Background: Cervical sponylotic myelopathy (CSM) may present with neck and arm pain. This study investiagtes the change in neck/arm pain post-operatively in CSM. Methods: This ambispective study llocated 402 patients through the Canadian Spine Outcomes and Research Network. Outcome measures were the visual analogue scales for neck and arm pain (VAS-NP and VAS-AP) and the neck disability index (NDI). The thresholds for minimum clinically important differences (MCIDs) for VAS-NP and VAS-AP were determined to be 2.6 and 4.1. Results: VAS-NP improved from mean of 5.6±2.9 to 3.8±2.7 at 12 months (P<0.001). VAS-AP improved from 5.8±2.9 to 3.5±3.0 at 12 months (P<0.001). The MCIDs for VAS-NP and VAS-AP were also reached at 12 months. Based on the NDI, patients were grouped into those with mild pain/no pain (33%) versus moderate/severe pain (67%). At 3 months, a significantly high proportion of patients with moderate/severe pain (45.8%) demonstrated an improvement into mild/no pain, whereas 27.2% with mild/no pain demonstrated worsening into moderate/severe pain (P <0.001). At 12 months, 17.4% with mild/no pain experienced worsening of their NDI (P<0.001). Conclusions: This study suggests that neck and arm pain responds to surgical decompression in patients with CSM and reaches the MCIDs for VAS-AP and VAS-NP at 12 months.

Background: Diffuse low-grade gliomas (LGGs) are primary brain tumours with infiltrative, anisotropic growth related to surrounding white and grey matter structures. Deformation-based morphometry (DBM) is a simple and objective image analysis method that can identify areas of local volume change over time. In this study, we illustrate the use of DBM to study the local expansion patterns of LGGs monitored by serial magnetic resonance imaging (MRI). Methods: We developed an image processing pipeline optimized for the study of LGG growth involving the fusion of follow-up MRIs for a given patient into an average template space using nonlinear registration. The displacement maps derived from nonlinear registration were converted to Jacobian maps, which estimate local tissue expansion and contraction over time. Results: Our results demonstrate that neoplastic growth occurs primarily around the edges of the tumour while the lesion core and areas adjacent to obstacles, such as the skull, show no significant expansion. Regions of normal brain tissue surrounding the lesion show slight contraction over time, representing compression due to mass effect of the tumour. Conclusions: DBM is a useful tool to understand the long-term clinical course of individual tumours and identify areas of rapid growth, which may explain the current presentation and/or predict future symptoms.

Background: The purpose of this study is to compare 1-year postoperative clinical outcomes between posterior instrumented fusion with (P/TLIF) and without (PLF) interbody fusion in patients with isthmic spondylolisthesis. Methods: This is a multi-centre retrospective study using the Canadian Spine Outcomes and Research Network. Adult patients who received surgical management for isthmic spondylolisthesis were included in this study. The primary outcome was change in Oswestry Disability Index at 1-year. Secondary outcomes were change in EQ-5D, SF-12 PCS, back pain, leg pain, estimated blood loss, length of surgery, length of stay, rate of transfusions and adverse events. Descriptive statistics, Student t-test, Chi-Squared test, and stepwise multivariable regression were used for analysis. Results: A total of 300 patients (252 P/TLIF, 48 PLF) were included in this study. The mean age was 50 years. The P/TLIF group had poorer baseline leg pain scores (t=2.02, p=0.01). There were no significant differences in primary and secondary outcomes between the two groups. Addition of interbody fusion was not a significant variable in the stepwise multivariable regression analysis. Conclusions: There were no significant differences in clinical outcomes at 1 year. Addition of interbody fusion was not associated with higher complication rates or length of stay.

Background: The zona incerta (ZI) is a small structure in the deep brain first identified by Auguste Forel for which robust in vivo visualization has remained elusive. The increased inherent signal from ultra-high field (7-Tesla or greater; 7T) magnetic resonance imaging (MRI) presents an opportunity to see structures not previously visible. In this study, we investigated the possibility of using quantitative T1 mapping at 7T to visualize the ZI region. Methods: We recruited healthy participants (N=32) and patients being considered for deep brain stimulation therapy as part of a prospective imaging study at 7T. Computational methods were used to process and fuse images to produce a high-resolution group average from which ZI anatomy could be delineated. Results: We pooled 7T data using image fusion methods and found that the contrast from quantitative T1 mapping was strikingly similar to classic histological staining, permitting facile identification of the ZI and nearby structures in reference to conventional stereotactic atlases. Conclusions: Using computational neuroimaging techniques, we demonstrate for the first time that the ZI is visible in vivo. Furthermore, we determined that this nuclear region can be decoupled from surrounding fibre pathways. This work paves the way for more accurate patient-specific optimization of deep brain targets for neuromodulation.

