👤 Ana Camacho

An accurate understanding of prognosis in Parkinson's disease (PD) is important for patient information provision, personalized treatment, and clinical trial design, but most previous research has been biased towards younger, healthier patients. To describe key clinical outcomes longitudinally and identify baseline prognostic factors (predictors) for these outcomes using population-representative PD cohorts. We meta-analyzed individual patient data from six incidence cohorts in Western Europe (Norway, Sweden, and UK). Each cohort aimed to recruit and follow up all newly diagnosed cases in defined population/incidence periods (between 2000 and 2011). We described postural instability (Hoehn & Yahr Stage 3), functional dependency (needing help with daily activities), dementia, and death with up to 12 years' follow-up and investigated clinical and genetic predictors using frailty Cox models. In 883 population-based incident patients, median age at motor symptom onset was 69.2 years. Median time to postural instability and functional dependency was 7.4 years. Dementia affected 49.6% by 10 years and 54.7% had died by 12 years (median survival 9.4 years). Older age, higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) score, and lower Mini-Mental State Examination (MMSE) were significantly associated with all outcomes; cognitive symptoms and GBA polymorphisms with each outcome except mortality; and APOE ε4 with increased mortality and dementia. This first individual patient data meta-analysis of population-based incidence cohorts provides robust prognostic data, with fewer selection biases than previous PD studies, for informing people with PD about prognosis. In incidence cohorts, overall PD prognosis is worse than previously suggested, with key outcomes often occurring early. Further work should develop validated prognostic models for objective stratification of prognostic risk and for personalized medicine. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less

Extracellular matrix (ECM) remodelling is critical in abdominal aortic aneurysm (AAA), a life-threatening condition lacking effective pharmacotherapy. However, key ECM components regulating vascular integrity and remodelling remain poorly understood. Transcriptome profiling and studies in human AAA and in aneurysms from two models susceptible to angiotensin II (Ang II)-induced AAA-apolipoprotein E knockout mice (ApoE Transcriptome profiling highlighted the relevance of the ECM-mediated pathway and the upregulation of THBS4 in human AAA. In a large cohort of patients and donors and in Ang II-infused ApoE We uncover the early and sustained induction of TSP4 in AAA and its protective role in limiting vascular inflammation and destructive remodelling. Modulation of TSP4-dependent pathways may represent a novel avenue to improve vascular stability in AAA. Show less

In rheumatoid arthritis (RA), the risk of cardiovascular death is 50% higher compared to the general population. This increased risk is partly due to the systemic inflammation characteristic of RA and changes in the lipoprotein profiles. This study investigated plasma lipid levels, lipid ratios, and the composition and functionality of high-density lipoprotein (HDL) in control individuals and RA subjects based on the disease's inflammatory score (DAS28). This study included 50 control (CTR) individuals and 56 subjects with RA, divided into remission/low-activity disease (DAS28 < 3.2; Show less

Alzheimer's disease (AD) is characterized pathologically by amyloid β (Aβ)-containing plaques. Generation of Aβ from amyloid precursor protein (APP) by two enzymes, β- and γ-secretase, has therefore been in the AD research spotlight for decades. Despite this, how the physical interaction of APP with the secretases influences APP processing is not fully understood. Herein, we compared two genetically identical human iPSC-derived neuronal cell types: low Aβ-secreting neuroprogenitor cells (NPCs) and high Aβ-secreting mature neurons, as models of low versus high Aβ production. We investigated levels of substrate, enzymes and products of APP amyloidogenic processing and correlated them with the proximity of APP to β- and γ-secretase in endo-lysosomal organelles. In mature neurons, increased colocalization of full-length APP with the β-secretase BACE1 correlated with increased β-cleavage product sAPPβ. Increased flAPP/BACE1 colocalization was mainly found in early endosomes. In the same way, increased colocalization of APP-derived C-terminal fragment (CTF) with presenilin-1 (PSEN1), the catalytic subunit of γ-secretase, was seen in neurons as compared to NPCs. Furthermore, most of the interaction of APP with BACE1 in low Aβ-secreting NPCs seemed to derive from CTF, the remaining APP part after BACE1 cleavage, indicating a possible novel product-enzyme inhibition. In conclusion, our results suggest that interaction of APP and APP cleavage products with their secretases can regulate Aβ production both positively and negatively. β- and γ-Secretases are difficult targets for AD treatment due to their ubiquitous nature and wide range of substrates. Therefore, targeting APP-secretase interactions could be a novel treatment strategy for AD. Colocalization of APP species with BACE1 in a novel model of low- versus high-Aβ secretion-Two genetically identical human iPSC-derived neuronal cell types: low Aβ-secreting neuroprogenitor cells (NPCs) and high Aβ secreting mature neurons, were compared. Increased full-length APP (flAPP)/BACE1 colocalization in early endosomes was seen in neurons, while APP-CTF/BACE1 colocalization was much higher than flAPP/BACE1 colocalization in NPCs, although the cellular location was not determined. Show less

