In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

COPPADIS Study Group.[Introduction] We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia.[Methods] The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models.[Results] Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02).[Conclusions] Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.This work was supported by the Alzheimer Forschung Initiative e.V. (AFI International Training Grant to MJG), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, PI19/01576, PI20/00613], the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019], the Fundación Alicia Koplowitz and the Fundación “Curemos el Parkinson” (https://www.curemoselparkinson.org). MJG is supported by the “Miguel Servet” program [CP19/00031], MALE by the University of Seville [USE-20046-J], JFM by the “Sara Borrell” program [CD13/00229] and VI-PPIT-US from the University of Seville [USE-18817-A], SJ by the “Acción B-Clínicos-Investigadores” program [B-0007-2019], and DMG by the “Río Hortega” program [CM18/00142].Peer reviewe

Neurons in the white matter of the adult human neocortex

The white matter (WM) of the adult human neocortex contains the so-called &ldquo;interstitial neurons&rdquo;. They are most numerous in the superficial WM underlying the cortical gyri, and decrease in density toward the deep WM. They are morphologically heterogeneous. A subgroup of interstitial neurons display pyramidal-cell like morphologies, characterized by a polarized dendritic tree with a dominant apical dendrite, and covered with a variable number of dendritic spines. In addition, a large contingent of interstitial neurons can be classified as interneurons based on their neurochemical profile as well as on morphological criteria. WM- interneurons have multipolar or bipolar shapes and express GABA and a variety of other neuronal markers, such as calbindin and calretinin, the extracellular matrix protein reelin, or neuropeptide Y, somatostatin, and nitric oxide synthase. The heterogeneity of interstitial neurons may be relevant for the pathogenesis of Alzheimer disease and schizophrenia. Interstitial neurons are most prominent in human brain, and only rudimentary in the brain of non-primate mammals. These evolutionary differences have precluded adequate experimental work on this cell population, which is usually considered as a relict of the subplate, a transient compartment proper of development and without a known function in the adult brain. The primate-specific prominence of the subplate in late fetal stages points to an important role in the establishment of interstitial neurons. Neurons in the adult WM may be actively involved in coordinating inter-areal connectivity and regulation of blood flow. Further studies in primates will be needed to elucidate the developmental history, adult components and activities of this large neuronal system

High ultrasensitive serum C-reactive protein may be related to freezing of gait in Parkinson’s disease patients

