Facial emotion recognition deficits are associated with hypomimia and related brain correlates in Parkinson's disease.

Hypomimia is a frequent manifestation in Parkinson's disease (PD) that can affect interpersonal relationships and quality of life. Recent studies have suggested that hypomimia is not only related to motor dysfunction but also to impairment in emotional processing networks. Therefore, we hypothesized that the severity of hypomimia could be associated with performance on a task aimed at assessing facial emotion recognition. In this study, we explored the association between hypomimia, recognition of facial expressions of basic emotions using the Ekman 60 Faces Test (EF), and brain correlates of both hypomimia and performance on the EF. A total of 94 subjects underwent clinical assessments (neurological and neuropsychological examinations), and 56 of them participated in the neuroimaging study. We found significant correlation between hypomimia, EF Disgust (r = -0.242, p = 0.022) and EF Happiness (r = -0.264, p = 0.012); an independent reduction in Cortical Thickness (Cth) in the postcentral gyrus, insula, middle and superior temporal gyri, supramarginal gyrus, banks of the superior temporal sulcus, bilateral fusiform gyri, entorhinal cortex, parahippocampal gyrus, inferior and superior parietal cortex, and right cuneus and precuneus; and multiple correlations between negative emotions such as EF Disgust or EF Anger and a reduced Cth in fronto-temporo-parietal regions. In conclusion, these results suggest that the association between hypomimia and emotion recognition deficits in individuals with PD might be mediated by shared circuits, supporting the concept that hypomimia is not only the result of the dysfunction of motor circuits, but also of higher cognitive functions.

Predicting Impulse Control Disorders in Parkinson Disease through Incentive Biomarkers.

OBJECTIVE: This study was undertaken to evaluate whether the feedback-related negativity (FRN)-a neurophysiological marker of incentive processing-can be used to predict the development of impulse control disorders (ICDs) in Parkinson disease (PD). METHODS: The longitudinal cohort consisted of consecutive nondemented PD patients with no ICD history. We recorded FRN signals while they performed a gambling task. We calculated the mean amplitude difference between losses and gains (FRNdiff) to be used as a predictor of future ICD development. We performed prospective biannual follow-up assessments for 30 months to detect incident ICDs. Finally, we evaluated how basal FRNdiff was associated with posterior development of ICDs using survival models. RESULTS: Between October 7, 2015 and December 16, 2016, we screened 120 patients. Among them, 94 patients performed the gambling and 92 completed the follow-up. Eighteen patients developed ICDs during follow-up, whereas 74 remained free of ICDs. Baseline FRNdiff was greater in patients who developed ICDs than in those who did not (-2.33µV vs -0.84µV, p = 0.001). No other significant baseline differences were found. The FRNdiff was significantly associated with ICD development in the survival models both when not adjusted (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.58-0.91, p = 0.006) and when controlling for dopamine replacement therapy, sex, and age (HR = 0.74, 95% CI = 0.55-0.97, p = 0.035). None of the impulsivity measures evaluated was related to ICD development. INTERPRETATION: Reward-processing differences measured by FRN signals precede ICD development in PD. This neurophysiological marker permits identification of patients with high risk of ICD development. ANN NEUROL 2022;92:974-984.

Depression as a Risk Factor for Impulse Control Disorders in Parkinson Disease.

OBJECTIVE: To longitudinally evaluate the role of depression in the development of impulse control disorders (ICDs) in Parkinson disease (PD) patients. METHODS: Using data from the Parkinson's Progression Markers Initiative, we included PD patients without ICDs at baseline according to the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Patients were prospectively evaluated first quarterly and then biannually. Development of an ICD was defined as an increase in QUIP scores during follow-up. Using survival proportional hazard models, we studied the effect of baseline depression on ICD risk. We also evaluated this effect controlling for dopamine agonist use as a time-dependent variable and for other potential confounders. RESULTS: Among 354 patients, 68 were depressed at baseline. The median follow-up was 4.08 years. Depression at baseline was associated with higher ICD risk (hazard ratio [HR] = 1.96, 95% confidence interval [CI] = 1.32-2.9, p < 0.001). This risk remained significant after controlling for dopamine agonist use (HR = 1.97, 95% CI = 1.33-2.9, p < 0.001), which was also independently linked to ICD development (HR = 1.87, 95% CI = 1.3-2.7, p < 0.001). Therefore, depressed patients faced an even higher ICD risk when receiving dopamine agonists. Controlling for multiple potential confounders did not alter these results. INTERPRETATION: Depression predisposes to the development of ICDs in PD. This risk is magnified by dopamine agonists. Dopamine agonists should thus be used cautiously in depressed PD patients. ANN NEUROL 2019;86:762-769.

