Journal of Parkinson's Disease - Volume 10, issue 1

Authors: Sakakibara, Satoko | Hashimoto, Rina | Katayama, Taiji | Kenjyo, Masakuni | Yokokawa, Yuki | Saito, Yufuko | Hirakawa, Akihiro | Ito, Mizuki | Nakamura, Tomohiko | Hara, Kazuhiro | Hashizume, Atsushi | Aiba, Ikuko | Inukai, Akira | Katsuno, Masahisa

Article Type: Research Article

Abstract: Background: Both Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorder affecting striatonigral system. Although various lines of evidence demonstrate that dopaminergic neuron degeneration emerges before the onset of motor symptoms in PD, preclinical/prodromal progression of neurodegeneration is far less understood in MSA. Objective: The aim of this study was to clarify the difference in the progression of dopaminergic degeneration in MSA and PD using dopamine transporter single-photon emission computed tomography (DAT SPECT). Methods: We analyzed longitudinal data of the specific binding ratio (SBR), a measure of striatal radiotracer uptake, in DAT SPECT from …7 patients with MSA-C, 5 patients with MSA-P, and 18 patients with PD. We performed 2.7±0.7 scans with an interval of 9.85±6.00 months for MSA and 2 scans with an interval of 2.16±0.16 years for PD. Results: The rate of SBR decline was faster in both subtypes of MSA compared with PD, but the value was similar between MSA-P and MSA-C. The estimated SBR at the onset of initial motor symptoms was lower in PD and MSA-P than in MSA-C, especially in the predominantly affected side. SBR of the predominantly affected side starts to decrease before the onset of motor symptoms in PD and MSA-P, whereas the initiation of SBR decline is around the onset in MSA-C individuals. The decline of SBR in the less affected side was not clearly shown before the onset in MSA-P or MSA-C. Conclusions: Our results suggest that the SBR in DAT SPECT analysis is an important pathophysiological marker reflecting the disease- and subtype-specific progression of dopaminergic degeneration in MSA and PD. Show more

Keywords: Parkinson’s disease, multiple system atrophy, DAT SPECT, striatonigral degeneration, prodromal stage, preclinical

DOI: 10.3233/JPD-191710

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 123-130, 2020

Authors: Tanaka, Yasuhiro | Tsuboi, Takashi | Watanabe, Hirohisa | Nakatsubo, Daisuke | Maesawa, Satoshi | Kato, Sachiko | Kajita, Yasukazu | Sato, Maki | Oodake, Reiko | Hattori, Makoto | Yamamoto, Masahiko | Wakabayashi, Toshihiko | Katsuno, Masahisa | Sobue, Gen

Article Type: Research Article

Abstract: Background: Speech disorders are among the most common adverse effects after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients. However, longitudinal speech changes after STN-DBS are not fully understood. Objective: We performed a two-year prospective study on PD patients who underwent STN-DBS and analyzed changes in speech function to clarify factors predicting for speech deterioration. Methods: Twenty-five PD patients were assessed before and up to two years after STN implantation. Speech function was evaluated in the on-stimulation condition and 30 min after stimulation cessation using auditory-perceptual assessment. Patients who experienced overall worsening in speech …intelligibility or naturalness ≥1 point during follow-up were classified into a deteriorated group (n  = 16), with the remaining subjects being classified into a stable group (n  = 9). Cognitive and motor functions were also assessed. Results: The stable group had significantly better values of low volume, monoloudness, and asthenic voice subscores of the auditory-perceptual assessment in the on-stimulation condition compared with the off-stimulation condition. Imprecise consonants, excess loudness variation, and strained voice subscores were improved via cessation of stimulation in both groups. Before surgery, the deteriorated group had significantly lower scores in the Stroop Color-Word Test and Digit Span compared to the stable group. Conclusions: During follow-up, some subscores showed significant worsening in the on-stimulation condition in both groups. However, beneficial effects of STN-DBS on speech appeared to counterbalance negative effects of STN-DBS on speech function only in the stable group. Worse cognitive function may be a potential predictor for speech deterioration after STN-DBS in PD patients. Show more