Background: Insertion of an external ventricular drain (EVD) is performed to treat elevated intracranial pressure. EVD catheters are associated with complications such as EVD catheter infection (ECI), intracranial hemorrhage (ICH) and suboptimal catheter placement. As part of the Canadian Neurosurgery Research Collaborative, we sought to investigate the national rate of such complications and their risk factors. Methods: Prospective study of 273 patients from eight academic Canadian neurosurgery centres Results: Infection rate was 6% and predicted by smaller incisions and not peri-procedure antibiotics, tunneling distance, type of antiseptic used or catheter flushing (p>0.05). The mean duration of EVD was 17.7±3.7 in ECI and ventriculitis group which was significantly higher than in patients without ECI (9.4±8.1) (p=0.045). Although the risk of developing ICH was 9.3%, symptomatic ICH was rare. Pre-procedure pharmacological DVT prophylaxis predicted EVD-related ICH(OR 4.73). The rate of suboptimal catheter location was 31% and predicted by the number of passes (p=0.02), but not image guidance, level of training or catheter placement in an operating room setting (p>0.05). Conclusions: This study reports EVD complication rates and their associated risk factors observed within an academic, multicentre Canadian cohort. This information will help to identify strategies to increase the safety of this common neurosurgical procedure.

Background: Challenges in predicting risk of recurrence for individual patients with meningioma limits appropriate selection of patients who may benefit from adjuvant radiation therapy to delay recurrence. Here, we aimed to develop and validate a combined clinicomolecular predictor of early recurrence for individual patients with meningiomas. Methods: A methylation-based predictor of 5-year recurrence-free-survival (RFS) was developed using DNA-methylation profiles from a training cohort of 228 patients. Model performance was compared to a standard-of-care histological-based model using three independent cohorts (N=54 ;N=140; N=64 patients). Subsequently, a nomogram that integrated the methylome-based predictor with prognostic clinical factors was developed and validated. Results: The methylome-based predictor of 5-year RFS performed favorably compared to a grade-based predictor when tested using the three validation cohorts (ΔAUC=0.10, 95%CI 0.03 – 0.018) and was independently associated with RFS on multivariable Cox regression analysis (HR=3.6, 95%CI 1.8–7.2, P<0.001). A nomogram combining the methylome-predictor with clinical factors demonstrated greater discrimination for recurrence than a nomogram using clinical factors alone (ΔAUC=0.25, 95%CI 0.22–0.27) and resulted in two risk groups with distinct recurrence patterns (HR=7.7, 95%CI 5.3–11.1, P<0.001) and clinical implications. Conclusions: Our validated models provide important novel prognostic information that could be used to individualize decisions regarding post-operative therapeutic interventions in meningioma.

Background: To determine whether there is a difference in the average annual rate of decline in Mini Mental Status Examination (MMSE) scores between those with Alzheimer’s disease, vascular dementia, frontotemporal dementia and dementia with Lewy bodies. Methods: We conducted a retrospective chart review of 225 consecutive patients with dementia who attended the Rural and Remote Memory Clinic in Saskatoon, Saskatchewan. The data collected included MMSE scores and demographic information. Statistical analysis with ANOVA compared the average the annual rate of decline in MMSE score between patients with different types of dementia. Results: There was no statistically significant difference in the rate of MMSE score decline between these groups. Patients with frontotemporal dementia and vascular dementia were referred to the clinic at younger ages than those with Alzheimer’s disease and dementia with Lewy bodies. Conclusions: The rate of decline in MMSE did not differ between these four types of dementia. Patients with frontotemporal dementia and vascular dementia often experience cognitive decline earlier in life than those with Alzheimer’s disease and dementia with Lewy bodies.