To analyze the expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in somatotropinomas specimens and compare clinical, biochemical, radiological, therapeutic, molecular, and pathological data among those who overexpressed (GIPR +) and those who did not overexpress (GIPR - ) GIPR. Clinical, biochemical, radiological, molecular, and pathological data were collected. GNAS1 sequencing was performed with the Sanger method. Protein expression of somatostatin receptor subtypes 2 and 5 and CAM 5.2 were analyzed by immunohistochemistry. Quantitative real-time PCR was performed to analyze the mRNA expression of GIPR with the TaqMan® method. Positive expression was considered when the fold change (FC) was above 17.2 (GIPR +). A total of 74 patients (54% female) were included. Eighteen tumors (24%) were GIPR + . Gsp mutation was detected in 30 tumors (40%). GIPR + tumors were more frequently densely granulated adenomas (83% vs 47%, p = 0.028). There was no difference in clinical, biochemical, radiological, therapeutic (surgical cure or response to medical therapy), or other pathological features between GIPR + and GIPR -  tumors. Twenty-eight out of 56 (50%) GIPR -  tumors harbored a gsp mutation, whereas two out of 18 (11%) GIPR + tumors harbored a gsp mutation (p = 0.005). We described, for the first time, that GIPR + and gsp mutations are not mutually exclusive, but gsp mutations are less common in GIPR + tumors. GIPR + and GIPR -  tumors have similar clinical, biochemical, radiological, therapeutic, and pathological features, with the exception of a high frequency of densely granulated adenomas among GIPR + tumors. Show less

Familial chylomicronemia syndrome (FCS) is an extremely rare lipoprotein disorder caused by mutations in at least 5 genes of the lipoprotein lipase (LPL) complex. This work shows the molecular analysis of patients diagnosed with FCS, who attended the Spanish Arteriosclerosis Society lipid units and were included in the National Dyslipidemia Registry. Among the 238 patients registered with severe hypertriglyceridemia (fasting triglycerides >1000 mg/dL), 26 were diagnosed with FCS as they had confirmed postheparin plasma LPL activity deficiency and/or homozygosity for loss-of-function mutations in LPL, GPIHBP1, APOC2, LMF1, or Apolipoprotein A5 (APOA5). Among the 26 FCS cases, 23 had mutations in the homozygous state: 19 in LPL and 4 in the GPIHBP1 gene. The molecular analysis revealed 3 novel mutations: 2 in LPL, in 2 unrelated patients (c.312delA; p.Asp105Thrfs*66 and c.629A>G; p.His210Arg), and 1 in GPHIBP1 in a third patient (c.502delC; p.Leu168Serfs*83). These 3 patients had confirmed lack of LPL activity. Three additional patients with confirmed LPL activity deficiency were heterozygous carriers of mutations in the genes analyzed. Among these, we found 2 novel mutations in APOA5 (c.50-1G>A and c.326₃₂₇insC; p.Tyr110Leufs*158). We have identified 5 novel pathogenic mutations: 2 in LPL, 1 in GPIHBP1, and 2 in the APOA5 gene. The genetic defaults accounting for the LPL activity deficiency of 23 of them have been clearly identified and 3 patients, who harbored mutations in heterozygosity, were diagnosed based on LPL activity deficiency, which raises the question of the involvement of new genes in the manifestation of FCS. Show less

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124₁₁₂₇dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management. Show less

Rapsyn (RAPSN) mutations are a common cause of postsynaptic congenital myasthenic syndromes. We present a comprehensive description of the clinical and molecular findings of ten patients with CMS due to mutations in RAPSN, mostly with a long-term follow-up. Two patients were homozygous and eight were heterozygous for the common p.Asn88Lys mutation. In three of the heterozygous patients we have identified three novel mutations (c.869T > C; p.Leu290Pro, c.1185delG; p.Thr396Profs*12, and c.358delC; p.Gln120Serfs*8). In our cohort, the RAPSN mutations lead to a relatively homogeneous phenotype, characterized by fluctuating ptosis, occasional bulbar symptoms, neck muscle weakness, and mild proximal muscle weakness with exacerbations precipitated by minor infections. Interestingly, episodic exacerbations continue to occur during adulthood. These were characterized by proximal limb girdle weakness and ptosis, and not so much by respiratory insufficiency after age 6. All patients presented during neonatal period and responded to cholinergic agonists. In most of the affected patients, additional use of 3,4-diaminopyridine resulted in significant clinical benefit. The disease course is stable except for intermittent worsening. Show less