Structural and microstructural predictors of cognitive decline in deep brain stimulation of subthalamic nucleus in Parkinson's disease.

BACKGROUND AND OBJECTIVES: The intricate relationship between deep brain stimulation (DBS) in Parkinson's disease (PD) and cognitive impairment has lately garnered substantial attention. The presented study evaluated pre-DBS structural and microstructural cerebral patterns as possible predictors of future cognitive decline in PD DBS patients. METHODS: Pre-DBS MRI data in 72 PD patients were combined with neuropsychological examinations and follow-up for an average of 2.3 years after DBS implantation procedure using a screening cognitive test validated for diagnosis of mild cognitive impairment in PD in a Czech population - Dementia Rating Scale 2. RESULTS: PD patients who would exhibit post-DBS cognitive decline were found to have, already at the pre-DBS stage, significantly lower cortical thickness and lower microstructural complexity than cognitively stable PD patients. Differences in the regions directly related to cognition as bilateral parietal, insular and cingulate cortices, but also occipital and sensorimotor cortex were detected. Furthermore, hippocampi, putamina, cerebellum and upper brainstem were implicated as well, all despite the absence of pre-DBS differences in cognitive performance and in the position of DBS leads or stimulation parameters between the two groups. CONCLUSIONS: Our findings indicate that the cognitive decline in the presented PD cohort was not attributable primarily to DBS of the subthalamic nucleus but was associated with a clinically silent structural and microstructural predisposition to future cognitive deterioration present already before the DBS system implantation.

Impaired dual-task gait in Parkinson's disease is associated with brain morphology changes.

In Parkinson's disease (PD), impaired gait and cognition affect daily activities, particularly in the more advanced stages of the disease. This study investigated the relationship between gait parameters, cognitive performance, and brain morphology in patients with early untreated PD. 64 drug-naive PD patients and 47 healthy controls (HC) participated in the study. Single- and dual-task gait (counting task) were examined using an expanded Timed Up & Go Test measured on a GaitRite walkway. Measurements included gait speed, stride length, and cadence. A brain morphometry analysis was performed on T1-weighted magnetic resonance (MR) images. In PD patients compared to HC, gait analysis revealed reduced speed (p < 0.001) and stride length (p < 0.001) in single-task gait, as well as greater dual-task cost (DTC) for speed (p = 0.007), stride length (p = 0.014) and cadence (p = 0.029). Based on the DTC measures in HC, PD patients were further divided into two subgroups with normal DTC (PD-nDTC) and abnormally increased DTC (PD-iDTC). For PD-nDTC, voxel-based morphometric correlation analysis revealed a positive correlation between a cluster in the left primary motor cortex and stride-length DTC (r = 0.57, p = 0.027). For PD-iDTC, a negative correlation was found between a cluster in the right lingual gyrus and the DTC for gait cadence (r=-0.35, pFWE = 0.018). No significant correlations were found in HC. The associations found between brain morphometry and gait performance with a concurrent cognitive task may represent the substrate for gait and cognitive impairment occurring since the early stages of PD.

Directed functional connectivity of the default-mode-network of young and older healthy subjects.

Alterations in the default mode network (DMN) are associated with aging. We assessed age-dependent changes of DMN interactions and correlations with a battery of neuropsychological tests, to understand the differences of DMN directed connectivity between young and older subjects. Using a novel multivariate analysis method on resting-state functional MRI data from fifty young and thirty-one healthy older subjects, we calculated intra- and inter-DMN 4-nodes directed pathways. For the old subject group, we calculated the partial correlations of inter-DMN pathways with: psychomotor speed and working memory, executive function, language, long-term memory and visuospatial function. Pathways connecting the DMN with visual and limbic regions in older subjects engaged at BOLD low frequency and involved the dorsal posterior cingulate cortex (PCC), whereas in young subjects, they were at high frequency and involved the ventral PCC. Pathways combining the sensorimotor (SM) cortex and the DMN, were SM efferent in the young subjects and SM afferent in the older subjects. Most DMN efferent pathways correlated with reduced speed and working memory. We suggest that the reduced sensorimotor efferent and the increased need to control such activities, cause a higher dependency on external versus internal cues thus suggesting how physical activity might slow aging.

Comparison of quantitative REM without atonia parameters in isolated REM sleep behavior disorder and early untreated Parkinson's disease.