Background: Quality of life (QOL) is of great importance in dementia. We examined QOL across types of dementia in patients presenting to a rural and remote memory clinic (RRMC). Methods: This analysis included 343 RRMC patients seen between 2004 and 2016. Patients were diagnosed with mild cognitive impairment (MCI, n=74), frontotemporal dementia (FTD, n=42), Alzheimer’s disease (AD, n=187), vascular dementia (VD, n=22), or Lewy Body dementia (DLB, n=18). Patients and caregivers completed questionnaires at their initial visit. Data collection included patient-rated patient QOL (QOL-PT), caregiver-rated patient QOL (QOL-CG), MMSE score, age, and other patient demographics. Statistical analysis assessed patient variables and differences in QOL across types of dementia using one-way ANOVA, χ2 tests, and t-tests. Results: QOL-PT did not differ by diagnosis, whereas QOL-CG did. QOL-CG was significantly higher in MCI (34.6±7.1) compared to FTD (30.9±5.2) and AD (31.7±5.9). QOL-PT and QOL-CG differed in certain dementia types. QOL-PT was significantly higher than QOL-CG in MCI (QOL-PT=37.3±5.0, QOL-CG=35.3±7.3), FTD (QOL-PT=37.2±6.1, QOL-CG=31.7±5.5), and AD (QOL-PT=37.0±9.7, QOL-CG=32.1±5.9). Conclusions: We found that QOL-PT does not differ across dementia types, QOL-CG is higher in MCI compared to FTD and AD, and patients rate their own QOL higher than their caregivers do in MCI, FTD, and AD.

Background: Young-onset dementia (YOD) patients and their caregivers face unique challenges in diagnosis and management. We aimed to compare the characteristics of rural YOD and late-onset dementia (LOD) patients. Methods: A total of 333 consecutive patients (YOD=61, LOD=272) at a rural and remote memory clinic between March 2004 and July 2016 were included in this study. Each patient had neuropsychological assessment. Health, mood, function, behaviour, and social factors were also measured. Both groups were compared using χ2 tests and independent sample tests. Results: YOD patients were more likely to be married, employed, current smokers, and highly educated. They reported fewer cognitive symptoms, but had more depressive symptoms. YOD patients were less likely to live alone and use homecare services. YOD caregivers were also more likely to be a spouse and had higher levels of distress than LOD caregivers. Conclusions: Our findings indicate YOD and LOD patients have distinct characteristics and services must be modified to better meet YOD patient needs. In particular, the use of homecare services and caregiver support may alleviate the higher levels of distress found in YOD patients and their caregivers. Additional research should be directed to addressing YOD patient depression, caregiver distress, and barriers to services.

Background: Previous post-hoc analysis of three 12-week, double-blind, placebo-controlled trials of adjunctive brivaracetam (BRV) in patients with focal seizures demonstrated similar efficacy over placebo regardless of previous carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or topiramate (TPM) failure. This analysis explored long-term retention of adjunctive BRV in patients with previous CBZ/LTG/LEV/TPM. Methods: Post-hoc analysis of double-blind, placebo-controlled trial (N01358 [NCT01261325]) and open-label extension (N01379 [NCT01339559]; cut-off 15-March-2017) of adjunctive BRV in patients (≥16 years) with focal seizures. Outcomes were assessed in patients randomized to BRV (100 or 200 mg/day) who had previous CBZ/LTG/LEV/TPM (stopped ≥90 days before BRV initiation). Results: 503 patients were analyzed. Baseline characteristics were generally similar in subgroups with previous CBZ/LTG/LEV/TPM (n=209/162/256/182). Overall, Kaplan-Meier-estimated BRV retention at 1-, 3-, and 5-years was 71.0%, 50.9%, and 32.4%. Across previous antiepileptic drug (AED) subgroups, Kaplan-Meier-estimated BRV retention (1-year: 64.8%–73.2%; 3-year: 41.9%–49.9%; 5-year: 31.5%–35.7%), BRV discontinuations (58.4%–63.0%), and most common reasons for discontinuation (lack of efficacy: 23.0%–25.3%; adverse event: 16.7%–22.2%) were generally similar. Conclusions: Post-hoc analysis demonstrated similar long-term retention rates and discontinuation reasons with adjunctive BRV in adults previously treated with CBZ/LTG/LEV/TPM. Adjunctive BRV provides long-term effectiveness in patients who failed common AED treatments, including LEV.