Keywords: Parkinson’s disease, subthalamic nucleus deep brain stimulation, dysarthria, speech, voice, longitudinal change

DOI: 10.3233/JPD-191798

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 131-140, 2020

Authors: Gago, Miguel Fernandes | Azevedo, Olga | Guimarães, Andreia | Teresa Vide, Ana | Lamas, Nuno J. | Oliveira, Tiago Gil | Gaspar, Paulo | Bicho, Estela | Miltenberger-Miltenyi, Gabriel | Ferreira, Joaquim | Sousa, Nuno

Article Type: Research Article

Abstract: Background: Sporadic Parkinson’s disease (PD) patients have lower α -galactosidase A (α -GAL A) enzymatic activity and Fabry disease (FD) patients potentially carry an increased risk of PD. Objective: Determination of PD prevalence in FD and clinical, biochemical and vascular neuroimaging description of FD pedigrees with concomitant PD. Methods: Clinical screening for PD in 229 FD patients belonging to 31 families, harbouring GLA gene mutation p.F113L, and subsequent pedigree analysis. Gender-stratified comparison of FD+/PD+ patients with their family members with FD but without PD (FD+/PD–) regarding Mainz scores, plasma & leukocytes α -GAL A enzymatic …activity, urinary Gb3 and plasma Lyso-Gb3, vascular brain neuroimaging. Results: Prevalence of PD in FD was 1.3% (3/229) (3% in patients aged ≥50 years). Three FD patients, one female (73 years old) (P1) and two males (60 and 65 years old) (P2 and P3), three different pedigrees, presented akinetic-rigid PD, with weak response to levodopa (16% – 36%), and dopaminergic deficiency on 18F-DOPA PET. No pathogenic mutations were found in a PD gene panel. FD+/PD+ patients had worse clinical severity of FD (above upper 75% IQR in Mainz scores), and cortico-subcortical white matter/small vessel lesions. P3 patient was under enzyme therapy, started 1 year before PD diagnosis. P2-P3 patients had higher leucocyte α -GAL A activity (2,2-3 vs.1,0 (median)(nmol/h/mg)). Conclusion: We have shown a high prevalence of PD in a late-onset phenotype of FD, presenting high cerebrovascular burden and weak response to levodopa. Further studies will untangle how much of this PD phenotype is due to Gb3 deposition versus cerebrovascular lesions in the nigro-striatal network. Show more

Keywords: Fabry disease, Parkinson’s disease, GLA, α-galactosidase A, Gb3, brain magnetic resonance imaging

DOI: 10.3233/JPD-191704

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 141-152, 2020

Authors: Yoo, Sang-Won | Oh, Yoon-Sang | Yoo, Ji-Yeon | Ryu, Dong-Woo | Lee, Kwang-Soo | Shin, Na-Young | Kim, Joong-Seok

Article Type: Research Article

Abstract: Background: Cognitive impairment and cardiovascular dysautonomia are two major non-motor features of Parkinson’s disease (PD). They have been investigated separately and extensively, but their interactive outcomes have rarely been studied. Objective: The purpose of this study was to examine the association between central atrophy and cognition and to assess the influence of cardiovascular lability on this association in PD patients. Methods: Out of 151 early PD patients, 47 subjects were ultimately enrolled according to our selection criteria. Their cognitive status was examined by comprehensive neuropsychological tests assessing five domains of cognition. Supine and orthostatic blood pressures …were recorded during head-up tilt tests, and orthostatic mean arterial pressure change was calculated. Every patient underwent brain magnetic resonance imaging, and intercaudate nucleus ratio was obtained as a central atrophy surrogate marker. The associations and interactions between central atrophy, cognition, and blood pressure variability were analyzed. Results: Among 47 subjects, 20 (42.6%) had orthostatic hypotension. Attention/working memory, executive function, and delayed recall were inversely associated with central atrophy (r  = –0.332, p  = 0.028; r  = –0.314, p  = 0.038; r  = –0.399, p  = 0.024; respectively). In a multiple regression model, only attention/working memory was independently associated with central atrophy when modulated by orthostatic mean arterial pressure change (p  < 0.05). Conclusion: This study revealed that cardiovascular dysautonomia interacted with the inverse association between cerebral atrophy and cognition, and it reinforced its relationship. Interaction between these two non-motor features should be kept in mind in clinical practice, particularly in PD patients with co-morbid vascular factors. Show more

