Background: Tirzepatide (TZP), the first approved dual glucagon‐like peptide 1 (GLP‐1)/glucose‐dependent insulinotropic polypeptide (GIP) agonist, has shown neuroprotective effects in preclinical models and early observational studies. This review maps and appraises current preclinical and clinical evidence on TZP's potential neuroprotective effects in neurodegenerative diseases (Alzheimer's and Parkinson's disease), neuroinflammation, cerebrovascular outcomes, neurovestibular disorders, brain tumor response, and idiopathic intracranial hypertension. Methods: PubMed, Scopus, Web of Science, Embase, and Elton B. Stephens Company (EBSCO) were searched through September 30, 2025. Eligible sources included original preclinical or clinical studies reporting neurological or neuroprotective effects of TZP. Quality was assessed using SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) and Collaborative Approach to Meta‐Analysis and Review of Animal Data from Experimental Studies (CAMARADE) for in vivo studies, toxicological data reliability assessment tool (ToxRTool) for in vitro, Newcastle‐Ottawa scale (NOS) for cohorts, and Joanna Briggs Institute (JBI) for case reports. Results: Twenty‐two studies met inclusion criteria as follows: 11 preclinical investigations, 3 retrospective cohorts, and 8 case reports. Preclinical studies demonstrated mitochondrial stabilization (adenosine triphosphate [ATP] restoration; PINK1/Parkin), anti‐oxidative and anti‐inflammatory signaling, synaptic support (PSD‐95/synaptophysin), and blood–brain barrier reinforcement (claudin‐1), alongside behavioral improvements. Retrospective cohorts reported reduced cerebrovascular and neurodegenerative disease incidence, papilledema, and headaches, though one cohort identified higher risk of central vertigo and vestibular neuronitis. Case reports documented compression neuropathies, autoimmune encephalitis, hypoglycemia‐related seizures, psychiatric reactions, and rhabdomyolysis, most resolving with dose adjustment or discontinuation. Risk‐of‐bias appraisal revealed frequent “unclear” ratings in animal studies, “reliable with restrictions” in vitro, and high NOS scores for cohorts. Conclusions: TZP exhibits biologically plausible neuroprotective mechanisms preclinically. Prospective trials with standardized neurological endpoints, active‐comparator designs, and structured safety monitoring are warranted.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits in type 2 diabetes mellitus (T2DM); however, their association with post-stroke outcomes following acute ischemic stroke (AIS) remains uncertain. Methods: We conducted a retrospective propensity score-matched (PSM) cohort study using the TriNetX Global Collaborative Network. Adults with T2DM and AIS between January 2020 and January 2025 were included. Pre-stroke GLP-1 RA users were compared with non-users. Primary outcomes were all-cause mortality, intracerebral hemorrhage (ICH), ICD-10-coded stroke severity (NIHSS categories), and transient ischemic attack (TIA). Results: After PSM, GLP-1 RA use was associated with significantly lower all-cause mortality at all time points (RR 0.44–0.52; HR 0.43–0.45; all p<0.001). ICH risk was reduced within 1–3 days (RR 0.683; 95% CI 0.496–0.940; p=0.019) and within 7 days (RR 0.575; 95% CI 0.516–0.641; p20; RR 0.327; all p<0.001). TIA risk was 29% lower (RR 0.712; 95% CI 0.668–0.759; p<0.001). E-value analysis demonstrated that an unmeasured confounder would need to be associated with both GLP-1 RA use and 30-day mortality by a risk ratio of at least 3.95 to fully explain the observed association, and by a risk ratio of at least 3.53 to shift the confidence interval to include the null. Conclusions: In this large real-world cohort, pre-stroke GLP-1 RA use was associated with lower post-stroke mortality, reduced ICH, and a severity-dependent reduction in ICD-10-coded stroke severity among patients with T2DM. Residual confounding cannot be excluded, and these findings warrant confirmation in prospective randomized trials.