UCB Pharma-sponsored

Background: Previous post-hoc analysis of three 12-week, double-blind, placebo-controlled trials showed adjunctive brivaracetam (BRV) reduced focal and secondarily generalized tonic-clonic seizures (SGTCS; Type IC) in patients with baseline SGTCS. This analysis explored long-term efficacy of adjunctive BRV in these patients. Methods: Patients (≥16 years) with focal seizures with SGTCS at Baseline were identified from 12-week double-blind, placebo-controlled trials (NCT00490035/NCT00464269/NCT01261325) and subsequent open-label, long-term follow-up (LTFU) trials (NCT00175916/NCT00150800/NCT01339559). Outcomes were assessed at protocol-specified time-points (up to 60 months). We report post-hoc efficacy data for patients receiving BRV (50–200 mg/day). Results: At double-blind Baseline, 409 patients had SGTCS (mean epilepsy duration: 22.2 years); 28.4%, 38.9%, and 32.8% had 0–1, 2–4, and ≥5 previous AEDs. Baseline median seizure frequency/28 days was 8.1 (focal) and 3.0 (SGTCS only). 325/409 patients (79.5%) entered LTFU. In the 12-month (n=150), 24-month (n=89), 36-month (n=73), 48-month (n=68) and 60-month (n=57) exposure cohorts, median percent reduction from Baseline in SGTCS frequency/28 days was 81.1%, 84.0%, 89.2%, 91.0%, and 90.6%, respectively. ≥50% responder rates for SGTCS were 75.3%, 78.7%, 80.8%, 79.4%, and 78.9%. No safety concerns were identified. Conclusions: Adjunctive BRV (50–200 mg/day) reduced SGTCS frequency during LTFU (up to 60 months) in patients with SGTCS at Baseline.

Background: Déjà vu is a common manifestation of temporal lobe seizures. It can be reproduced by electrical stimulation of the hippocampus, amygdala and temporal neocortex with stereotactically implanted electrodes. We report here déjà vu triggered by the stimulation of the insula. Methods: Two patients suffering from intractable temporal lobe epilepsy exhibiting auras of déjà vu underwent invasive EEG studies. One patient had a prior temporal lobectomy with reoccurrence of similar symptoms after surgery. We performed functional connectivity analyses using phase locking value (PLV) to estimate changes in connectivity between different brain regions in the standard EEG frequency bands during stimulation. Results: Stimulation of the insular cortex induced reproducible déjà vu symptoms in both patients. In one patient, PLV analysis showed increased synchronization in the alpha band between insular and temporal regions after an evoked déjà vu compared to a control stimulation. Conclusions: Our results suggest that the insula may in rare occasions generate déjà vu. This implies that insular epileptogenicity cannot be ruled out in patients exhibiting such an aura nor in patients with persisting déjà vu despite an initial amygdalo-hippocampectomy.

Background: Powassan virus is a tick borne virus which can lead to encephalitis. Methods: 63 year old woman with history of migraine presented with 2 days of fever, headache, language difficulty and right sided facial droop. Her examination revealed right upper motor neuron type facial weakness and expressive aphasia. She rapidly deteriorated within 24 hours becoming non verbal and ultimately comatose. Results: MRI brain revealed T2 hyperintensities in bilateral caudate and putamen. Subsequent MRI brain showed progression of the caudate and basal ganglia changes and new T2 hyperintensities in bilateral thalami and midbrain with no abnormal enhancement. CSF revealed lymphocytic pleocytosis with normal protein and glucose. Viral Encephalitis was suspected and she was continued on Acyclovir until Varicella zoster and Herpes simplex virus serology in CSF returned negative. Prolonged video EEG showed near continuous generalized triphasic pattern without any evolution or seizure pattern. There was no improvement in clinical status or EEG with antiepileptic treatment. Paraneoplastic panel , serum HIV, Lyme and 14-3-3 protein were negative. Extensive viral serologies were sent and ultimately Powassan serology came back positive. Conclusions: This case highlights powassan virus as a cause of encephalitis and occurrence of triphasic waves in non metabolic causes of encephalopathy such as infectious encephalitis.

Background: There are few studies exploring rates of drug resistant epilepsy in populations with new-onset epilepsy (NOE). This prospective cohort study characterizes the development of drug-resistant epilepsy (DRE) and risk factors in an adult cohort with NOE or newly-diagnosed epilepsy (NDE). Methods: Patients are from the Single Seizure Clinic (SSC) in Saskatoon, SK between 2011 and 2018. The SSC sees patients who experience their first seizure; approximately 30% are diagnosed with epilepsy. Patients were followed prospectively. We identified the following variables in the cohort: epilepsy type, seizure onset, etiology, syndromes, and rates of DRE. Inclusion criteria included patients with NO and NDE, at least 18 years at diagnosis, and a minimum 1 year of follow-up. Results: Ninety-five patients were included, 46 females and 49 males. Median age of onset was 33 years. Of those, 28.4% developed DRE. Average time between onset and DRE diagnosis was 1.44 years. Bivariate analysis identified age, gender, and cranial trauma as significant risk factors for DRE. The multivariate model was not significant. Conclusions: Our study shows that patients with new-onset epilepsy have are less likely to develop DRE compared with patients from epilepsy clinics. This study contributes valuable information about NO epilepsy in adults and the development of DRE.

