Background
Parkinsonian syndromes are characterized by a wide spectrum of non-motor symptoms. A few studies explored cognitive deficits and neuropsychiatric symptoms in atypical parkinsonism compared ...to Parkinson’s disease (PD). The study was performed to identify cognitive and neuropsychiatric differences between PD, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and to evaluate the influence of clinical features, depressive symptomatology and apathy on cognitive performances in the three groups.
Methods
Fifty-five PD, 44 MSA and 42 PSP patients underwent cognitive tests assessing attention, language, memory, visuospatial and executive functions as well as scales assessing depression and apathy. Out of these patients, 20 PD, 20 MSA and 20 PSP patients were selected to be matched for age, education and global cognitive status. Within each whole patients group, correlational analysis was performed between clinical, behavioural and cognitive parameters.
Results
The main difference among the groups matched was on cognitive tests exploring verbal learning, executive and linguistic functions. The PSP group was more impaired than the PD and MSA groups on cognitive tests assessing executive functions. On the other hand, MSA group obtained similar cognitive performance to the PD group. As to behavioural symptoms, in whole PSP and MSA groups, apathy and depression were more severe than in PD group, while apathy (but not depression) were more severe in the PSP group as compared to the MSA group.
Conclusions
The present study underlined the pervasiveness of cognitive deficits, apathy and depressive symptoms in PSP, whereas little cognitive differences were found between PD and MSA. The findings indirectly supported a dysfunction of prefronto-subcortical circuitries (i.e., dorsolateral prefrontal and limbic circuits) in PSP and PD. Cognitive similarities between MSA and PD reinforced the pivotal role of altered basal ganglia and corresponding frontal deafferentation in the occurrence of the cognitive deficits.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To evaluate intraocular pressure (IOP) and choroidal thickness (ChT) postural changes in multiple system atrophy (MSA), Parkinson's disease (PD) patients and healthy controls (HC). 20 MSA patients, ...21 PD patients and 14 HC, were examined. All subjects underwent a complete examination, including corneal thickness, ChT, IOP and axial length (AL) measurements. IOP measurement was performed in supine, sitting, and standing positions, whereas ChT in sitting and standing positions. Supine to standing IOP variations were significantly higher in MSA vs PD(p = 0.01) and in MSA vs HC (p < 0.0001), whereas no significant differences were observed between PD and HC (p = 0.397). Mean sub-foveal ChT in MSA was 240 ± 92 μm in sitting position, and 215 ± 94 μm in standing position with a significant reduction (p = 0.008). Mean sub-foveal ChT in PD was 258 ± 79 μm in sitting position, and 259 ± 76 μm in standing position (p = 0.887). In HC it was 244 ± 36 μm in sitting position, and 256 ± 37 μm in standing position with a significant increase (p = 0.007). The significant IOP and ChT postural changes can be considered additional hallmarks of autonomic dysfunction in MSA and further studies are needed to consider them as biomarkers in the differential diagnosis with PD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Progressive supranuclear palsy (PSP) is a rare and rapidly progressing atypical parkinsonism. Albeit existing clinical criteria for PSP have good specificity and sensitivity, there is a need for ...biomarkers able to capture early objective disease-specific abnormalities. This study aimed to identify gait patterns specifically associated with early PSP. The study population comprised 104 consecutively enrolled participants (83 PD and 21 PSP patients). Gait was investigated using a gait analysis system during normal gait and a cognitive dual task. Univariate statistical analysis and binary logistic regression were used to compare all PD patients and all PSP patients, as well as newly diagnosed PD and early PSP patients. Gait pattern was poorer in PSP patients than in PD patients, even from early stages. PSP patients exhibited reduced velocity and increased measures of dynamic instability when compared to PD patients. Application of predictive models to gait data revealed that PD gait pattern was typified by increased cadence and longer cycle length, whereas a longer stance phase characterized PSP patients in both mid and early disease stages. The present study demonstrates that quantitative gait evaluation clearly distinguishes PSP patients from PD patients since the earliest stages of disease. First, this might candidate gait analysis as a reliable biomarker in both clinical and research setting. Furthermore, our results may offer speculative clues for conceiving early disease-specific rehabilitation strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the ...presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinson's disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P2, but this function appears normal in SynaptojaninRQ knock‐in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P2, two lipids found in autophagosomal membranes. Using advanced imaging, we show that SynaptojaninRQ mutants accumulate the PI(3)P/PI(3,5)P2‐binding protein Atg18a on nascent synaptic autophagosomes, blocking autophagosome maturation at fly synapses and in neurites of human patient induced pluripotent stem cell‐derived neurons. Additionally, we observe neurodegeneration, including dopaminergic neuron loss, in SynaptojaninRQ flies. Thus, synaptojanin is essential for macroautophagy within presynaptic terminals, coupling protein turnover with synaptic vesicle cycling and linking presynaptic‐specific autophagy defects to Parkinson's disease.
Synopsis
Parkinson's disease‐related human synaptojanin 1 (SYNJ1) or Drosophila synaptojanin (Synj) SAC1 function drives autophagosome biogenesis within synapses by dephosphorylating PI(3)P/PI(3,5)P2, releasing WIPI2/Atg18a from immature autophagosomes, independent from Synj function in endocytosis.
Parkinson's disease related synaptojanin RQ SAC1 mutation does not affect synaptic vesicle endocytosis at fly excitatory glutamatergic neurons and photoreceptors.