OBJECTIVES: To analyze REM sleep without atonia (RWA) metrics in patients with isolated REM sleep behavior disorder (iRBD), Parkinson's disease (PD) and healthy subjects and compare them in terms of degree of presumed brainstem damage. METHODS: Forty-nine iRBD patients, 62 PD patients and 38 healthy controls were included into the analysis. Detailed polysomnographic and clinical data including motor, olfactory, autonomic, and cognitive assessment were obtained in all participants and subsequently compared within groups without RBD (i.e., healthy controls, PD-RBD-) and with RBD (i.e., iRBD, PD-RBD+). SINBAR criteria were used to score RWA. RESULTS: Twenty-one PD patients (33.8 %) had RBD. When comparing PD-RBD-patients and controls, RWA tonic (p = 0.001) and RWA mixed (p = 0.03) were higher in PD-RBD-group. PD-RBD-patients had worse olfactory function than controls (p < 0.001); no significant difference in autonomic or cognitive function was registered. There were no significant differences in RWA parameters when comparing iRBD and PD-RBD + groups. iRBD patients had better olfactory function than PD-RBD+ (p = 0.006); no significant difference in autonomic or cognitive function was registered. PD-RBD + had worse autonomic (p = 0.006) and olfactory (p = 0.001) but not motor and cognitive function compared to PD-RBD-. CONCLUSIONS: Untreated de-novo PD patients without RBD have increased RWA metrics compared to healthy subjects indicating subclinical degeneration of brainstem nuclei responsible for RWA. iRBD patients do not differ in RWA metrics from untreated de-novo PD patients with premotor RBD suggesting a similar level of brainstem degeneration caudal to substantia nigra in both groups. Groups with RBD are associated with autonomic dysfunction.

Cortical and subcortical morphometric changes and their relation to cognitive impairment in isolated REM sleep behavior disorder.

OBJECTIVE: To date, very few studies have focused on structural changes and their association with cognitive performance in isolated REM sleep behaviour disorder (iRBD). Moreover, the results of these studies are inconclusive. This study aims to evaluate differences in the associations between brain morphology and cognitive tests in iRBD and healthy controls. METHODS: Sixty-three patients with iRBD and thirty-six controls underwent MRI with a 3 T scanner. The cognitive performance was assessed by a comprehensive neuropsychological battery. Based on performance, the iRBD group was divided into two subgroups with (iRBD-MCI) and without mild cognitive impairment (iRBD-NC). The high-resolution T1-weighted images were analysed using an automated atlas segmentation tool, voxel-based (VBM) and deformation-based (DBM) morphometry to identify between-group differences and correlations with cognitive performance. RESULTS: VBM, DBM and the comparison of ROI volumes yielded no significant differences between iRBD and controls. In the iRBD group, significant correlations in VBM were found between several cortical and subcortical structures primarily located in the temporal, parietal, occipital lobe, cerebellum, and basal ganglia and three cognitive tests assessing psychomotor speed and one memory test. Between-group analysis of cognition revealed a significant difference between iRBD-MCI and iRBD-NC in tests including a processing speed component. CONCLUSIONS: iRBD shows deficits in several cognitive tests that correlate with morphological changes, the most prominent of which is in psychomotor speed and visual attention as measured by the TMT-A and associated with the volume of striatum, insula, cerebellum, temporal lobe, pallidum and amygdala.

Directed functional connectivity of the sensorimotor system in young and older individuals.

Introduction: Studies in the sensorimotor system of older versus young individuals have shown alterations in functional connectivity and organization. Our objective was to explore the implications of these differences in terms of local organizations, and to identify processes that correlate with neuropsychological parameters. Methods: Using a novel multivariate analysis method on resting-state functional MRI data obtained from 50 young and 31 older healthy individuals, we identified directed 4-node functional pathways within the sensorimotor system and examined their correlations with neuropsychological assessments. Results: In young individuals, the functional pathways were unidirectional, flowing from the primary motor and sensory cortices to higher motor and visual regions. In older individuals, the functional pathways were more complex. They originated either from the calcarine sulcus or the insula and passed through mutually coupled high-order motor areas before reaching the primary sensory and motor cortices. Additionally, the pathways in older individuals that resembled those found in young individuals exhibited a positive correlation with years of education. Discussion: The flow pattern of young individuals suggests efficient and fast information transfer. In contrast, the mutual coupling of high-order motor regions in older individuals suggests an inefficient and slow transfer, a less segregated and a more integrated organization. The differences in the number of sensorimotor pathways and of their directionality suggests reduced efferent degenerated pathways and increased afferent compensated pathways. Furthermore, the positive effect of years of education may be associated with the Cognitive Reserve Hypothesis, implying that cognitive reserve could be maintained through specific information transfer pathways.