Background: To evaluate efficacy, safety, and tolerability of ubrogepant for acute treatment of migraine attacks. Methods: Multicenter, double-blind, phase 3 study (NCT02867709). Randomized patients (1:1:1, placebo or ubrogepant 25mg or 50mg) had 60 days to treat one migraine attack (moderate/severe pain intensity). Co-primary efficacy endpoints (2 hours post initial dose): headache pain freedom and absence of most bothersome migraine-associated symptom (MBS). Secondary endpoints: pain relief, sustained pain relief, sustained pain freedom, and absence of migraine-associated symptoms. Results: 1686 patients were randomized (safety population: n=1465; mITT population: n=1355). Mean age: 41 years; white: 81%; female: 89%. Significantly greater proportions of ubrogepant- than placebo-treated patients achieved 2-hour pain freedom (placebo: 14.3%; 25mg: 20.7%, adjusted P=0.0285; 50mg: 21.8%, adjusted P=0.0129) and absence of MBS for 50mg (placebo: 27.4%; 50mg: 38.9%, adjusted P=0.0129). Secondary endpoints (except absence of nausea at 2h) met statistical significance versus placebo for ubrogepant 50mg. Absence of MBS and secondary outcomes were not significant for 25mg after multiplicity adjustment. Ubrogepant’s and placebo’s AE profiles were similar. Conclusions: Co-primary endpoints were met for ubrogepant 50mg. Ubrogepant 25mg was significantly superior to placebo for 2h pain freedom. Ubrogepant was well tolerated. Results support the efficacy, tolerability, and safety of ubrogepant for acute treatment of migraine attacks.

Background: We assessed long-term health-related quality of life (HRQoL) and functioning in adults receiving onabotulinumtoxinA for CM. Methods: Interim analysis of multicentre, prospective, observational study in adults naïve to botulinum toxin (NCT02502123). Mean change from baseline in Migraine-Specific Quality of Life (MSQ) score (primary); healthcare resource utilization (HRU) and work productivity (secondary) assessed in patients receiving 4 of 7 onabotulinumtoxinA treatments (Tx4; ~10 months). Results: Across treatments (baseline, n=196, post-Tx2, n=173, post-Tx4, n=137), the mean (SD) between-session interval and onabotulinumtoxinA dose was 13.1 weeks and 170.4 (17.2) U, respectively. MSQ scores increased significantly (P<0.0001) (baseline to post-Tx4; all role function domains). Patient percentages declined from baseline to post-Tx2 and post-Tx4 for emergency room visits (17.3%; 9.3%; 6.6%), hospital admissions (3.6%; 2.9%; 1.5%), and headache-related diagnostic testing (35.9%; 15.9%; 8.1%). The percentages of patients employed at baseline (73.5%) and post-Tx4 (72.3%) were similar. Hours worked increased slightly from baseline to post-Tx4 (28.0 [SD=15.4]; 29.4 [SD=16.0]). Headache-related missed work hours decreased (5.9 [SD=9.5]; 2.5 [SD=5.9]). Patients reported less headache-related impact on work productivity from baseline to post-Tx4 (5.4 [SD=2.1] vs 3.9 [SD=2.6]) and ability to perform daily activities (6.1 [SD=2.1] vs 4.2 [SD=2.8]). Conclusions: OnabotulinumtoxinA for CM improved HRQoL and work productivity and reduced HRU.