COPPADIS Study Group.C-reactive protein (CRP) is a biomarker of systemic inflammation that has been linked to accelerated decline in walking speed in older adults. The aim of the present study was to compare the CRP levels of PD patients with vs patients without freezing of gait (FOG). Patients and controls participating in the COPPADIS-2015 study that performed blood extraction for determining molecular serum biomarkers were included. Patients with FOG were identified as those with a score of 1 or greater on item-3 of the Freezing of Gait Questionnaire (FOG-Q). Immunoassay was used for determining ultrasensitive CRP (US-CRP) level (mg/dL). In the PD group (n = 225; 61.8 ± 9.5 years old, 61.8% males), 32% of the patients presented FOG but none in the control group (n = 65; 60.3 ± 6.1 years old, 56.9% males) (p < 0.0001). Differences in US-CRP level were significant in patients with FOG vs patients without FOG and vs controls (0.31 ± 0.52 vs 0.16 ± 0.21 vs 0.21 ± 0.22; p = 0.04). Significant differences were also observed between patients with vs without FOG (p = 0.001) but not between patients and controls (p = 0.163). US-CRP level was related to FOG (OR = 4.369; 95% CI 1.105–17.275; p = 0.036) along with H&Y (OR = 2.974; 95% CI 1.113–7.943; p = 0.030) and non-motor symptoms burden (NMSS total score; OR = 1.017; 95% CI 1.005–1.029; p = 0.006) after adjusting for age, gender, disease duration, equivalent daily levodopa dose, number of non-antiparkinsonian drugs per day, motor fluctuations, cognition, motor phenotype, and chronic use of anti-inflammatory drugs. The present study suggests that serum US-CRP level is related to FOG in PD patients. Inflammation could be linked to FOG development.Santos-García D. has received honoraria for educational presentations and/or advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. de Deus Fonticoba T. has received honoraria for educational presentations and advice service by Abbvie. Suárez Castro E: None. Aneiros Díaz A: None. Paz González JM. has received honoraria for educational presentations and/or advice service by UCB Pharma, Lundbeck, KRKA, and Zambon. Feal Panceiras MJ: None. García Sancho C: None. Jesús S. has received honoraria from Abbvie, Bial, Merz, UCB, and Zambon. She holds the competitive contract “Juan Rodés” supported by the Instituto de Salud Carlos III. Also, she has received grants from the Spanish Ministry of Economy and Competitiveness (PI18/01898) as well as the Consejería de Salud de la Junta de Andalucía (PI-0459-2018). Mir P. has received honoraria from Abbvie, Abbott, Allergan, Bial, Merz, UCB, and Zambon. He has received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación). He also received grants from Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, and the Fundación Mutua Madrileña. Aguilar M: UCB and Schwabe with assistance to a Congress; Nutricia with assistance to a Congress and payment of lecture. Pastor P: None. Hernández Vara J: has received travel bursaries and educational grants from Abbvie and has received honoraria for educational presentations from Abbvie, Teva, Bial, Zambon, Italfarmaco, and Sanofi-Genzyme. de Fábregues-Boixar O. has received honoraria for educational presentations and advice service by Bial, Zambon, Abbvie, KRKA, and Teva. Puente V. has served as consultant for Abbvie and Zambon; has received grant/research from Abbvie. Crespo Cuevas A: None. González-Aramburu I: None. Infante J. has received travel bursaries and honoraria for educational presentations from Abbvie and Zambon. Carrillo Padilla F. has received honoraria from Zambon (SEN Congress assistance). Pueyo M. has received honoraria from Zambon for educational presentations and SEN Congress assistance and of Medtronic for course assistance. Escalante S. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. Bernardo N: None. Solano B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, and Bial. Cots Foraster A has received honoraria for educational presentations by UCB and Zambon, Has received financial help to Master courses (Master en Trastornos del Movimiento, Ed Viguera, 2017–2018) from UCB an Zambon. Martinez-Martin P: Honoraria: from Editorial Viguera for lecturing in courses; International Parkinson and Movement Disorder Society for management of the Program on Rating Scales; Air Liquide, Abbvie, and HM Hospitales de Madrid for advice in clinic-epidemiological studies. License fee payments for the King’s Parkinson’s Disease Pain scale

Increased homocysteine levels correlate with cortical structural damage in Parkinson's disease

[Background] Blood homocysteine appears to be increased in Parkinson's disease (PD) and may play a role in the development and progression of this disorder. However, the specific contribution of abnormal homocysteine levels to cortical degeneration in PD remains elusive.[Objective] To characterize the cortical structural correlates of homocysteine levels in PD.[Methods] From the COPPADIS cohort, we identified a subset of PD patients and healthy controls (HC) with available homocysteine and imaging data. Surface-based vertex-wise multiple regression analyses were performed to investigate the cortical macrostructural (cortical thinning) and microstructural (increased intracortical diffusivity) correlates of homocysteine levels in this sample.[Results] A total of 137 PD patients and 43 HC were included. Homocysteine levels were increased in the PD group (t = −2.2, p = 0.03), correlating in turn with cognitive performance (r = −0.2, p = 0.03). Homocysteine in PD was also associated with frontal cortical thinning and, in a subset of patients with available DTI data, with microstructural damage in frontal and posterior-cortical regions (p < 0.05 Monte-Carlo corrected).[Conclusions] Homocysteine in PD appears to be associated with cognitive performance and structural damage in the cerebral cortex. These findings not only reinforce the presence and importance of cortical degeneration in PD, but also suggest that homocysteine plays a role among the multiple pathological processes thought to be involved in its development.This work was partially supported by funds from CERCA, CIBERNED, la Marató de TV3 (grants #2014/U/477 and #20142910), Fondo de Investigaciones Sanitarias (grants #PI15/00962 and #PI18/01717FIS), Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER). MJG receives support from the “Miguel Servet” program [CP19/00031] and a research grant [PI20/00613] from the ISCIII-FEDER. MALE receives support from the VI-PPIT-US project at the University of Seville [USE-20046-J].Peer reviewe

Non-motor symptoms burden, mood, and gait problems are the most significant factors contributing to a poor quality of life in non-demented Parkinson's disease patients: Results from the COPPADIS Study Cohort