Keywords: Parkinson’s disease, subcortical atrophy, cardiovascular dysautonomia, cognition

DOI: 10.3233/JPD-191748

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 153-160, 2020

Authors: Hansen, Allan K. | Parbo, Peter | Ismail, Rola | Østergaard, Karen | Brooks, David J. | Borghammer, Per

Article Type: Research Article

Abstract: Background: Flortaucipir PET, a marker of tau tangles, has shown lower than expected cortical uptake in Parkinson’s disease (PD), than would be predicted from neuropathologic estimates of Alzheimer’s disease co-pathology. Instead, the most characteristic finding of flortaucipir imaging in PD is decreased uptake in the substantia nigra, reflecting reduction in its “off-target” binding to neuromelanin. We have previously reported these observations in cross-sectional studies. Objective: Here, we present two-year follow-up data of cortical and nigral flortaucipir uptake in PD patients. Methods: Seventeen PD patients received repeat flortaucipir PET two years after baseline. We interrogated vertex-based group-wise …cortical tracer binding (SUVRs) with a cerebellar reference using the general linear model while mean substantia nigra SUVRs were compared with volumes of interest group comparisons and voxel-wise group analyses using ANOVA. Finally, we performed linear regressions of tau load with changes in MoCA and UPDRS motor scores. Results: We found no significant changes in substantia nigra or cortex flortaucipir uptake in Parkinson’s disease patients over two years and no association with changes in cognitive symptoms. Signal reduction in the medial substantia nigra trended towards an association with worsening of motor symptoms. Conclusion: No significant increase in tau tangles occurred after a two-year follow-up of Parkinson’s disease patients using flortaucipir PET. Show more

Keywords: Parkinson’s disease, dementia, neurofibrillary tangles, melanins, positron emission tomography

DOI: 10.3233/JPD-191774

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 161-171, 2020

Authors: Snineh, Muneer Abu | Hajyahya, Amal | Linetsky, Eduard | Eitan, Renana | Bergman, Hagai | Israel, Zvi | Arkadir, David

Article Type: Research Article

Abstract: Background: A wide variety of conversion factors for a levodopa-equivalent-dose (LED) have been proposed for each Parkinson’s disease (PD) medication. The currently-used set of conversion factors is based on studies that relied on subjective experience or theoretical assumptions. This set was never validated in patients receiving polytherapy. Objectives: To use real-life data to identify an optimal set of conversion factors independent of prior assumptions regarding clinical efficacy of different medications. Methods: Retrospective analysis of data from 206 cognitively-preserved patients with advanced PD receiving polytherapy before deep brain stimulation (DBS) surgery. A nonlinear automated problem solver was …used to find a set of conversion factors that, when applied, minimized the coefficient of variation of LEDs in a relatively homogenous cohort of patients. Results: Independent and model-free evaluation of a wide range of possible sets of conversion factors to LED suggested a set of normalized conversion factors for immediate release levodopa (1.00), controlled release levodopa (0.88), and amantadine (1.23). A minimal clinical benefit of entacapone was observed for patients with motor fluctuations. Our analysis could not detect conversion factors for dopamine agonists and MAO-B inhibitors, possibly because their clinical contribution when added to levodopa is limited. Conclusions: Independent from previous studies and prior assumptions we show that the currently-used LED conversion factors for immediate release levodopa, controlled release levodopa and amantadine are largely correct and that dopamine agonists, MAO-B inhibitors and entacapone, given in addition to levodopa, have little additional clinical value for PD patients with motor fluctuations. Show more