Synaptojanin is required for autophagosome formation in presynaptic terminals, analogous to synaptic vesicle uncoating by synaptojanin.
The PI(3)P/PI(3,5)P2‐binding protein, WIPI2/Atg18a accumulates in Synj mutant flies and SYNJ1 R258Q patient‐derived human induced neurons.
Synaptojanin regulates Atg18a mobility at autophagosomal membranes.
Synaptojanin RQ knock‐in flies show neurodegeneration.
The Parkinson's disease‐associated lipid phosphatase synaptojanin promotes synaptic autophagosome formation, a function that is impaired by pathogenic mutations.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cervical dstonia (CD) is a chronic disorder with a significant detrimental impact on quality of life, requiring long-term treatment. Intramuscular injections of botulinum neurotoxin (BoNT) every 12 ...to 16 weeks have become the first-line option for CD. Despite the remarkable efficacy of BoNT as a treatment for CD, a significantly high proportion of patients report poor outcomes and discontinue the treatment. The reasons that drive sub-optimal response or treatment failure in a proportion of patients include but are not limited to inappropriate muscle targets and/or BoNT dosing, improper method of injections, subjective feeling of inefficacy, and the formation of neutralizing antibodies against the neurotoxin. The current review aims to complement published research focusing on the identification of the factors that might explain the failure of BoNT treatment in CD, highlighting possible solutions to improve its outcomes. Thus, the use of the new phenomenological classification of cervical dystonia known as COL-CAP might improve the identification of the muscle targets, but more sensitive information might come from the use of kinematic or scintigraphic techniques and the use of electromyographic or ultrasound guidance might ensure the accuracy of the injections. Suggestions are made for the development of a patient-centered model for the management of cervical dystonia and to emphasize that unmet needs in the field are to increase awareness about the non-motor spectrum of CD, which might influence the perception of the efficacy from BoNT injections, and the development of dedicated rehabilitation programs for CD that might enhance its effectiveness.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The variability in the clinical phenotype of Parkinson's disease seems to suggest the existence of several subtypes of the disease. To test this hypothesis we performed a cluster analysis using data ...assessing both motor and non-motor symptoms in a large cohort of newly diagnosed untreated PD patients.
We collected data on demographic, motor, and the whole complex of non-motor symptoms from 100 consecutive newly diagnosed untreated outpatients. Statistical cluster analysis allowed the identification of different subgroups, which have been subsequently explored.
The data driven approach identified four distinct groups of patients, we have labeled: 1) Benign Pure Motor; 2) Benign mixed Motor-Non-Motor; 3) Non-Motor Dominant; and 4) Motor Dominant.
Our results confirmed the existence of different subgroups of early PD patients. Cluster analysis revealed the presence of distinct subtypes of patients profiled according to the relevance of both motor and non-motor symptoms. Identification of such subtypes may have important implications for generating pathogenetic hypotheses and therapeutic strategies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The use of wearable sensors for calculating gait parameters has become increasingly popular as an alternative to optoelectronic systems, currently recognized as the gold standard. The objective of ...the study was to evaluate the agreement between the wearable Opal system and the optoelectronic BTS SMART DX system for assessing spatiotemporal gait parameters. Fifteen subjects with progressive supranuclear palsy walked at their self-selected speed on a straight path, and six spatiotemporal parameters were compared between the two measurement systems. The agreement was carried out through paired data test, Passing Bablok regression, and Bland-Altman Analysis. The results showed a perfect agreement for speed, a very close agreement for cadence and cycle duration, while, in the other cases, Opal system either under- or over-estimated the measurement of the BTS system. Some suggestions about these misalignments are proposed in the paper, considering that Opal system is widely used in the clinical context.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Introduction In PD, Mild Cognitive Impairment (PD-MCI) occurs since early stages of disease. The aims were to assess presence of PD-MCI in untreated, drug-naive PD patients, and to follow-up ...the sample over 4 years to ascertain evolution of neurocognitive profile. Methods Seventy-six patients underwent neuropsychological testing at baseline (T0), and after 2 (T1:n = 62) and 4 years (T2:n = 55). Diagnosis of PD-MCI and PD-associated dementia (PDD) was made according to current consensus criteria. Results PD-MCI occurred in 25/76 patients (32.9%) at baseline, and 4 of them reverted from PD-MCI to Normal Cognition (Reverters), 7 remained stable (Non-Reverters) and 2 developed PDD at T2; 12 patients were lost to the follow-up. Among the 51 patients with normal cognition (PD-CN) at T0, 27 had normal cognition at T2 (5 of them were Reverters with respect to diagnosis at T1), 5 had MCI at T1 and T2 (Non-Reverters), 9 had MCI at T2 only, whereas 1 developed PDD; 9 patients were lost to the follow-up. At baseline, Reverters (n = 9) had younger age at onset and better performance on constructional visuospatial task than Non-Reverters (n = 12). Compared to patients without PD-MCI at all evaluations (n = 19), Reverters had poorer performance on verbal immediate recall and attention tasks and higher level of apathy at T0. Reduced performance on the Stroop Test at baseline predicted PD-MCI at T2. Conclusion Executive dysfunctions predicted development of PD-MCI after few years from onset. Reversal from PD-MCI to PD-CN was related to young age at onset and high level of apathy at baseline evaluation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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