representing more frequent multigenic forms. Most of these variants have been discovered in patients of European ancestry. Since the genetic basis of PD can vary significantly between populations due to differences in allele frequencies, little is known about the genetics of PD in other populations, particularly from Africa. Morocco, located in a region of North Africa, constitutes a subcontinent known for a weak external genetic influence and for a local genetic continuity for millennia, which makes it a region of interest to study the genetic causes of PD. Summary: This review aimed to summarize published research data on the genetic profile of PD patients from the Moroccan population to describe its genetic architecture. Unlike in Western countries, PD in Morocco is predominantly a Mendelian disease reaching up to 50%, due to the high prevalence of the LRRK2 G2019S dominant variant and to relatively less frequent PRKN and PINK1 recessive variants due to the high rate of consanguinity. Additionally, rare high-risk variants in LRRK2, VPS13C, MAPT, and POLG, in oligo- or polygenic ways, may contribute to increasing the genetic risk of the disease. Key Messages: We, therefore, show that the genetic architecture of PD in Morocco, a country in the subcontinent of North Africa, was different from that of sub-Saharan Africa and the rest of the world. This will help improve diagnostic accuracy, subdivide the clinical variability of the disease into groups of common genetic and biological causes for a better therapeutic management strategy, and test molecules from ongoing clinical trials.

Introduction: Neuromuscular ultrasound has been increasingly used in the detection and diagnosis of amyotrophic lateral sclerosis (ALS), commonly characterized by peripheral nerve atrophy, degeneration, and muscle fasciculations. The aim of this study was to assess the ultrasound characteristics of ALS patients. Methods: A total of 67 consecutive patients with sporadic ALS and 19 with ALS mimics (63.16% peripheral neuropathy) were recruited. Ultrasound and electrophysiological examinations were performed; the peripheral nerve cross-sectional area (CSA) and fasciculation grades were compared between the groups, and correlations between ultrasound and electrophysiological data in ALS patients were determined. Results: ALS patients had smaller proximal median and ulnar nerve CSAs than those of ALS mimics, who exhibited asymmetric changes. Fasciculation differences in the trapezius, triceps brachii, extensor digitorum communis, thenar, and first dorsal interosseous muscles were observed. In ALS patients, the CSA and fasciculation relative scores were correlated with electrophysiological indicators. Conclusion: Ultrasound is a valuable tool for monitoring peripheral nerve CSA and muscle fasciculations, both of which correlate with electrophysiological indices, in ALS patients.

Background: The glymphatic system is a waste clearance system that facilitates the efficient removal of interstitial solutes, including neurotoxic substances such as β-amyloid, from the central nervous system. Numerous studies have highlighted its pivotal role in the pathophysiology of neurodegenerative diseases and cerebrospinal fluid (CSF) disorders. A comprehensive understanding and accurate evaluation of the glymphatic system are of significant clinical importance. Furthermore, emerging evidence suggests that modulating glymphatic activity holds therapeutic potential, including enhancing drug delivery across the brain. Summary: This review consolidates current insights into the glymphatic system, addressing areas of consensus as well as ongoing controversies. The relationship between glymphatic dysfunction and CSF disorders is discussed, alongside advancements in evaluation methodologies. Additionally, therapeutic applications of glymphatic modulation are summarized, particularly its role in optimizing drug distribution within the brain. Key Messages: This review provides a comprehensive overview of the current knowledge on the glymphatic system and highlights imaging techniques used to assess human glymphatic function, including magnetic resonance imaging (MRI) with contrast agents, diffusion tensor imaging, and emerging techniques such as MRI with 17O-labeled water. Furthermore, the therapeutic implications of glymphatic modulation are discussed, and directions for future research are proposed.

Background: In respect to the circulatory system, the central nervous system (CNS) differs from other organs in the body by three main features. First, the CNS is surrounded by a compartment filled with cerebrospinal fluid (CSF). Second, the CNS is devoid of lymphatic vessels, which are found in the dura mater of the meninges. Third, the CNS blood vasculature serves as a scaffold to perivascular spaces allowing CSF to circulate into the CNS parenchyma via the glymphatic system. Summary: This review highlights the contribution of the glymphatic system and meningeal lymphatic vasculature to CNS homeostasis and also recapitulates the alterations of glymphatic-meningeal lymphatic systems that have been associated to neurological disorders, especially neurodegenerative diseases. Key Message: We discuss the controversies and limitations in current research, emphasizing the need for cautious interpretation while highlighting the potential of glymphatic and meningeal lymphatic pathways as therapeutic targets in neurological disorders.