Neurodegenerative diseases (NDDs), including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Huntington’s Disease (HD), share pathologic mechanisms including oxidative stress, mitochondrial dysfunction, and protein aggregation. However, they differ in age of onset and clinical progression. Emerging evidence highlights primary cilia (PC) as a key regulator of neuronal aging and the progression of these diseases. Dysfunctional PC may impair key signaling pathways, such as Sonic Hedgehog (Shh) and Wnt, promote oxidative stress, mitochondrial damage, and epigenetic instability. PC may also influence intercellular communication by regulating the biogenesis of exosomes and modulating tunneling nanotube (TNT) formation, both of which propagate toxic proteins between neurons. Mechanistically, the regulation of ciliary length is disrupted in AD, which leads to ciliary dysfunction that interferes with signaling pathways and promotes the aggregation of amyloid-beta. This amyloid-beta is then propagated through TNTs and exosomes, spreading neuronal damage. In PD, the accumulation of alpha-synuclein (α-syn) also impairs cilia function, thereby compromising the cell’s response to oxidative stress. This results in the formation of abnormal TNTs and defective exosome-mediated clearance, ultimately contributing to neurodegeneration. Similarly, the mutant huntingtin protein aggregates within primary cilia in HD, morphologically disrupting them by obstructing intraflagellar transport. Damaged cilia are also associated with increased TNT formation and the exosomal release of toxic proteins, which leads to mitochondrial and epigenetic instability, ultimately promoting neuronal aging. Together, targeting ciliary function and its downstream regulation of TNTs and exosomes may provide a novel approach for slowing or halting disease progression across neurodegenerative diseases.

Background: Large-diameter head total hip arthroplasty (LDH-THA) emerged in the late 1990s as a stemmed alternative to hip resurfacing arthroplasty (HRA). Both procedures use metal-on-metal (MoM) bearings to permit larger heads, lower dislocation risk, and optimize function in younger, active patients. While concerns over metal ion release and adverse local tissue reactions curtailed MoM use, long-term follow-up remains critical for the substantial population with these devices in situ. This review compares LDH-THA and HRA in clinical outcomes, metal ion levels, and revision rates to guide long-term management and future implant design. Methods: PubMed, Embase, and Scopus were searched for studies reporting patient-reported outcomes, metal ion levels, or revision rates for both LDH-THA and HRA. The risk of bias was assessed using the Methodological Index for Non-Randomized Studies score. Random-effects meta-analysis evaluated revision risk; cobalt and chromium levels; University of California, Los Angeles (UCLA) activity; Harris-Hip Scores (HHS); Oxford Hip Scores (OHS); and Western Ontario and McMaster Universities Osteoarthritis Index. Results: Of 221 studies, 21 met inclusion criteria, including 5,545 LDH-THAs and 3,197 HRAs. The unweighted pooled revision rate was 16% for THA and 7.8% for HRA. Meta-analysis showed higher cobalt (standardized mean difference [SMD] 1.07) and chromium (SMD 0.53) levels in THA. Revision risk (odds ratio 1.75), UCLA (−0.44), and HHS (−0.32) favored HRA, though not significantly. Conclusion: Although the usage of large-head MoM THA is largely historic, our findings suggest that MoM hip resurfacing arthroplasty has a more favorable outcomes profile with reduced systemic metal ion exposure, reinforcing its role in younger, active patients, where conventional or large-head THA may fall short. Level of Evidence: Level III , systematic review of Level I, II, and III studies. See Instructions for Authors for a complete description of levels of evidence.