Antonia Campolongo

Background: The Huntington's Disease Integrated Staging System (HD‐ISS) provides a framework for staging HD but does not incorporate fluid biomarkers. Objective: The aim of this study was to examine neurofilament light chain (NfL) and mutant huntingtin (mHTT) and total tau across HD‐ISS stages and their associations with genetic burden, neuroimaging, and clinical measures. Methods: We performed cross‐sectional analysis of the Barcelona‐Huntington's Disease (BCN‐HD) cohort with external replication in the multicenter HDClarity study. HD gene expansion carriers were classified as HD‐ISS stages 0 to 3. NfL (cerebrospinal fluid [CSF] and plasma), CSF mHTT, total tau, striatal volumes, and Unified Huntington's Disease Rating Scale measures were quantified. Group differences and associations were analyzed using adjusted models. Results: The BCN‐HD cohort included 78 participants (50 HD gene expansion carriers [HDGECs], 28 controls) and HDClarity included 218 participants (166 HDGECs, 52 controls). CSF NfL increased across HD‐ISS stages and discriminated premanifest from manifest individuals, as well as HD‐ISS stage 0 from stage 1. Plasma NfL showed parallel increases and strongly correlated with CSF NfL ( ρ = 0.88, P < 0.001). More than half of HD‐ISS 0 individuals had NfL levels above the age‐adjusted 95th percentile (P95) and shorter predicted time to onset (13 years for CSF and 10 years for plasma). From HD‐ISS 1 onward, NfL levels exceeded P95 in most individuals. Higher NfL concentrations were associated with genetic burden, striatal atrophy, and clinical measures (all P < 0.001). CSF mHTT was detectable from HD‐ISS 0 but showed weaker associations, whereas CSF total tau increased only from HD‐ISS 3. Conclusions: NfL identifies biological activity across the HD‐ISS continuum and shows neuroaxonal injury in a subset of individuals classified as stage 0. These findings suggest that fluid biomarkers may complement current HD‐ISS criteria and support biological stratification in observational studies and clinical trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The H1 haplotype of the 17q21.31 inversion polymorphism has been consistently associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson's disease in Caucasians. Recently, large polymorphic segmental duplications resulting into complex rearrangements at this locus with a high diversity range in human populations have been revealed. We sought to explore whether the two multi‐allelic copy number variants that are present in the H1 clade (with segmental duplications of 300 and 218 kilobases in length) could be responsible for the known H1‐related risk of developing these neurodegenerative disorders. A total of 857 Spanish subjects including 330 patients with Parkinson's disease, 96 with progressive supranuclear palsy, 55 with corticobasal degeneration, 51 dementia with Lewy bodies, and 325 neurologically healthy controls, were genotyped for the H1/H2 haplotype. Subsequently, the two copy number variants that are characteristic of the H1 haplotype were evaluated through a high‐resolution approach based on droplet digital polymerase chain reaction, in all H1 homozygous subjects. The H1 allele was significantly overrepresented in all diagnostic groups compared with controls (Parkinson's disease, P = 0.0001; progressive supranuclear palsy, P = 1.22 × 10⁻⁶; corticobasal degeneration, P = 0.0002; and dementia with Lewy bodies, P = 0.032). However, no dosage differences were found for any of the two copy number variants analyzed. The H1 haplotype is associated with the risk of several neurodegenerative disorders, including dementia with Lewy bodies. However, common structural diversity within the 17q21.31‐H1 clade does not explain this genetic association.

Parkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10–20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6–7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease.

Lack of validated data on cutoff scores for mild cognitive impairment (MCI) and sensitivity to change in predementia stages of Parkinson's disease (PD) limit the utility of instruments measuring global cognition as screening and outcome measures in therapeutic trials. Investigators who were blinded to PD‐Cognitive Rating Scale (PD‐CRS) scores classified a cohort of prospectively recruited, nondemented patients into a PD with normal cognition (PD‐NC) group and a PD with MCI (PD‐MCI) group using Clinical Dementia Rating (CDR) and the Mattis Dementia Rating Scale‐2 (MDRS‐2). The discriminative power of the PD‐CRS for PD‐MCI was examined in a representative sample of 234 patients (145 in the PD‐NC group; 89 in the PD‐MCI group) and in a control group of 98 healthy individuals. Sensitivity to change in the PD‐CRS score (the minimal clinically important difference was examined with the Clinical Global Impression of Change scale and was calculated with a combination of distribution‐based and anchor‐based approaches) was explored in a 6‐month observational multicenter trial involving a subset of 120 patients (PD‐NC, 63; PD‐MCI, 57). Regression analysis demonstrated that PD‐CRS total scores (P < 0.001) and age (P = 0.01) independently differentiated PD‐NC from PD‐MCI. Area under the receiver operating characteristic curve (AUC) analysis (AUC, 0.85; 95% confidence interval, 0.80–0.90) indicated that a score ≤81 of 134 was the optimal cutoff point on the total score for the PD‐CRS (sensitivity, 79%; specificity, 80%; positive predictive value, 59%; negative predictive value, 91%). A range of change from 10 to 13 points on the PD‐CRS total score was indicative of clinically significant change. These findings suggest that the PD‐CRS is a useful tool to identify PD‐MCI and to track cognitive changes in nondemented patients with PD. © 2013 International Parkinson and Movement Disorder Society