Keywords: Parkinson’s disease, clinical pharmacology, levodopa, dopamine agonists, amantadine, retrospective study

DOI: 10.3233/JPD-191769

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 173-178, 2020

Authors: Stang, Cole D. | Turcano, Pierpaolo | Mielke, Michelle M. | Josephs, Keith A. | Bower, James H. | Ahlskog, J. Eric | Boeve, Bradley F. | Martin, Peter R. | Upadhyaya, Sudhindra G. | Savica, Rodolfo

Article Type: Research Article

Abstract: Background: Few studies have investigated the incidence of PSP and CBS in the population. Objective: To examine the incidence of and trends in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) in a population-based cohort of residents of Olmsted County, MN. Methods: We used the 1991-2005 population-based, Olmsted County Parkinsonism-cohort study, defined via the Rochester Epidemiology Project. A movement-disorder specialist reviewed medical records, to confirm PSP and CBS diagnoses. Results: We identified 21 patients with these diagnoses 1991-2005 : 18 (85.7%), PSP; 3 (14.3%), CBS. The median diagnosis age was 78 (range: 66-88). 13/21 (62.0%) were …male. MRI was performed pre-diagnosis in 11 patients (8 PSP and 3 CBD); 10 showed atrophy consistent with clinical diagnoses. We observed concordance between clinical and pathological diagnoses in two PSP patients who underwent autopsy. Combined incidence for PSP and CBS in Olmsted County was 3.1 per 100,000 person-years (2.6 per 100,000 person-years, PSP; 0.4 per 100,000 person-years, CBS). Incidence was higher in men (4.5, 95% CI, 2.0-7.0) than women (1.8, 95% CI, 0.5-2.9). A combined, significant trend of increasing incidence was observed between 1991 and 2005 (B=0.69, 95% CI 0.42, 0.96, p<0.001). Median time from symptom onset to death among both groups was 6 years (range PSP, 1-10 years; range CBS, 3-8 years). Conclusions: The combined incidence for PSP and CBS was 3.1 per 100,000 person-years, higher in men than women. We observed a significant increase in both PSP and CBS, likely due to advancing imaging technology and improved diagnostic ability among physicians. Show more

Keywords: Progressive supranuclear palsy, corticobasal syndrome, incidence, population-based cohort

DOI: 10.3233/JPD-191744

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 179-184, 2020

Authors: Vidal-Martinez, Guadalupe | Chin, Brandon | Camarillo, Cynthia | Herrera, Gloria V. | Yang, Barbara | Sarosiek, Irene | Perez, Ruth G.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) and multiple system atrophy (MSA) patients often suffer from gastrointestinal (GI) dysfunction and GI dysbiosis (microbial imbalance). GI dysfunction also occurs in mouse models of PD and MSA. Objectives: To assess gut dysfunction and dysbiosis in PD subjects as compared to controls, identify potential shared microbial taxa in humans and mouse models of PD and MSA, and to assess the effects of potential therapies on mouse GI microbiota. Methods: In this human pilot study, GI function was assessed by fecal consistency/frequency measured using the Bristol Stool Form Scale and GI transit time …assessed using Sitzmarks pills and abdominal radiology. Human and mouse microbiota were analyzed by extracting fecal genomic DNA followed by 16S rRNA sequencing. Results: In our PD patients genera Akkermansia significantly increased while a trend toward increased Bifidobacterium and decreased Prevotella was observed. Families Bacteroidaceae and Lachnospiraceae and genera Prevotella and Bacteroides were detected in both humans and PD mice, suggesting potential shared biomarkers. In mice treated with the approved multiple sclerosis drug, FTY720, or with our FTY720-Mitoxy-derivative, we saw that FTY720 had little effect while FTY720-Mitoxy increased beneficial Ruminococcus and decreased Rickenellaceae family. Conclusion: Akkermansia and Prevotellaceae data reported by others were replicated in our human pilot study suggesting the use of those taxa as potential biomarkers for PD diagnosis. The effect of FTY720-Mitoxy on taxa Rikenellaceae and Ruminococcus and the relevance of S24-7 await further evaluation. It also remains to be determined if mouse microbiota have predictive power for human subjects. Show more