Preservation of brain metabolism in recently diagnosed Parkinson's impulse control disorders.

BACKGROUND: Impulse control disorders (ICD) are a common and disrupting complication of Parkinson's disease (PD) treatment. Although their relationship with dopaminergic activity is well studied, their brain metabolic correlates are mostly unknown. METHODS: In this work we studied brain metabolism using brain 18F-FDG-PET. We performed a case-control study nested within a cohort of PD patients free of ICD at baseline to compare ICD patients right after ICD diagnosis and prior to any treatment modification with matched ICD-free patients. We also compared both PD groups with healthy controls. RESULTS: When compared with ICD-free PD patients, PD patients with recently diagnosed ICD showed higher glucose metabolism in widespread areas comprising prefrontal cortices, both amygdalae and default mode network hubs (p < 0.05, corrected). When compared to healthy controls, they did not show hypermetabolism, and the only hypometabolic region was the right caudate. In turn, ICD-free patients showed diffuse hypometabolism when compared to healthy controls. CONCLUSION: Our results suggest brain metabolism is more preserved in PD patients with ICD than patients without ICD. This metabolic preservation could be related to ICD development.

CLU rs11136000 promotes early cognitive decline in Parkinson's disease.

BACKGROUND: The C allele of the rs11136000 genetic variant of the clusterin gene has been associated with increased risk of Alzheimer's disease. However, a comprehensive characterization of the role of this genetic variant in early cognitive deterioration in PD is lacking. METHODS: Using the Parkinson's Progression Markers Initiative database, we compared baseline and 5-year cognitive performance between high-risk and low-risk clusterin genotypes. RESULTS: At baseline, recently diagnosed and drug-naive de novo PD patients with the high-risk clusterin genotype showed lower cognitive scores in memory and executive function tests. These differences were even higher at the 5-year follow-up, when they showed a higher prevalence of clinically diagnosed mild cognitive impairment or dementia. They also showed cortical thinning at baseline and increased annual thinning in frontal and posterior cortical regions. DISCUSSION: Our results provide evidence of this clusterin genotype promoting early cognitive deterioration in PD, but further research is needed to delineate the specific neurodegenerative pathways underlying this clinical association. © 2020 International Parkinson and Movement Disorder Society.

Dopaminergic degeneration induces early posterior cortical thinning in Parkinson's disease.

BACKGROUND: Cognitive decline in Parkinson's disease (PD) is a highly prevalent condition with no effective treatment. Cortical atrophy is thought to promote its development but to design optimal therapeutic approaches in this clinical setting we need to understand the physiopathological mechanisms leading to this disorder. OBJECTIVE: To characterize the impact of dopaminergic degeneration on cortical integrity in early PD. METHODS: We studied 87 recently-diagnosed PD patients and 38 healthy controls from the Parkinson's Progression Marker Initiative who underwent I123-ioflupane SPECT (DATSCAN) and T1-MRI imaging. Using Freesurfer 6.0, we characterized baseline and longitudinal (one-year) correlations between striatal DAT uptake and cortical thickness. We also addressed the association between these imaging biomarkers and cognitive measures. RESULTS: Reduced DAT uptake in PD patients was associated with cross-sectional and longitudinal cortical thinning in frontal and posterior-cortical brain regions. Imaging parameters correlated with cognitive indicators in multiple domains that extend beyond frontal-executive tasks. Dopaminergic medication attenuated the longitudinal loss of cortical integrity in frontal and a subset of parietal regions, but not in other key regions such as the precuneus. DISCUSSION: To date, posterior cortical alterations in PD, known to play a major role in the development of PD-dementia, have mainly been attributed to a cholinergic degeneration occurring in later stages of the disease. Our results suggest that dopamine loss also promotes posterior-cortical atrophy from the very early stages of Parkinson's disease, which may have potential clinical and therapeutic implications.

A divergent breakdown of neurocognitive networks in Parkinson's Disease mild cognitive impairment.

Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD-MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level-1 Movement Disorders Society-Task Force Criteria. Voxel-based morphometry, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD-MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD.

Disruption of the default mode network and its intrinsic functional connectivity underlies minor hallucinations in Parkinson's disease.