Background: Parkinson’s disease (PD) is clinically heterogeneous, yet the genetic architecture underlying this heterogeneity remains incompletely understood. We examined the genetic correlates of four complementary PD subtyping frameworks: the clinical motor subtype (tremor-dominant [TD] vs. postural instability/gait difficulty [PIGD]), alpha-synuclein seed amplification assay status (SAA+ vs. SAA−), the pathological subtype (brain-first vs. body-first, based on the presence of REM sleep behavior disorder), and the data-driven subtype (diffuse malignant [DM] vs. mild-motor predominant [MMP] vs. intermediate [IM]). Methods: We analyzed 1390 PD patients from the Parkinson’s Progression Markers Initiative (PPMI) with genotypes available for seven PD-associated genes (LRRK2, GBA1, SNCA, PRKN, PINK1, PARK7, VPS35), including specific variant resolutions (LRRK2 G2019S, R1441G/C/H; GBA1 N409S, severe variants; SNCAA53T), and APOE (ε2/ε3/ε4 alleles). Genetic variant frequencies were compared across subtypes using chi-square or Fisher’s exact tests with the Benjamini–Hochberg false discovery rate (FDR) correction. Effect sizes were quantified using Cramér’s V. multivariable logistic regression estimated adjusted odds ratios with Wald-based 95% confidence intervals. Results: Among genotyped PD patients, LRRK2 carriers constituted 13.7% (190/1390; 170 G2019S, 18 R1441G/C/H), GBA1 8.6% (119/1390; 96 N409S, 23 severe), and SNCA 2.0% (28/1390; all A53T). APOE ε4 carriers comprised 23.4% (323/1380). SAA-negative patients were markedly enriched for LRRK2 variants (37.1% vs. 10.2%, p = 3.7 × 10⁻¹⁹, q < 0.001, V = 0.25), specifically G2019S (28.5% vs. 9.6%, p = 4.9 × 10⁻¹¹, q < 0.001) and R1441G/C/H (7.9% vs. 0.5%, p = 2.7 × 10⁻¹², q < 0.001). Body-first PD was enriched for GBA1 carriers (12.3% vs. 6.7%, p = 0.004, q = 0.021) and had less LRRK2 carriers (7.9% vs. 15.0%, p = 0.002, q = 0.013). The DM subtype had the highest GBA1 frequency (14.0% vs. MMP 5.9%, p < 0.001, q = 0.003). After FDR correction, 10 out of 48 univariate tests remained significant. Clinical subtypes (TD vs. PIGD) showed only nominal LRRK2 differences that did not survive FDR correction. The APOE genotype did not differ across any framework. Conclusions: PD subtypes defined by alpha-synuclein pathology (SAA), pathological onset pattern (brain-first/body-first), and data-driven classification (DM/MMP/IM) show distinct genetic profiles that survive multiple comparison correction. LRRK2 variants strongly associate with SAA negativity (V = 0.25); GBA1 variants associate with the severe body-first onset and the diffuse malignant subtype.

Purpose: Pilates-based exercise has gained attention as a non-pharmacological rehabilitation strategy for people with multiple sclerosis (MS), yet the comparative effectiveness of different Pilates modalities remains uncertain. This systematic review and network meta-analysis evaluated and ranked Pilates-based interventions for functional mobility, balance, walking performance, fatigue, and health-related quality of life in adults with MS. Methods: PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched from inception to October 24, 2025. Eligible studies were randomized controlled trials of structured Pilates-based interventions lasting at least four weeks in adults with MS. The primary outcome was functional mobility measured by the Timed Up and Go test. Secondary outcomes included balance, walking endurance, fatigue, walking performance, and MS-specific quality of life. A frequentist random-effects network meta-analysis was performed; treatment ranking was summarized using SUCRA, risk of bias using RoB 2, and certainty of evidence using GRADE-NMA through CINeMA. Results: Twenty-two randomized controlled trials involving 901 participants were included. Pilates ranked first for functional mobility and significantly improved Timed Up and Go performance versus control (MD: -5.23 s; 95% CI: -6.39 to -4.06). It also ranked first for balance, with a mean improvement of 8.58 points on the Berg Balance Scale (95% CI: 7.86 to 9.30). Pilates combined with Pilates-based telerehabilitation ranked highest for the 6-Minute Walk Test (MD: 50.81 m; 95% CI: 0.16 to 101.46) and significantly improved Fatigue Severity Scale scores. Home-based Pilates showed the largest reduction in Modified Fatigue Impact Scale scores. No comparison reached high certainty under GRADE-NMA. Conclusion: Pilates-based interventions may improve mobility, balance, walking endurance, fatigue, and quality of life in people with MS. Sparse networks, risk of bias, heterogeneity, imprecision, and limited follow-up warrant cautious interpretation. Adequately powered trials with standardized protocols are needed before routine implementation can be recommended.

