Factors Associated with High Parent- and Youth-Rated Irritability Score in Early-Onset Mood Disorders: A Cross-Sectional Study with the Affective Reactivity Index (ARI).

Correct classification of irritability is extremely important to assess prognosis and treatment indications of juvenile mood disorders. We assessed factors associated with low versus high parent- and self-rated irritability using the affective reactivity index (ARI) in a sample of 289 adolescents diagnosed with a bipolar or a major depressive disorder. Bivariate analyses were followed by multilinear logistic regression model. Factors significantly and independently associated with high versus low parent-rated ARI score were: more severe emotional dysregulation and bipolar disorders diagnosis. Factors significantly and independently associated with high versus low self-rated ARI score were: lower children depression rating scale (CDRS-R) difficulty of having fun item score, greater children depression inventory (CDI-2) self-report score, more severe emotional dysregulation, and greater CDRS-R appetite disturbance item score. High parent-rated irritability was strictly related with a bipolar disorder diagnosis, whereas high youth-rated irritability was related to depressive phenotype characterized by appetite/food-intake dysregulation, mood lability, and less anhedonia and apathy.

Effect of Time From Onset of Major Depressive Disorder on the Therapeutic Response to Esmethadone (REL-1017).

Objective: The relationship between the duration of major depressive disorder (MDD) and therapeutic response to standard antidepressant treatment (SAT) is unknown. N-methyl-D-aspartate receptor uncompetitive antagonists are emerging drugs for MDD. We investigated whether the antidepressant effect of esmethadone (REL-1017) could be related to the duration of depression.Methods: We analyzed data from a Phase 2a study of adjunctive treatment with esmethadone in MDD patients (DSM-5) with inadequate response to ongoing SAT (May 2018-August 2019). Patients were randomized to treatment with esmethadone 25 mg, esmethadone 50 mg, or placebo for 7 days, followed by an observation period (Days 7-14). Duration of depression was derived from 2 measures: (1) time from onset (TFO), calculated as the difference in years between age at trial enrollment and age at the onset of the first major depressive episode (MDE), and (2) TFO index, calculated by computing the years of illness duration (number of years from the beginning of MDD), divided by age and multiplied by 100. First, bivariate correlations between TFO and change from baseline (CFB) were calculated by Spearman ρ. Linear mixed-model analyses were also conducted.Results: A total of 62 patients participated in the trial. The median values of time from MDD onset for the 62 patients were 11 years (absolute value) and 22% (percentage of life-years). Duration of depression was significantly correlated with Montgomery-Asberg Depression Rating Scale (MADRS) CFB on Day 14, even when controlling for the effect of current depression severity (MADRS baseline). In the linear mixed-model analyses, we found a significant effect of duration on reduction in MADRS score from T0 to subsequent assessments (P < .05). Number of previous MDEs and effect of esmethadone 50 mg when compared to 25 mg were not significant.Conclusion: Esmethadone 25 and 50 mg were more effective in reducing MADRS scores in patients with shorter time from first MDE onset.Trial Registration: ClinicalTrials.gov identifier: NCT03051256.

Childhood Clinical Features Preceding the Onset of Bipolar Versus Major Depressive Disorders During Adolescence.

OBJECTIVE: To identify childhood psychopathological features that predict the onset of adolescent Bipolar (BD) versus Unipolar Major Depressive Disorder (UD) during adolescence. METHOD: We analyzed clinical data from 495 juveniles diagnosed with DSM-5 UD (n = 359), and BD (n = 136), using bivariate analysis and multivariate logistic regression model. RESULTS: BD subjects exhibited earlier onset of any psychiatric feature compared to UD. Antecedents associated with later BD were: oppositional defiant > specific phobias > ADHD > obsessive compulsive (OCD). Antecedents selectively associated with later UD were: social anxiety and separation anxiety. Factors significantly and independently associated with later BD diagnosis were: [a] emotional dysregulation at onset of the mood disorder; [b] first depressive episode with mixed features; [c] antecedent ADHD; [d] antecedent OCD, and [e] antecedent oppositional-defiance. CONCLUSION: Identifying developmental differences in BD and UD symptoms can aid clinicians in early identification and treatment planning for bipolar disorder in youth.