BACKGROUND: Minor hallucinations and well-structured hallucinations are considered in the severity continuum of the psychotic spectrum associated with Parkinson's disease. Although their chronological relationship is largely unknown, the spatial patterns of brain atrophy in these 2 forms of hallucinations partially overlap, suggesting they share similar pathophysiological processes. Functional connectivity studies show that disruption of functional networks involved in perception and attention could be relevant in the emergence of well-structured hallucinations. However, functional neuroimaging studies in patients with isolated minor hallucinations are lacking. The objectives of this study were to explore the structural and functional changes underlying minor hallucinations. METHODS: We compared patients with (n = 18) and without (n = 14) minor hallucinations using a multimodal structural (gray-matter volume voxel-based morphometry) and functional (seed-to-whole-brain resting-state functional MRI) neuroimaging study. RESULTS: Coincident with previously described structural changes in well-structured hallucinations in Parkinson's disease, patients with minor hallucinations exhibited gray-matter atrophy with significant voxel-wise differences in visuoperceptual processing areas and core regions of the default mode network. Functional connectivity changes consisted of altered connectivity within the default mode network, reduced negative correlation with task-positive network, and aberrant connectivity between posterior regions of the default mode network and visual-processing areas. These changes are in accordance with the attentional networks hypothesis proposed for well-structured hallucinations. CONCLUSIONS: Although longitudinal studies are needed to assess the potential role of minor hallucinations as an early clinical biomarker of progression to well-structured hallucinations, the present findings show that the 2 phenomena share similar structural and functional brain correlates. © 2018 International Parkinson and Movement Disorder Society.

The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight.

BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country. METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.

Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson's Disease Is Modified by the SNCA rs356181 Polymorphism.

The role of cerebrospinal fluid (CSF) biomarkers such as CSF α-synuclein and CSF tau in predicting cognitive decline in Parkinson's disease (PD) continues to be inconsistent. Here, using a cohort of de novo PD patients with preserved cognition from the Parkinson's Progression Markers Initiative (PPMI), we show that the SNCA rs356181 single nucleotide polymorphism (SNP) modulates the effect of these CSF biomarkers on cortical thinning. Depending on this SNP's genotype, cortical atrophy was associated with either higher or lower CSF biomarker levels. Additionally, this SNP modified age-related atrophy. Importantly, the integrity of the brain regions where this phenomenon was observed correlated with cognitive measures. These results suggest that this genetic variation of the gene encoding the α-synuclein protein, known to be involved in the development of PD, also interferes in its subsequent neurodegeneration. Overall, our findings could shed light on the so far incongruent association of common CSF biomarkers with cognitive decline in PD.

Linking Essential Tremor to the Cerebellum: Neurochemical Evidence.

The pathophysiology and the exact anatomy of essential tremor (ET) is not well known. One of the pillars that support the cerebellum as the main anatomical locus in ET is neurochemistry. This review examines the link between neurochemical abnormalities found in ET and cerebellum. The review is based on published data about neurochemical abnormalities described in ET both in human and in animal studies. We try to link those findings with cerebellum. γ-aminobutyric acid (GABA) is the main neurotransmitter involved in the pathophysiology of ET. There are several studies about GABA that clearly points to a main role of the cerebellum. There are few data about other neurochemical abnormalities in ET. These include studies with noradrenaline, glutamate, adenosine, proteins, and T-type calcium channels. One single study reveals high levels of noradrenaline in the cerebellar cortex. Another study about serotonin neurotransmitter results negative for cerebellum involvement. Finally, studies on T-type calcium channels yield positive results linking the rhythmicity of ET and cerebellum. Neurochemistry supports the cerebellum as the main anatomical locus in ET. The main neurotransmitter involved is GABA, and the GABA hypothesis remains the most robust pathophysiological theory of ET to date. However, this hypothesis does not rule out other mechanisms and may be seen as the main scaffold to support findings in other systems. We clearly need to perform more studies about neurochemistry in ET to better understand the relations among the diverse systems implied in ET. This is mandatory to develop more effective pharmacological therapies.

Essential Tremor: Update of Therapeutic Strategies. / Temblor esencial: actualización de las estrategias terapéuticas.

In the last decades there has been progress in the treatment of essential tremor (TE) especially in the surgical field and to a lesser extent in the pharmacological field. We carry out a review of the currently available treatments. The first intervention is the use of non-pharmacological and non-surgical strategies (general advice, occupational therapy, speech therapy, psychotherapy). With discrete advances, the pharmacological treatment is not very satisfactory. Only 30-60% of patients have a positive response, and in these the anti-tremor effectiveness is 40-60%. The first-line drugs are still propranolol and primidone. In cases with severe tremor we will consider a surgical option, the method of choice being thalamotomy using high-intensity focused ultrasound. In the future we must continue to study the pathophysiology of TE, develop drugs specifically designed for TE and improve the technology of available invasive techniques.