Instrumental activities of daily living and mild cognitive impairment.

BACKGROUND: Functional impairments are a necessary requirement for the diagnosis of a dementia along with observed cognitive impairment. Comparatively, functional abilities are often relatively intact in those with mild cognitive impairment (MCI). OBJECTIVE: The current research examined the associations between memory clinic participants classified as cognitively intact, amnestic MCI, and mixed/dysexecutive MCI, using Jak-Bondi criteria, and Instrumental Activities of Daily Living - Compensation Scale (IADL-C) abilities, an informant-based questionnaire that quantifies functional abilities. The associations between functional abilities as assessed with the IADL-C and performance on neuropsychological tests were also investigated. METHODS: IADLC scores were obtained along with a comprehensive neuropsychological protocol on memory clinic participants (n = 100) classified as cognitively normal (CN), amnestic MCI (aMCI), or a combined mixed/dysexecutive (mixed/dys) MCI. Regression analyses were employed to determine how the IADLC related to neuropsychological test performance. RESULTS: On the IADLC, greater functional impairment was commonly observed in the mixed/dys MCI group compared to CN participants. Furthermore, the mixed/dys MCI group had lower scores on activities such as Money and Self-Management, Travel and Event Memory subscales compared to the CN group. Linear regression analyses found greater functional impairment in relation to lower scores on executive and episodic memory tests. CONCLUSIONS: Greater functional impairment as assessed with the IADL-C appears to be disproportionately associated with dysexecutive difficulty, and to a lesser degree, episodic memory.

Magnetic susceptibility changes in the brainstem reflect REM sleep without atonia severity in isolated REM sleep behavior disorder.

REM sleep without atonia (RWA) is the hallmark of isolated REM sleep behavior disorder (iRBD) and is caused by neurodegeneration of brainstem structures. Previously, quantitative susceptibility mapping (QSM) was shown to detect microstructural tissue changes in neurodegenerative diseases. The goal of the study was to compare brainstem magnetic susceptibility (MS) in iRBD and controls using the voxel-based QSM approach and to examine the association between brainstem MS and severity of RWA in iRBD. Sixty iRBD patients and 41 healthy controls were included in the study. Phasic, tonic, mixed RWA and SINBAR score was quantified. QSM maps were reconstructed with QSMbox software from a multi-gradient-echo sequence acquired at 3T MRI system and normalized using a custom T1 template. Voxel-based analysis with age and gender as covariates was performed using a two-sample t-test model for between-group comparison and using a linear regression model for association with the RWA parameters. Statistical maps were generated using threshold free cluster enhancement with p-value p < 0.05, corrected for family wise error. Compared to controls, the iRBD group had higher MS in bilateral substantia nigra (SN), red nucleus and the ventral tegmental area. MS positively correlated with iRBD duration in the right pedunculotegmental nucleus and white matter of caudal mesencephalic and pontine tegmentum and with phasic RWA in bilateral SN. QSM was able to detect MS abnormalities in several brainstem structures in iRBD. Association of MS levels in the brainstem with the intensity of RWA suggests that increased iron content in SN is related to RWA severity.

Establishing normative data for the evaluation of cognitive performance in Huntington's disease considering the impact of gender, age, language, and education.

BACKGROUND: A declining cognitive performance is a hallmark of Huntington's disease (HD). The neuropsychological battery of the Unified HD Rating Scale (UHDRS'99) is commonly used for assessing cognition. However, there is a need to identify and minimize the impact of confounding factors, such as language, gender, age, and education level on cognitive decline. OBJECTIVES: Aim is to provide appropriate, normative data to allow clinicians to identify disease-associated cognitive decline in diverse HD populations by compensating for the impact of confounding factors METHODS: Sample data, N = 3267 (60.5% females; mean age of 46.9 years (SD = 14.61, range 18-86) of healthy controls were used to create a normative dataset. For each neuropsychological test, a Bayesian generalized additive model with age, education, gender, and language as predictors was constructed to appropriately stratify the normative dataset. RESULTS: With advancing age, there was a non-linear decline in cognitive performance. In addition, performance was dependent on educational levels and language in all tests. Gender had a more limited impact. Standardized scores have been calculated to ease the interpretation of an individual's test outcome. A web-based online tool has been created to provide free access to normative data. CONCLUSION: For defined neuropsychological tests, the impact of gender, age, education, and language as factors confounding disease-associated cognitive decline can be minimized at the level of a single patient examination.