Urgent Psychiatric Consultations for Suicidal Ideation and Behaviors in Italian Adolescents during Different COVID-19 Pandemic Phases.

Access to the emergency department (ED) for acute psychiatric problems, especially for suicide attempts (SA), has increased in the last decade. This increase has exceptionally accelerated after the COVID-19 pandemic. The aim of this project was to study the increase in acute psychiatric care demand of children and adolescents in the short and medium term after the pandemic, in relation to public health measures and in comparison with a pre pandemic reference period. We retrospectively studied 5445 child psychiatric (CP) consultations requested for any reason and for suicide attempt (SA), suicidal ideation (SI) and non-suicidal self-injury (NSSI) in a pediatric ED during three different pandemic periods in Italy (from March 2020 to May 2022) and compared them to a pre-pandemic reference period (from January 2018 to February 2020). Monthly CP consultations for any reason increased significantly by 2.2 times from 70.9 in 2018 to 157 in 2022 (p < 0.001). During the pandemic, monthly CP consultations for any reason increased significantly from 75/month in the first lockdown to 153/month in the second lockdown, remaining stable in the following year. CP consultations for SA increased significantly from 5/month in the first lockdown to 16/month in the second. Consultations for SI increased gradually but significantly from the pre-pandemic period to the end of the pandemic. Juveniles evaluated for SA during the pandemic vs. pre-pandemic more frequently attempted suicide by self-poisoning and less frequently by precipitation, and they were more likely to be diagnosed with a major depressive disorder. CP consultations for any reason and for suicide attempts significantly increased in the decade before the pandemic and peaked in the second lockdown period in Italy.

Urgent psychiatric consultations for suicide attempt and suicidal ideation before and after the COVID-19 pandemic in an Italian pediatric emergency setting.

Introduction: Suicidal attempts (SAs) in youth have been increasing during the last decades. Methods: We studied consultations, SA, and suicidal ideation (SI) in a pediatric emergency department (ED). Results: From 1 January 2011 to 31 May 2022, 606,159 patients accessed the ED, 8,397 of who had a child psychiatry consultation (CPC). CPCs increased significantly by 11 times in the last decade (155 in 2011 vs. 1,824 in 2021, p < 0.001); CPCs for SA increased significantly by 33 times, from 6 in 2011 to 200 in 2021 (3.9% of total CPC vs. 11%, p < 0.001). While total CPCs increased constantly during the entire period (annual percent change (APC) of 21.7 from 2011 to 2021 in a 0 joinpoint model), CPCs for SA increased significantly from 2011 to 2016, were approximately stable from 2016 to 2020, and then had a peak in 2021 after the COVID-19 pandemic (APC from 2011 to 2016 of 64.1, APC of 1.2 from 2016 to 2020, and APC of 230 after 2020 in a 2-joinpoint model). Discussion: Total CPCs in ED as well as evaluation for SA and SI increased significantly during the last decade. CPCs for SA had an additional increase after the COVID-19 pandemic. This picture warrants timely and efficient improvements in emergency settings and mental health resources.

α-Synuclein seeding activity in duodenum biopsies from Parkinson's disease patients.

Abnormal deposition of α-synuclein is a key feature and biomarker of Parkinson's disease. α-Synuclein aggregates can propagate themselves by a prion-like seeding-based mechanism within and between tissues and are hypothesized to move between the intestine and brain. α-Synuclein RT-QuIC seed amplification assays have detected Parkinson's-associated α-synuclein in multiple biospecimens including post-mortem colon samples. Here we show intra vitam detection of seeds in duodenum biopsies from 22/23 Parkinson's patients, but not in 6 healthy controls by RT-QuICR. In contrast, no tau seeding activity was detected in any of the biopsies. Our seed amplifications provide evidence that the upper intestine contains a form(s) of α-synuclein with self-propagating activity. The diagnostic sensitivity and specificity for PD in this biopsy panel were 95.7% and 100% respectively. End-point dilution analysis indicated up to 106 SD50 seeding units per mg of tissue with positivity in two contemporaneous biopsies from individual patients suggesting widespread distribution within the superior and descending parts of duodenum. Our detection of α-synuclein seeding activity in duodenum biopsies of Parkinson's disease patients suggests not only that such analyses may be useful in ante-mortem diagnosis, but also that the duodenum may be a source or a destination for pathological, self-propagating α-synuclein assemblies.