Genome sequence analyses identify novel risk loci for multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

Microbleed burden and hematoma expansion in acute intracerebral hemorrhage.

BACKGROUND: Intracranial amyloid and hypertensive angiopathy have been related to impaired blood vessel function and the etiology of intracerebral hemorrhage (ICH). Microbleeds (MBs) are surrogate radiological markers that are associated with these underlying angiopathies. We assessed the hypothesis that MBs are associated with hematoma expansion (HE) in patients with hyperacute ICH. METHODS: We studied patients with spontaneous supratentorial ICH within the first 6 h after onset. HE was defined as an increase≥33% in the volume of hematoma on the follow-up CT in comparison with the admission CT. The volume was calculated using the ABC/2 formula. MBs were detected by specific magnetic resonance sequences (gradient-echo). The presence, number and distribution of MBs were analyzed. RESULTS: Our study included 44 patients. Their mean age was 68.9±11.1 years, and 70.5% of them were men. HE was observed in 14 of the patients (31.8%). HE was more prevalent in patients with more than 10 MBs compared with patients with 1-10 MBs (60 vs 12.5%; p=0.03). CONCLUSION: A high burden of MBs is associated with an increased risk of HE in patients with ICH. This is probably a marker of a more severe underlying angiopathy.

Non-Persistence of Tremorolytic Effect of Perampanel in Essential Tremor: Real-World Experience with 50 Patients.

Background: We describe our experience of using perampanel to treat essential tremor (ET) over 12 months. Methods: We enrolled 50 ET patients in an open-label trial. Perampanel was titrated to 4 mg/day as adjuvant therapy. The main outcome measures were baseline, +1, +3, +6, and + 12 month scores of the Tremor Clinical Rating Scale (TCRS) and the Glass scale (GS). Results: Twenty patients withdrew because of adverse effects. At +1 month, 27 of 30 patients improved: 68% reduction in both TCRS 1 + 2 (P < 0.001) and TCRS 3 (P < 0.001); TCRS 4 + 1.8 and GS 1.1 point reduction. By +12 months non-persistence of therapeutic effect occurred in 70% of patients: the mean reduction in TCRS 1 + 2 was 33% (P = 0.03), TCRS 3 (0.04), TCRS 4 + 0.8, GS 0.2 points reduction. Conclusions: We report important peramapanel acute tremorolytic effects, but poor tolerance to adverse effects and a non-sustained therapeutic effect in most patients.

Apathy Reflects Extra-Striatal Dopaminergic Degeneration in de novo Parkinson's Disease.

BACKGROUND: Apathy represents a core neuropsychiatric symptom in Parkinson's disease (PD). As there is currently no established effective treatment for apathy in PD, further investigating the biological origin of this symptom is needed to design novel therapeutic strategies. Among the multiple neurotransmitter alterations that have been associated with apathy, the involvement of extra-striatal dopaminergic degeneration remains to be fully explored. OBJECTIVE: To investigate whether apathy in PD reflects increased dopaminergic degeneration extending beyond striatal regions. METHODS: In the de novo PD cohort of the Parkinson's Progression Markers Initiative (PPMI), we performed whole-brain I123-Ioflupane Single Photon Emission Computed Tomography (DAT-SPECT) analyses to characterize cross-sectional and longitudinal differences in DAT uptake associated with the presence of apathy. We also assessed the relationship between apathy and cognition in this sample, as apathy has been suggested to herald cognitive decline. RESULTS: Apathetic PD patients (N = 70) had similar sociodemographic, clinical, and biomarker profiles compared to the non-apathetic group (N = 333) at baseline. However, apathy was associated with an increased risk of developing cognitive impairment after a four-year follow-up period (p = 0.006). Compared to non-apathetic patients, apathetic patients showed a widespread reduction of extra-striatal DAT uptake at baseline as well as an increased longitudinal loss of DAT uptake (corrected p < 0.05). CONCLUSIONS: Isolated apathy in PD is associated with extra-striatal dopaminergic degeneration. As this abnormal dopamine depletion was in turn related to cognitive performance, this might explain, at least partially, the increased risk of apathetic PD patients to develop cognitive impairment or dementia.

A Randomized Clinical Trial to Evaluate the Effects of Safinamide on Apathetic Non-demented Patients With Parkinson's Disease.

