Parkinson disease

Clinical and genetic predictors of dementia in Parkinson's disease (2026)

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Type of publication:

Journal article

Author(s):

Solomons M.R.; Hannaway N.; Fox O.; Costantini A.; Real R.; Zarkali A.; Morris H.R.; Weil R.S.; Alty J.; Amar K.; Anthony A.; Arianayagam S.; Bennet C.; Buccoliero R.; Cosgrove J.; Croucher Y.; Dean S.; Dellafera D.; Dharia S.; Evans J.; *Gibson H.; Gregory R.; Guy J.; Henderson E.; Hodgson M.; Jones E.; Juada J.; King E.; Lewis A.; Mann C.; McDermott C.; Moffitt V.; Molloy S.; Niccolini F.; Pitman C.; Rhule N.; Saifee T.A.; Schrag A.; Sophia R.; *Stickley J.; Sullivan L.; Thompson A.; Wickremaratchi M.

Citation:

medRxiv. (no pagination), 2026. Date of Publication: 06 Mar 2026.

Abstract:

Importance: Dementia is common in Parkinson's disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised.
Objective(s): To investigate whether visual deficits and genetic factors predict PD dementia.
Design(s): Large prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months.
Setting(s): Cases were recruited between 2017-2020 at 35 UK PD clinics.
Participant(s): People with PD without dementia at baseline were included.
Main Outcomes and Measures: Visual function was measured using a web-based platform. The main outcome measure was global cognition, measured as the Montreal Cognitive Assessment (MoCA). Blood samples were collected for genetics.
Result(s): 450 patients with PD were included. Mean age of PD patients was 71.7 (SD=7.8), 68% male. Mean baseline MoCA was 27.7 (SD=1.7). 263 patients with PD were classed as poor-vision based on baseline visual tests: mean age 74.4 (SD=6.8) compared to 69.7 (SD=7.5) with good-vision. Poor-vision PD patients had higher rates of progression to mild cognitive impairment (PD-MCI) (HR=2.34, CI=1.58-3.48, pFDR=0.00062, age- and sex-corrected). The combination of genetic factors together with vision influenced outcomes. In good-vision PD patients, high-risk GBA1 gene variants were linked with greater progression to PD-MCI (HR=4.61, CI=1.73-12.28, pFDR=0.0068). Polygenic Risk Score (PRS) for both PD and Alzheimer's disease (AD) also modified cognitive survival when combined with vision status. High PD-PRS was associated with greater progression to PD-MCI in good-vision patients (HR=2.66, CI=1.21-5.81, pFDR=0.0381); and high AD-PRS with greater progression to PD-MCI in poor-vision PD patients (HR=1.91, CI=1.10-3.32, pFDR=0.04999). Combining high PD- and AD-PRS, compared to low PD- and AD-PRS in good-vision PD showed even higher progression to PD-MCI (HR=6.14, CI=1.36-27.83, pFDR=0.046). Simulations showed that adding visual and genetic stratification reduced sample size from n=705 to n=160 for clinical trials. Conclusions and relevance: Poor vision in PD predicts progression to PD-MCI and dementia. This combines with the effects of genetic factors including GBA risk variants and PD- and AD-PRS. These findings can enable enrichment of clinical trials for patients at higher risk of PD dementia, for more efficient trial design for interventions to slow progression.

DOI: 10.64898/2026.03.06.26347693

Parkinson's families project: a UK-wide study of early onset and familial Parkinson's disease (2024)

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Type of publication:

Journal article

Author(s):

Fang Z.-H.; Tan M.M.X.; Schmaderer T.M.; Stafford E.J.; Pollard M.; Tilney R.; Hodgson M.; Wu L.; Labrum R.; Hehir J.; Polke J.; Lange L.M.; Schapira A.H.V.; Bhatia K.P.; Hartley L.; Nacorda A.; Gentilini I.; Wales E.; Amar K.; Tuck S.; Raw J.; Crouch R.; Walker R.; Hand A.; Strens L.; Sveinbjornsdottir S.; Webster G.; Williams S.; Schrag A.; Nath U.; Mann C.; D'Costa D.; Barnes C.; Jones E.; Slaght S.J.; Wiblin L.; Archibald N.; *Capps E.; Jones S.; Sophia R.; Vickers C.; Dean S.; Truscott R.; Sheridan R.; Brierley C.; Kunc M.; Funaki A.; Asad S.; Tai Y.; Chaudhuri R.; Guptha S.; Cosgrove J.; Misbahuddin A.; Padiachy D.; Paviour D.; Bandmann O.; Buccoliero R.; Wickremaratchi M.; Gregory R.; Molloy S.; Shaik S.; Arianayagam S.; Saifee T.; Wakeman E.; Towns C.; Jasaityte S.; Jarman P.R.; Singleton A.B.; Blauwendraat C.; Klein C.; Houlden H.; Wood N.W.; Morris H.R.; Real R.

Citation:

npj Parkinson's Disease. 10(1) (no pagination), 2024. Article Number: 188. Date of Publication: December 2024.

Abstract:

The Parkinson's Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson's disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset <=45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset <=35 years. We identified pathogenic variants in LRRK2 in 4.2% of families, and biallelic pathogenic variants in PRKN in 3.6% of families. We also identified two families with SNCA duplications and three families with a pathogenic repeat expansion in ATXN2, as well as single families with pathogenic variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk GBA1 variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.

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Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome (2020)

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Type of publication:
Journal article

Author(s):
Jabbari E, Holland N, Chelban V, Jones PS, Lamb R, Rawlinson C, Guo T, Costantini AA, Tan MMX, Heslegrave AJ, Roncaroli F, Klein JC, Ansorge O, Allinson KSJ, Jaunmuktane Z, Holton JL, Revesz T, Warner TT, Lees AJ, Zetterberg H, Russell LL, Bocchetta M, Rohrer JD, Williams NM, Grosset DG, Burn DJ, Pavese N, Gerhard A, Kobylecki C, Leigh PN, Church A, Hu MTM, Woodside J, Houlden H, Rowe JB, Morris HR.

Patients at Shrewsbury and Telford Hospital NHS Trust were recruited into this study.

Citation:
JAMA Neurol. 2020 Mar 1;77(3):377-387.

Abstract:
IMPORTANCE:
Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied.

OBJECTIVE:
To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD.

DESIGN, SETTING, PARTICIPANTS:
This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019.

MAIN OUTCOMES AND MEASURES:
Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures.

RESULTS:
A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05).

CONCLUSIONS AND RELEVANCE:
These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

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