CT features of primary bone neoplasia of the thoracic wall in dogs.

Primary thoracic wall neoplasia is uncommon in dogs and the prognosis depends on tumor type. The aims of this retrospective, multi-center, observational study were to describe CT features of primary thoracic wall neoplasia in dogs and to test the hypothesis that CT features would differ among tumor types. Dogs with a diagnosis of primary thoracic wall bone neoplasia and thoracic CT study were included. CT findings recorded were as follows: dimensions, location, invasiveness, grade and type of mineral attenuation, periosteal reaction, contrast enhancement, and presence of presumed pulmonary metastases, pleural effusion, and sternal lymphadenopathy. Fifty-eight cases were included (54 ribs and four sternum). Fifty-six were malignant (sarcomas - SARC) and two were benign (chondromas - CHO). Out of the 56 malignant tumors, 41 had histological confirmation of the tumor type: 23 (56%) osteosarcomas (OSA), 10 (24%) chondrosarcomas (CSA), and eight (20%) hemangiosarcomas (HSA). The majority of rib tumors were right-sided (59%) and ventrally located (72%). Malignant masses showed severe invasiveness, mild/moderate contrast enhancement, and different grades of mineral attenuation. Sternal lymphadenopathy was significantly more frequent in dogs with OSA and HSA compared to dogs with CSA (p = 0.004 and p = 0.023). Dogs with HSA showed significantly lower mineral attenuation grades compared to dogs with OSA (p = 0.043). Primary thoracic wall bone neoplasias were more frequently arising from the ribs, with only a few cases of sternal masses. Findings can be used to help prioritize differential diagnoses for CT studies of dogs with thoracic wall neoplasia.

Subanalysis of Subjective Cognitive Measures From a Phase 2, Double-Blind, Randomized Trial of REL-1017 in Patients With Major Depressive Disorder.

Objective: Improvement of cognitive function in patients with major depressive disorder (MDD) is an important treatment outcome. REL-1017 (esmethadone HCl) is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and a potentially rapidly acting antidepressant. The objective of this study was to define the effects of REL-1017 on subjective cognitive measures in patients with MDD.Methods: Post hoc analysis was conducted of subjective cognitive measures from the Montgomery-Asberg Depression Rating Scale (MADRS) and the Symptoms of Depression Questionnaire (SDQ) from a randomized, double-blind, placebo-controlled, Phase 2a study. The study, designed to assess the safety, tolerability, and efficacy of 2 dosages (25 mg and 50 mg) of REL-1017 as an adjunctive treatment in patients with MDD unresponsive to standard antidepressants, included 62 patients. We analyzed subjective cognitive measures derived from the MADRS and SDQ scales at baseline and up to day 14, 7 days after the last dose of study drug. We developed 2 composite indexes that included subjective cognitive measures selected from the MADRS and SDQ.Results: The subanalysis of single measures and the 2 composite indexes derived from the MADRS and SDQ measures showed clinically meaningful and statistically significant improvements in cognitive function (P < .05).Conclusions: In a Phase 2a clinical trial, REL-1017 improved subjective measures of cognitive impairment, in addition to improving total MADRS and SDQ scores. These results need to be confirmed in larger and longer studies in MDD that include objective measures of cognitive function. Phase 3 studies of REL-1017 for MDD are currently underway.Clinical Trials Registration: ClinicalTrials.gov identifier: NCT03051256.

Gender Differences in the Psychopathology of Mixed Depression in Adolescents with a Major Depressive Episode.