Keywords: Microbiota, Parkinson’s disease, multiple system atrophy, FTY720, FTY720-Mitoxy, transgenic mouse models

DOI: 10.3233/JPD-191693

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 185-192, 2020

Authors: Martin-Ruiz, Carmen | Williams-Gray, Caroline H. | Yarnall, Alison J. | Boucher, John J. | Lawson, Rachael A. | Wijeyekoon, Ruwani S. | Barker, Roger A. | Kolenda, Claire | Parker, Craig | Burn, David J. | Von Zglinicki, Thomas | Saretzki, Gabriele

Article Type: Research Article

Abstract: Background: Cognitive decline is a frequent complication of Parkinson’s disease (PD) and the identification of predictive biomarkers for it would help in its management. Objective: Our aim was to analyse whether senescence markers (telomere length, p16 and p21) or their change over time could help to better predict cognitive and motor progression of newly diagnosed PD patients. We also compared these senescence markers to previously analysed markers of inflammation for the same purpose. Methods: This study examined the association of blood-derived markers of cell senescence and inflammation with motor and cognitive function over time in an …incident PD cohort (the ICICLE-PD study). Participants (154 newly diagnosed PD patients and 99 controls) underwent physical and cognitive assessments over 36 months of follow up. Mean leukocyte telomere length and the expression of senescence markers p21 and p16 were measured at two time points (baseline and 18 months). Additionally, we selected five inflammatory markers from existing baseline data. Results: We found that PD patients had shorter telomeres at baseline and 18 months compared to age-matched healthy controls which also correlated to dementia at 36 months. Baseline p16 levels were associated with faster rates of motor and cognitive decline over 36 months in PD cases, while a simple inflammatory summary score at baseline best predicted cognitive score over this same time period in PD patients. Conclusion: Our study suggests that both inflammatory and senescence markers (p16) are valuable predictors of clinical progression in PD patients. Show more

Keywords: Parkinson’s disease, telomere length, senescence, p16, p21, inflammation, biomarker, cognitive impairment, dementia

DOI: 10.3233/JPD-191724

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 193-206, 2020

Authors: Rompen, Lonneke | de Vries, Nienke M. | Munneke, Marten | Neff, Carolyn | Sachs, Todd | Cedrone, Steve | Cheves, Jason | Bloem, Bastiaan R.

Article Type: Research Article

Abstract: Background: Early 2014, Kaiser Permanente decided to adopt an innovative model for network-based allied healthcare for persons with Parkinson’s disease (PD), based on the principles of the Dutch ParkinsonNet. Objective: We present the interventions that were performed to implement this method at Kaiser Permanente and we show the first outcomes based on these interventions. Methods: In this study, 57 physical therapists, 18 speech therapists and 20 occupational therapists, as well as 13 medical centers across the state of California were included. Nine interventions were performed more or less simultaneously, including training and education of healthcare providers …and patients, a train the trainer curriculum, organizing IT, streamlining referral processes and building networks. Results: At the start, less than 30% of the patients within the Southern California Region received specialized allied health treatment (consisting of, i.e., gait training, voice training or guidance in activities of daily life). After one year, almost 55% of patients received specialized allied health treatment. In the second year, this number increased to just under 67%, suggesting a sustained concentration of care (the second core component of networked care). This can be seen as a first indicator for successful implementation of the ParkinsonNet network at Kaiser Permanente. Conclusions: The importance of these findings lies in the fact that a healthcare innovation that proved effective in one country can be transferred successfully to another country and to another healthcare system. Show more

Keywords: Networks, integrated care, health reform, Parkinson’s disease, ParkinsonNet, Kaiser Permanente

DOI: 10.3233/JPD-191620

Citation: Journal of Parkinson's Disease, vol. 10, no. 1, pp. 207-212, 2020