Longitudinal clinical, cognitive, and neuroanatomical changes over 5 years in GBA-positive Parkinson’s disease patients

Leocadi, Michela; Canu, Elisa; Donzuso, Giulia; Stojković, Tanja; Basaia, Silvia; Kresojević, Nikola; Stanković, Iva; Sarasso, Elisabetta; Piramide, Noemi; Tomić, Aleksandra; Marković, Vladana; Petrović, Igor; Stefanova, Elka; Kostić, Vladimir; Filippi, Massimo

doi:10.1007/s00415-021-10713-4

Cited by 28 publications

(26 citation statements)

References 39 publications

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“…2,3,8,9,12 PD patients experienced a worsening of both motor and non-motor symptoms over time, with a significant progression of UPDRS and related subscores, as well as global cognitive test scores, and executive and visuospatial functions, as expected in consideration of PD's natural course. [22][23][24][25][26][27] The longitudinal analysis of WMH volume showed a significant progression over time, which was associated with the cognitive decline, especially regarding executive functions and language. By contrast, WMH volume increase was not correlated with the worsening of motor variables.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal White Matter Damage Evolution in Parkinson's Disease

et al. 2021

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Background White matter hyperintensities (WMHs) have a role in cognitive impairment in normal brain aging, while the effect on Parkinson's disease (PD) progression is still controversial. Objective To investigate the longitudinal evolution of micro‐ and macrostructural damage of cerebral white matter (WM) and its relationship with the clinical picture in PD. Methods A total of 154 PD patients underwent clinical, cognitive, and magnetic resonance imaging (MRI) assessment once a year for up to 4 years. Sixty healthy controls underwent the same protocol at baseline. WMHs were identified and total WMH volume was measured. WMHs were also used as exclusion masks to define normal‐appearing white matter (NAWM). Using tract‐based spatial statistics, diffusion tensor (DT) MRI metrics of whole‐brain WM and NAWM were obtained. Linear mixed‐effects models defined the longitudinal evolution and association between variables. WM alterations were tested as risk factors of disease progression using linear regression and Cox proportional hazards models. Results At baseline, PD patients showed alterations of all DT MRI measures compared to controls. Longitudinally, DT MRI measures did not vary significantly and no association with clinical variables was found. WMH volume changed over time and was associated with impairment in global cognition, executive functions, and language. Baseline WMH volume was a moderate risk factor for progression to mild cognitive impairment. Conclusions Our study suggests an association between WMHs and cognitive deterioration in PD, whereas WM microstructural damage is a negligible contributor to clinical deterioration. WMHs assessed by MRI can provide an important tool for monitoring the development of cognitive impairment in PD patients. © 2021 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 99%

Longitudinal White Matter Damage Evolution in Parkinson's Disease

et al. 2021

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“…NMSs form a significant aspect of the GBA1-PD disease course. PD patients with GBA1 mutations exhibit a threefold increased risk of cognitive decline, affecting working memory, executive and visuospatial functions (Alcalay et al 2012;Zokaei et al 2014;Mata et al 2016;Leocadi et al 2022). The degree of cognitive impairment is correlated with the severity of GBA1 mutations (Petrucci et al 2020;Szwedo et al 2022).…”

Section: Clinical Featuresmentioning

confidence: 99%

Glucocerebrosidase mutations and Parkinson disease

Vieira

Schapira

2022

J Neural Transm

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The discovery of glucocerebrosidase (GBA1) mutations as the greatest numerical genetic risk factor for the development of Parkinson disease (PD) resulted in a paradigm shift within the research landscape. Efforts to elucidate the mechanisms behind GBA1-associated PD have highlighted shared pathways in idiopathic PD including the loss and gain-of-function hypotheses, endoplasmic reticulum stress, lipid metabolism, neuroinflammation, mitochondrial dysfunction and altered autophagy–lysosomal pathway responsible for degradation of aggregated and misfolded a-synuclein. GBA1-associated PD exhibits subtle differences in phenotype and disease progression compared to idiopathic counterparts notably an earlier age of onset, faster motor decline and greater frequency of non-motor symptoms (which also constitute a significant aspect of the prodromal phase of the disease). GBA1-targeted therapies have been developed and are being investigated in clinical trials. The most notable are Ambroxol, a small molecule chaperone, and Venglustat, a blood–brain-barrier-penetrant substrate reduction therapy agent. It is imperative that further studies clarify the aetiology of GBA1-associated PD, enabling the development of a greater abundance of targeted therapies in this new era of precision medicine.

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“…These imaging findings were in line with clinical observations demonstrating a more rapid trajectory of motor and cognitive impairment in GBA-PD compared to iPD. 18 Also a study conducted on the Parkinson's Progression Markers Initiative (PPMI) cohort reported significant GM differences in GBA-PD compared with iPD patients. 17 In particular, both GBA-PD and late-onset (LO)-iPD showed greater structural volume reductions compared with the earlyonset (EO)-iPD group.…”

Section: Structural Mrimentioning

confidence: 99%

Neuroimaging in Glucocerebrosidase‐Associated Parkinsonism: A Systematic Review

2022

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Background Mutations in the GBA gene cause Gaucher's disease (GD) and constitute the most frequent genetic risk factor for idiopathic Parkinson's disease (iPD). Nonmanifesting carriers of GBA mutations/variants (GBA‐NMC) constitute a potential PD preclinical population, whereas PD patients carrying some GBA mutations/variants (GBA‐PD) have a higher risk of a more aggressive disease course. Different neuroimaging techniques are emerging as potential biomarkers in PD and have been used to study GBA‐associated parkinsonism. Objective The aim is to critically review studies applying neuroimaging to GBA‐associated parkinsonism. Methods Literature search was performed using PubMed and EMBASE databases (last search February 7, 2022). Studies reporting neuroimaging findings in GBA‐PD, GD with and without parkinsonism, and GBA‐NMC were included. Results Thirty‐five studies were included. In longitudinal studies, GBA‐PD patients show a more aggressive disease than iPD at both structural magnetic resonance imaging and 123‐fluoropropylcarbomethoxyiodophenylnortropane single‐photon emission computed tomography. Fluorodeoxyglucose‐positron emission tomography and brain perfusion studies reported a greater cortical involvement in GBA‐PD compared to iPD. Overall, contrasting evidence is available regarding GBA‐NMC for imaging and clinical findings, although subtle differences have been reported compared with healthy controls with no mutations. Conclusions Although results must be interpreted with caution due to limitations of the studies, in line with previous clinical observations, GBA‐PD showed a more aggressive disease progression in neuroimaging longitudinal studies compared to iPD. Cognitive impairment, a “clinical signature” of GBA‐PD, seems to find its neuroimaging correlate in the greater cortical burden displayed by these patients as compared to iPD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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Longitudinal clinical, cognitive, and neuroanatomical changes over 5 years in GBA-positive Parkinson’s disease patients

Cited by 28 publications

References 39 publications

Longitudinal White Matter Damage Evolution in Parkinson's Disease

Longitudinal White Matter Damage Evolution in Parkinson's Disease

Glucocerebrosidase mutations and Parkinson disease

Neuroimaging in Glucocerebrosidase‐Associated Parkinsonism: A Systematic Review

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