Höffding step and beyond: The impact of visual sensory impairment on cognitive performance in neuropsychological testing of survivors of acute methanol poisoning.

BACKGROUND: Sensory deficits can result in limitations regarding how well neuropsychological test findings can be interpreted. Only a few studies have investigated the influence of vision alteration on neuropsychological tests. In 2012 the Czech Republic experienced mass methanol poisoning. Methanol metabolites cause histotoxic hypoxia to the optic nerve. OBJECTIVE: In the current study, the effect of the toxic damage on the parts of the visual pathway on visual and non-visual neuropsychological measures was investigated using electrophysiological methods (visual evoked potential (VEP) and optical coherence tomography (OCT) with retinal nerve fibre layer (RNFL) thickness measurement. METHODS: 53 individuals who experienced methanol poisoning participated in this research (76% men; ages 24 to 74 years, mean = 43.8±14.6 years; education 11.9±1.4 years). Each participant underwent comprehensive neurological, ophthalmological, and neuropsychological examinations. RESULTS: The results of mixed-effect models revealed significant small to a medium association between the Stroop test weak interference and Grooved Pegboard with the left eye global, nasal and temporal RNFL thickness. Also, medium associations between the Finger Tapping test and the Stroop test weak interference and left eye temporal RNFL, right eye temporal RNFL, and the latency P1 of VEP in the left eye were significant. CONCLUSION: The results of this study found a small to medium association (r = .15- .33; p = .010- .046) between RNFL thickness and cognitive visual test performance. Careful interpretation is suggested regarding results obtained from visual tests of the executive or motor functioning with participants with RNFL decrease or other types of early visual processing damage.

Reducing misclassification of mild cognitive impairment based on base rate information from the Uniform data set.

The current study aimed to define and validate the criteria for characterizing possible and probable cognitive deficits based on the psychometric approach using the Uniform data set Czech version (UDS-CZ 2.0) to reduce the rate of misdiagnosis. We computed the prevalence of low scores on the 14 subtests of UDS-CZ 2.0 in a normative sample of healthy older adults and validated criteria for possible and probable cognitive impairment on the sample of amnestic Mild Cognitive Impairment (MCI) patients. The misclassification rate of the validation sample using psychometrically derived criteria remained low: for classification as possible impairment, we found 66-76% correct classification in the clinical sample and only 2-8% false positives in the healthy control validation sample, similar results were obtained for probable cognitive impairment. Our findings offer a psychometric approach and a computational tool to minimize the misdiagnosis of mild cognitive impairment compared to traditional criteria for MCI.

Characterization of memory profile in idiopathic REM sleep behavior disorder.

OBJECTIVE: The present study aims to examine whether declarative memory dysfunction relates to impaired core memory mechanisms or attentional and executive dysfunction in idiopathic REM Sleep Behavior Disorder (iRBD). METHOD: In this observational, cross-sectional study, were enrolled 82 individuals with the diagnosis of iRBD according to the International Classification of Sleep Disorders and 49-matched healthy controls fulfilling inclusion criteria. All participants underwent two memory tasks, namely the Rey Auditory Verbal Learning Test (RAVLT) and Memory Binding Test (MBT), which include conditions of varying degrees of dependence on executive functioning, as well as different indicators of core memory processes (e.g., learning, retention, relational binding). RESULTS: We used Bayesian multivariate generalized linear model analysis to evaluate the effect of iRBD on memory performance controlled for effects of age and sex. Individuals with iRBD displayed worse memory performance in the delayed free recall task (b = -0.37, 95% PPI [-0.69, -0.05]), but not on delayed recognition of the same material. Their performance in cued recall tasks both in immediate and delayed conditions was in comparison to controls relatively spared. Moreover, the deficit in delayed free recall was mediated by attention/processing speed. CONCLUSIONS: In iRBD, we replicated findings of reduced free recall based on inefficient retrieval (retrieval deficit), which was small in terms of effect size. Importantly, the memory profile across measures does not support the presence of core memory dysfunction, such as poor learning, retention or associative binding.