Background: Apathy is highly prevalent and disabling in Parkinson's disease (PD). Pharmacological options for its management lack sufficient evidence. Objective: We studied the effects of safinamide on apathy in PD. Methods: Prospective, 24-week, two-site, randomized, double-blind, placebo-controlled, parallel-group exploratory study in non-demented PD on stable dopaminergic therapy randomized 1:1 to adjunct safinamide (50 mg/day for 2 weeks and 100 mg/day for 22 weeks) or placebo. The primary endpoint was the mean change from baseline to week 24 on the Apathy Scale (AS) total score. Secondary endpoints included changes in cognition, activities of daily living, motor scores, the impression of change, and safety and tolerability measures. Results: In total, 30 participants (active treatment = 15; placebo = 15; 80% showing clinically significant apathetic symptoms according to the AS) were enrolled, and included in the intention-to-treat analysis. Change in AS (ANOVA) showed a trend to significance [p = 0.059] mediated by a more marked decrease in AS score with safinamide (-7.5 ± 6.9) than with placebo (-2.8 ± 5.7). Post-hoc analysis (paired t-test) showed a significant positive change in the AS score between 12-week and 24-week [p = 0.001] only in the active group. No significant or trend changes were found for any of the secondary outcome variables. Adverse events were few and only mild in both treatment groups. Conclusions: Safinamide was safe and well-tolerated, but failed to provide evidence of improved apathy. The positive trend observed in the post-hoc analyses deserves to be studied in depth in larger studies. Trial Registration: EudraCT 2017-003254-17.

The role of attentional control over interference in minor hallucinations in Parkinson's disease.

BACKGROUND: Minor hallucinations in Parkinson's disease are associated with connectivity changes in attentional networks and increased risk of structured hallucinations. However, the clinical translation of these abnormalities in attention processes is not well-defined, and commonly used neuropsychological tests are not able to detect significant deficits in Parkinson's disease patients with isolated minor hallucinations. OBJECTIVES: To analyze the behavioral and electrophysiological correlates of minor hallucinations in Parkinson's disease during an attentional task assessing response inhibition and interference control. METHODS: Fifty-five non-demented Parkinson's disease patients with (PD-mH; n = 27) and without minor hallucinations (PD-NH; n = 28) were included in the analysis. An Ericksen flanker task was performed to compare the effect of presenting congruent and incongruent stimuli on accuracy, reaction times and stimulus-locked event-related potentials morphology. RESULTS: Although both groups showed equivalent performance in a standard neuropsychological assessment, in the flanker task accuracy rates were lower in the PD-mH group in incongruent trials (p = 0.005). In the event-related potentials, PD-mH patients showed increased amplitude of the N2 at Fz [t(53); p < 0.05] and decreased amplitude of the P300 at Pz [t(53); p < 0.05] for the incongruent trials. CONCLUSIONS: Parkinson's disease patients with isolated minor hallucinations were more susceptible to interference mediated by irrelevant stimuli and had less cognitive control for suppressing these interferences. The failure of these systems could precipitate the intrusion and overrepresentation of peripheral irrelevant stimuli perceived as minor hallucinations. The Ericksen flanker task could be used as a sensitive clinical marker of the attentional defects leading to hallucinations in Parkinson's disease.

Dissociable contribution of plasma NfL and p-tau181 to cognitive impairment in Parkinson's disease.

BACKGROUND: Cognitive dysfunction is a disabling complication in Parkinson's disease (PD). Accuracy of diagnosis of mild cognitive impairment in PD (PD-MCI) depends on the tests performed, which limits results generalization. Blood-based biomarkers could provide additional objective information for PD-MCI diagnosis and progression. Blood neurofilament light chain (NfL), a marker of neuronal injury, has shown good performance for PD disease stratification and progression. While NfL is not disease-specific, phosphorylated-tau at threonine-181 (p-tau181) in blood is a highly specific marker of concomitant brain amyloid-ß and tau pathology. METHODS: We investigated the potential of plasma NfL and p-tau181 levels as markers of cognitive impairment in a prospective cohort of 109 PD patients with and without PD-MCI (age 68.1 ± 7 years, education 12.2± 5 years), and 40 comparable healthy controls. After a follow-up of 4 years, we evaluated their predictive value for progression to dementia. RESULTS: Although NfL and p-tau181 levels were significantly increased in PD compared with healthy controls, only NfL levels were significantly higher in PD-MCI compared with PD with normal cognition (PD-NC) at baseline. After a follow-up of 4 years, only NfL predicted progression to dementia (HR 1.23, 95% CI 1.02-1.53; p = 0.038). Significant correlations between fluid biomarkers and neuropsychological examination were only found with NfL levels. CONCLUSIONS: Plasma NfL levels objectively differentiates PD-MCI from PD-NC patients, and may serve as a plasma biomarker for predicting progression to dementia in PD. Plasma levels of p-tau181 does not seem to help in differentiating PD-MCI or to predict future cognitive deterioration.