Background: Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disease due to mutation of the VPS13A gene encoding the protein chorein. ChAc is a slowly progressive disorder that typically presents in early adulthood, and whose clinical features include chorea and dystonia with involuntary lip, cheek and tongue biting. Some patients also have seizures. Treatment for ChAc is symptomatic. A small number of ChAc patients have been treated with bilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi), and we now present an additional case. Methods: Patient chart, functional measures, and laboratory findings were reviewed from the time of ChAc diagnosis until 6 months after deep brain stimulation (DBS) surgery. Results: Here we present a case of ChAc in a 31 year old male positive for VPS13A gene muations who presented with chorea, tongue biting, dysarthria, weight loss, and mild cognitive dysfunction. GPi-DBS using monopolar stimulation was associated with significant improvement in chorea and dysarthria. Conclusions: This case adds to the current state of knowledge regarding the efficacy and safety of bilateral GPi-DBS for symptomatic control of drug-resistant hyperkinetic movements seen in ChAc. Controlled trials are needed to better assess the impact of DBS in ChAc.

Background: People with Parkinson disease (PD) face progressive mobility loss, but medical treatment is dependent on clinical assessment and examination. Regional patient and physician density patterns pose further problems to accessing care. Telehealth may improve access particularly among rural populations, but an approach to this problem should consider patient perspectives. Methods: We surveyed and conducted a focus group for people with PD and their caregivers. Questions assessed perceptions of barriers to neurological care and use of telehealth for PD management. Thematic analysis was performed to classify qualitative data. Results: 18 individuals completed the survey and 7 parties joined the focus group. 52% of participants travel >50km for neurologist appointments (range = 59 to 842km). Perceived barriers include cost and difficulty of travel, wait times, lack of interdisciplinary healthcare and deep brain stimulation outside large cities. 80% of participants (95% C.I. 64-96%) would likely or very likely use telehealth for follow-up neurologist appointments if proven as good as in-office visits. Participants associated telehealth with improved quality of care, improved access to care, and cost savings. Conclusions: This sample of people with PD and their caregivers report willingness to access care via telehealth to reduce perceived cost and travel for specialty care.

Background: The clinical benefit of onabotulinumtoxinA in cervical dystonia (CD) is proven, but its impact on health-related quality of life (HRQoL) is largely unknown. Methods: Multicentre, prospective, observational study (NCT01655862) of CD patients treated with onabotulinumtoxinA at physician discretion (maximum 9 treatments). Patient-reported HRQoL outcomes and work productivity were collected at baseline, 4- or 8-weeks post-treatment, and final visit (prior to 9th treatment). OnabotulinumtoxinA utilization was assessed. Results: 61 patients received ≥1 treatment; 74.1% completed all treatments. Average total dose/treatment was 186.9U. The splenius capitis was most frequently treated (100% patients). Average pain numeric rating scale score was significantly improved at final visit (2.1) versus baseline (4.6; p<0.001) as were CD impact profile questionnaire-58 scores across all subscales (head/neck symptoms, pain/discomfort, sleep, upper limb activities, walking, annoyance, mood, psychosocial functioning; all p<0.001). Fewer patients (16.0%) reported loss of work productivity at final visit versus baseline (48.4%). 121 AEs were reported by 67.2% patients. 62 AEs in 44.3% patients were treatment-related, the most common being neck pain (18%). One serious AE (not treatment-related) was reported by 1 patient. No new safety signals were identified. Conclusions: Long-term use of onabotulinumtoxinA is a safe, effective treatment for CD, improving HRQoL and work productivity.

Background: Parkinson’s disease (PD) varies in clinical manifestations and course of progression from person to person. Identification of distinct PD subtypes is of great priority to develop personalized care approaches. We aimed to compare long-term progression and prognosis between different PD subtypes. Methods: Data on 421 individuals with de novo early-onset PD was retrieved from Parkinson’s Progression Markers Initiative (PPMI). Using a newly developed multi-domain subtyping method (based on motor phenotype, RBD, autonomic disturbance, early cognitive deficit), we divided PD population into three subtypes at baseline: “mild motor-predominant”, “Diffuse malignant” and “Intermediate”. Rate of global progression (mixed motor and non-motor features) and developing dementia were compared between the subtypes. Results: Patients with “diffuse malignant” PD experienced 0.5 z-score further worsening of global composite outcome (p=0.017) and 2.2 further decline in MOCA score (p=0.001) after 6-years of follow-up. Hazard for MCI/dementia was significantly higher in “diffuse malignant” (HR=3.2, p<0.001) and “intermediate” (HR=1.8, p<0.001) subtypes. Individuals with “diffuse malignant” PD had the lowest level of CSF amyloid-beta (p=0.006) and SPECT striatal binding ratio (p=0.001). Conclusions: This multi-domain subtyping is a valid method to predict subgroups of PD with distinct patterns of long-term progression at drug-naïve early-stage with potential application in real-life clinical practice.