The Instrumental Activities of Daily Living in Parkinson's Disease Patients Treated by Subthalamic Deep Brain Stimulation.

Background: Everyday functioning and instrumental activities of daily living (IADL) play a vital role in preserving the quality of life in patients with Parkinson's disease (PD) after deep brain stimulation of the subthalamic nucleus (STN-DBS). Objective: The main goal of the current study was to examine IADL change in pre-and post-surgery of the STN-DBS. We also analyzed the influence of the levodopa equivalent daily dose (LEDD) and global cognitive performance (Dementia Rating Scale; DRS-2) as covariates in relation to IADL. Methods: Thirty-two non-demented PD patients were administered before and after STN-DBS neurosurgery the Penn Parkinson's Daily Activities Questionnaire (PDAQ; self-report), the DRS-2 and Beck Depression Inventory (BDI-II) to assess IADL change, global cognition, and depression. Results: We found a positive effect of STN-DBS on IADL in the post-surgery phase. Moreover, lower global cognition and lower LEDD are predictive of lower IADL in both pre-surgery and post-surgery examinations. Summary/Conclusion: STN-DBS in PD is a safe method for improvement of everyday functioning and IADL. In the post-surgery phase, we show a relation of IADL to the severity of cognitive impairment in PD and to LEDD.

Linguistic Abnormalities in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Patients with synucleinopathies frequently display language abnormalities. However, whether patients with isolated rapid eye movement sleep behavior disorder (iRBD) have prodromal language impairment remains unknown. OBJECTIVE: We examined whether the linguistic abnormalities in iRBD can serve as potential biomarkers for conversion to synucleinopathy, including the possible effect of mild cognitive impairment (MCI), speaking task, and automation of analysis procedure. METHODS: We enrolled 139 Czech native participants, including 40 iRBD without MCI and 14 iRBD with MCI, compared with 40 PD without MCI, 15 PD with MCI, and 30 healthy control subjects. Spontaneous discourse and story-tale narrative were transcribed and linguistically annotated. A quantitative analysis was performed computing three linguistic features. Human annotations were compared with fully automated annotations. RESULTS: Compared with control subjects, patients with iRBD showed poorer content density, reflecting the reduction of content words and modifiers. Both PD and iRBD subgroups with MCI manifested less occurrence of unique words and a higher number of n-grams repetitions, indicating poorer lexical richness. The spontaneous discourse task demonstrated language impairment in iRBD without MCI with an area under the curve of 0.72, while the story-tale narrative task better reflected the presence of MCI, discriminating both PD and iRBD subgroups with MCI from control subjects with an area under the curve of up to 0.81. A strong correlation between manually and automatically computed results was achieved. CONCLUSIONS: Linguistic features might provide a reliable automated method for detecting cognitive decline caused by prodromal neurodegeneration in subjects with iRBD, providing critical outcomes for future therapeutic trials. © 2022 International Parkinson and Movement Disorder Society.

Tower of London test - short version.

Tower of London (ToL) is a neuropsychological method for assessing planning ability. In this study, we attempted to introduce a shorter version of ToL. Two studies were carried out. In Study 1, patients with mild cognitive impairment due to Parkinson's Disease (n = 36) and a control group (n = 225) were included in order to select a suitable short version of ToL for Study 2. In Study 2, patients with schizophrenia (n = 30) and a control group (n = 31) were included in order to assess psychometric properties of the shortened version of ToL. Based on psychometric evaluations in Study 1, we offered three possible shortened versions. In Study 2, all three shortened versions proved to have good discriminative validity in our schizophrenia sample, but interestingly not in the healthy sample. We concluded that the use of shortened ToL is possible in specific psychiatric/neurological patient groups, although we do not recommend doing so in healthy individuals.

Cognition in Successful Aging: Systematic Review and Future Directions.