Mutations in the glucocerebrosidase gene are associated with Parkinson's disease and Lewy body dementia. However, whether these alterations have any effect on the clinical course of Parkinson's disease is not clear. The glucocerebrosidase coding region was fully sequenced in 225 Parkinson's disease patients, 17 pathologically confirmed Lewy body dementia patients, and 186 controls from Spain. Twenty‐two Parkinson's disease patients (9.8%) and 2 Lewy body dementia patients (11.8%) carried mutations in the glucocerebrosidase gene, compared with only 1 control (0.5%); P = .016 and P = .021 for Parkinson's disease and Lewy body dementia, respectively. The N370S and the L444P mutations represented 50% of the alterations. Two novel variants, L144V and S488T, and 7 previously described alterations were also found. Alterations in glucocerebrosidase were associated with a significant risk of dementia during the clinical course of Parkinson's disease (age at onset, years of evolution, and sex‐adjusted odds ratio, 5.8; P = .001). Mutation carriers did not show worse motor symptoms, had good response to L‐dopa, and tended to present the intermediate parkinsonian phenotype. Our findings suggest that mutations in the glucocerebrosidase gene not only increase the risk of both Parkinson's disease and Lewy body dementia but also strongly influence the course of Parkinson's disease with respect to the appearance of dementia. © 2011 Movement Disorder Society

One of the most common nonmotor symptoms in Parkinson disease (PD) is the co-occurrence of dementia, with a mean prevalence of 30%.¹ Dementia in PD is an important cause for nursing home placement,² caregiver distress,³ higher health care burden,⁴ and increased mortality.⁵ The combination of dementia and parkinsonism is also a key feature that characterizes dementia with Lewy bodies (LBD), the second most common cause of neurodegenerative dementia in the elderly after Alzheimer disease (AD). A recent genome-wide association study has provided unequivocal evidence for a genetic association of the microtubule-associated protein tau (MAPT) (GenBank NG_007398.1 and OMIM 157140) locus with PD in the population with European origin.⁶ However, these results were not replicated in an independent genome-wide association study performed in an Asian population.⁷ With up to 21 studies performed to date, MAPT seems to be undoubtedly associated with PD risk (http://www.pdgene.org). In particular, the MAPT H1 variant, an extended haplotype that results from a common genomic inversion of approximately 800 kb in chromosome 17q21 containing the MAPT gene, has been found to be related to PD risk.^8-14 Interestingly, the H1 variant has also been associated with cognitive decline in a longitudinal study of PD with a 3½-year follow-up.⁹ In a subsequent study by some of the same authors, the MAPT H1 allele was the strongest independent predictor of dementia among PD patients, with an odds ratio (OR) of 12.1 during 5 years of follow-up.¹⁵ Research addressing the effect of MAPT in other neurodegenerative disorders, such as AD, has yielded inconclusive results.^16-19 A fine-mapping study of the MAPT H1/H2 clades described the H1c subhaplotype, a version of the H1 haplotype, to be the specific variant associated with AD risk.¹⁸ However, this association has been inconsistently found in subsequent studies.^20,21 The specific MAPT subhaplotype linked to PD, Parkinson disease–dementia (PDD) complex, or LBD remains unknown.

Parkinson's disease (PD) patients may experience fluctuations in executive performance after oral levodopa (LD). Their relationship with the pharmacokinetic profile of LD and with distinct cognitive processes associated with frontal-basal ganglia circuits is not well understood. In this randomized, double-blind, crossover study we plotted acute cognitive changes in 14 PD patients challenged with faster (immediate-release, IR) versus slower (controlled-release, CR) increases in LD plasma concentrations. We monitored motor status, LD plasma levels, and performance on four tasks of executive function (Wisconsin Card Sorting Test—WCST, Sternberg test, Stroop and Tower of Hanoi), 1 hr before and over +6 hr after IR and CR-LD dose. Analysis of variance demonstrated significant but divergent changes in the Sternberg (6-digit but not 2- and 4-digit) test: improvement after CR-LD and worsening after IR-LD. Marginal improvement (p = .085) was observed with CR-LD in the WCST, while no significant differences were seen for the Stroop or Tower of Hanoi tests. Executive-related performance after LD challenge may differ depending on the LD time-to-peak plasma concentration and specific task demands. A slower rise in LD levels appears to have a more favorable impact on more difficult working memory tests. These results require replication to determine their generalization. (JINS, 2008, 14, 832–841.)