Background: Parkinson’s disease (PD) is clinically heterogeneous, yet the genetic architecture underlying this heterogeneity remains incompletely understood. We examined the genetic correlates of four complementary PD subtyping frameworks: clinical motor subtype (tremor-dominant [TD] vs. postural instability/gait difficulty [PIGD]), alpha-synuclein seed amplification assay status (SAA+ vs. SAA−), pathological subtype (brain-first vs. body-first, based on REM sleep behavior disorder), and data-driven subtype (diffuse malignant [DM] vs. mild-motor predominant [MMP] vs. intermediate [IM]). Methods: We analyzed 1,597 PD patients from the Parkinson’s Progression Markers Initiative (PPMI) with genetic testing for seven PD-associated genes (LRRK2, GBA, SNCA, PRKN, PINK1, PARK7, VPS35), including specific variant resolution (LRRK2 G2019S, R1441G/C/H; GBA N409S, severe variants; SNCA A53T), and APOE genotyping (ε2/ε3/ε4 alleles). Genetic variant frequencies were compared across subtypes using chi-square or Fisher’s exact tests with Benjamini–Hochberg false discovery rate (FDR) correction. Effect sizes were quantified using Cramér’s V. Multivariable logistic regression (statsmodels) estimated adjusted odds ratios with Wald-based 95% confidence intervals. Results: Among 1,390 genotyped PD patients, LRRK2 carriers constituted 13.7% (190/1,390; 170 G2019S, 18 R1441G/C/H), GBA 8.6% (119/1,390; 96 N409S, 23 severe), and SNCA 2.0% (28/1,390; all A53T). APOE ε4 carriers comprised 23.4% (323/1,380). SAA-negative patients were markedly enriched for LRRK2 variants (37.1% vs. 10.2%, P = 3.7 × 10⁻¹⁹, q < 0.001, V = 0.25), driven by G2019S (28.5% vs. 9.6%, P = 4.9 × 10⁻¹¹, q < 0.001) and R1441G/C/H (7.9% vs. 0.5%, P = 2.7 × 10⁻¹², q < 0.001). Body-first PD was enriched for GBA carriers (12.3% vs. 6.7%, P = 0.004, q = 0.021) and depleted for LRRK2 (7.9% vs. 15.0%, P = 0.002, q = 0.013). The DM subtype carried the highest GBA frequency (14.0% vs. MMP 5.9%, P < 0.001, q = 0.003). After FDR correction, 10 of 48 univariate tests remained significant. Clinical subtypes (TD vs. PIGD) showed only nominal LRRK2 differences that did not survive FDR correction. APOE genotype did not differ across any framework. Conclusions: PD subtypes defined by alpha-synuclein pathology (SAA), pathological onset pattern (brain-first/body-first), and data-driven classification (DM/MMP/IM) show distinct genetic profiles that survive multiple comparison correction. LRRK2 variants strongly associate with SAA-negativity (V = 0.25); GBA variants associate with the severe body-first onset and the diffuse malignant subtype.