Objectives: To characterize the inclusion of cognition in definitions of successful aging (SA) according to empirical studies published in peer-reviewed journals.Methods: A systematic review across ISI Web of Knowledge.Results: Of the 74 included studies, there were 65 studies (87.8%) analyzing cognition as one component of multicomponent SA model (cognitive component studies), and 9 studies (12.2%) focusing solely on successful cognitive aging (SCA studies). Most of the studies operationalized cognition in SA by defining SA group and analyzing single SA indicators. A minority of the studies calculated the SA index. Finally, emergent techniques to operationalize SA as a latent variable and emergent field of cognition in SA in pathology were identified.Conclusions: The results highlight that cognition is being included in SA using different levels of complexity. Even though research investigating SA in pathology is emerging, there is currently a lack of utilization of the concept in pathological and at-risk populations.Clinical implications: The current research of cognition in SA provides several valid options to evaluate if a person is aging successfully. The emerging research indicates that people from at-risk and pathological populations can age successfully.

A normative study of the Czech Edinburgh Cognitive and Behavioural ALS Screen (ECAS): a brief report.

Edinburgh Cognitive and Behavioural ALS Screen (ECAS) is a brief, standardized assessment of cognitiveimpairment inamyotrophic lateral sclerosis. OBJECTIVE: We aimed to createa normative dataset for the ECAS Czech version (ECAS-CZ) in order to make the assessment applicable for clinical settings. METHOD: Included were 102 healthy participants (mean age: 54.92 ± 14.55; education: 14.52 ± 2.44; 54:48 females/males) that fulfilled rigorous exclusion criteria and controlled for depressive symptoms. RESULTS: The internal consistency of ECAS-CZ was acceptable (Cronbach's α = .69). We found medium correlations (rho ≈ .5) of age and education with ECAS-CZ Total score but not with gender. Cut-offs with -2 SD's threshold are presented for the differentiation of cognitive impairment. We report percentile values for ECAS-CZ Total including all subscales. CONCLUSION: We provide normative values for ECAS-CZ that are well suited for the detection of cognitive impairment in clinical settings especially for patients with ALS.Supplemental data for this article is available online at https://doi.org/10.1080/13854046.2021.1978553 .

The normative data study of the Czech MATRICS consensus cognitive battery.

OBJECTIVE: The MATRICS consensus cognitive battery (MCCB) is a widely used neuropsychological battery for the assessment of cognitive dysfunction in schizophrenia. However, the accuracy of measurement is dependent on suitable normative data which are in the Czech Republic lacking. METHOD: The Czech academic research translation of the MCCB battery was administered to a sample of healthy volunteers aged 17 to 62 years (N = 573) and the effects of age, education and sex were examined. In addition, a comparison was made to examine the differences between the US and current normative data. RESULTS: Consistent with previous studies, significant effects of age, sex and education were found, however, in sex and education in distinct MCCB-domains. By comparing the original and current normative data, significant differences with small to large effect sizes were revealed in all domains except for Verbal Learning. CONCLUSIONS: We present nationally specific MCCB regression-based and tabular normative data applicable in research and clinical settings.

Asymmetry of the insula-sensorimotor circuit in Parkinson's disease.

Patients with Parkinson's disease (PD) experience motor and non-motor symptoms, suggesting alterations of the motor and/or limbic system or more probably of their communications. We hypothesized that the communication between the insula (part of the limbic system) and sensorimotor cortex in PD is altered and hemispheric asymmetric. Furthermore, that this asymmetry relates to non-motor symptoms, and specifically, that apathy-related asymmetry is unique to PD. To test these hypotheses, we used a novel multivariate time-frequency analysis method applied to resting-state functional magnetic resonance imaging (MRI) data of 28 controls and 25 participants with PD measured in their OFF medication state. The analysis infers directionality of coupling, that is, afferent or efferent, among four anatomical regions, thus defining directed pathways of information flow, which enables the extension of symmetry measures to include directionality. A major right asymmetry reduction of the dorsal-posterior insula efferent and a slight bilateral increase of insula afferent pathways were observed in participants with PD versus controls. Between-group pathways that correlated with mild cognitive impairments combined the central-executive and default-mode networks through the right insula. Apathy-correlated pathways of the posterior insula in participants with PD versus controls exhibited reduced right efferent and increased left afferent. Because apathy scores were comparable between the groups and effects of the other motor and non-motor symptoms were statistically removed by the analysis, the differences in apathy-correlated pathways were suggested as unique to PD. These pathways could be predictors in the pre-symptomatic phase in patients with apathy.