[Objective] To identify factors related to a poor health-related and global quality of life (QoL) in a cohort of non-demented Parkinson's disease (PD) patients and compare to a control group.[Methods] The data correspond to the baseline evaluation of the COPPADIS-2015 Study, an observational, 5-year follow-up, multicenter, evaluation study. Three instruments were used to assess QoL: (1) the 39-item Parkinson's disease Questionnaire (PDQ-39), (2) a subjective rating of global QoL (PQ-10), and (3) the EUROHIS-QOL 8-item index (EUROHIS-QOL8). Multiple linear regression methods were used to evaluate the direct impact of different variables on these QoL measures.[Results] QoL was worse in PD patients (n = 692; 62.6 ± 8.9 years old, 60.3% males) than controls (n = 206; 61 ± 8.3 years old, 49.5% males): PDQ-39, 17.1 ± 13.5 vs 4.4 ± 6.3 (p < 0.0001); PQ-10, 7.3 ± 1.6 vs 8.1 ± 1.2 (p < 0.0001); EUROHIS-QOL8, 3.8 ± 0.6 vs 4.2 ± 0.5 (p < 0.0001). A high correlation was observed between PDQ-39 and Non-Motor Symptoms Scale (NMSS) (r = 0.72; p < 0.0001), and PDQ-39 and Beck Depression Inventory-II (BDI-II) (r = 0.65; p < 0.0001). For health-related QoL (PDQ-39), non-motor symptoms burden (NMSS), mood (BDI-II), and gait problems (Freezing Of Gait Questionnaire [FOGQ]) provided the highest contribution to the model (β = 0.32, 0.28, and 0.27, respectively; p < 0.0001); whereas mood and gait problems contributed the most to global QoL (PQ-10, β = -0.46 and −0.21, respectively; EUROHIS-QOL8, β = -0.44 and −0.23, respectively).[Conclusions] QoL is worse in PD patients than in controls. Mood, non-motor symptoms burden, and gait problems seem to be the most relevant factors affecting health-related and global perceived QoL in non-demented PD patients.Peer reviewe

Predictors of clinically significant quality of life impairment in Parkinson's disease

Quality of life (QOL) plays an important role in independent living in Parkinson's disease (PD) patients, being crucial to know what factors impact QoL throughout the course of the disease. Here we identified predictors of QoL impairment in PD patients from a Spanish cohort. PD patients recruited from 35 centers of Spain from the COPPADIS cohort from January 2016, to November 2017, were followed up during 2 years. Health-related QoL (HRQoL) and global QoL (GQoL) were assessed with the 39-item Parkinson's disease Questionnaire (PDQ-39) and the EUROHIS-QOL 8-item index (EUROHIS-QOL8), respectively, at baseline (V0) and at 24 months ± 1 month (V2). Clinically significant QoL impairment was defined as presenting an increase (PDQ-39SI) or decrement (EUROHIS-QOL8) at V2 ≥ 10% of the score at baseline (V0). A comparison with a control group was conducted for GQoL. GQoL did not change significantly in PD patients (N = 507; p = 0.686) or in the control group (N = 119; p = 0.192). The mean PDQ-39SI was significantly increased in PD patients (62.7 ± 8.5 years old; 58.8% males; N = 500) by 21.6% (from 16.7 ± 13 to 20.3 ± 16.4; p < 0.0001) at V2. Ninety-three patients (18.6%) presented a clinically significant HRQoL impairment at V2. To be younger (OR = 0.896; 95% CI 0.829-0.968; p = 0.006), to be a female (OR = 4.181; 95% CI 1.422-12.290; p = 0.009), and to have a greater increase in BDI-II (Beck Depression Inventory-II) (OR = 1.139; 95% CI 1.053-1.231; p = 0.001) and NMSS (Non-Motor Symptoms Scale) (OR = 1.052; 95% CI 1.027-1.113; p < 0.0001) total scores from V0 to V2 were associated with clinically significant HRQoL impairment at the 2-year follow-up (Hosmer-Lemeshow test, p = 0.665; R = 0.655). An increase in ≥5 and ≥10 points of BDI-II and NMSS total score at V2 multiplied the probability of presenting clinically significant HRQoL impairment by 5 (OR = 5.453; 95% CI 1.663-17.876; p = 0.005) and 8 (OR = 8.217; 95% CI, 2.975-22.696; p = 0.002), respectively. In conclusion, age, gender, mood, and non-motor impairment were associated with clinically significant HRQoL impairment after the 2-year follow-up in PD patients