BACKGROUND: Gender differences have been reported in the severity and psychopathological features of major depressive disorders among adults but are poorly reported in adolescent samples. OBJECTIVE: This study aimed to examine gender differences in the psychopathology of mixed depression among adolescents. METHODS: We analyzed 341 outpatients with the current major depressive episode (MDE) retrospectively to identify patients with DSM-5 MDE with mixed features. We compared examiner-rated depressive and (hypo)manic symptoms and self- and parent-reported symptoms between sexes. RESULTS: We identified 76 patients with an MDE with mixed features (67.1% females, 32.9% with bipolar disorder). Depression severity was significantly greater in females versus males (CDRS-R total score 56.2 vs. 48.2, p = 0.014). Depressive symptoms were significantly and independently found to be more severe among females in a logistic regression model, including excessive fatigue (OR 1.68; p = 0.025), low self-esteem (OR 1.67; p = 0.04), excessive weeping (OR 1.62; p = 0.021), and CBCL AAA index (OR 1.04; p = 0.015). None of the depressive symptoms scored greater in males. Males had higher levels of motor activity (2.12 vs. 1.69; p = 0.048) and pressured speech (1.80 vs. 1.24; p = 0.004). Self-rated anxiety (69.3 vs. 56.8, p = 0.047) and CBCL AAA index (207 vs. 189; p = 0.007) were higher in females. CONCLUSION: Adolescent depression with mixed features is more severe in women, with a higher expression of core affective symptoms and excessive fatigue. While in males, slightly higher levels of psychomotor activation are reported, in females, emotional dysregulation and excessive weeping may subtend a difference in a broader spectrum of mixed features.

Can machine learning identify childhood characteristics that predict future development of bipolar disorder a decade later?

Early identification of bipolar disorder may provide appropriate support and treatment, however there is no current evidence for statistically predicting whether a child will develop bipolar disorder. Machine learning methods offer an opportunity for developing empirically-based predictors of bipolar disorder. This study examined whether bipolar disorder can be predicted using clinical data and machine learning algorithms. 492 children, ages 6-18 at baseline, were recruited from longitudinal case-control family studies. Participants were assessed at baseline, then followed-up after 10 years. In addition to sociodemographic data, children were assessed with psychometric scales, structured diagnostic interviews, and cognitive and social functioning assessments. Using the Balanced Random Forest algorithm, we examined whether the diagnostic outcome of full or subsyndromal bipolar disorder could be predicted from baseline data. 45 children (10%) developed bipolar disorder at follow-up. The model predicted subsequent bipolar disorder with 75% sensitivity, 76% specificity, and an Area Under the Receiver Operating Characteristics of 75%. Predictors best differentiating between children who did or did not develop bipolar disorder were the Child Behavioral Checklist Externalizing and Internalizing behaviors, the Child Behavioral Checklist Total t-score, problematic school functions indexed through the Child Behavioral Checklist School Competence scale, and the Child Behavioral Checklist Anxiety/Depression and Aggression scales. Our study provides the first quantitative model to predict bipolar disorder. Longitudinal prediction may help clinicians assess children with emergent psychopathology for future risk of bipolar disorder, an area of clinical and scientific importance. Machine learning algorithms could be implemented to alert clinicians to risk for bipolar disorder.

Relationship between CSF tau biomarkers and structural brain MRI measures in frontotemporal lobar degeneration.

BACKGROUND: Recently in the field neurodegenerative diseases increasing attention has been pointed to CSF biomarkers and their integration with neuroimaging (1). Frontotemporal lobar degeneration (FTLD) refers to a heterogeneous group of clinical syndromes with different underlying proteinopathies including tau pathology. CSF biomarkers have been proposed as diagnostic and prognostic factors. Aim of our study was to evaluate the relationship between CSF tau biomarkers and structural MRI brain measures in FTLD. METHODS: We included early FTLD patient. All included patients underwent lumbar puncture to evaluate amyloid, total-tau (t-tau), phospho-tau 181 (p-tau); p-tau/t-tau ratio was also calculated; brain MRI was performed to estimate whole brain volume, volume of principal deep grey matter structures and regional cortical thickness. RESULTS: Demographic characteristics of the 28 included patients were as follows: female/male: 9/19; mean ± SD age: 68.1 ± 7.8 years. The p-tau/t-tau ratio was significantly correlated with whole brain volume (r = 0.69; p: 0.001), left putamen volume (r = 0.55 p: 0.009), left pallidum volume (r = 0.41; p: 0.01), right accumbens area (r = 0.47; p: 0.02). P-tau/t tau ratio showed also a significant correlation with cortical thickness of left temporal lobe (r = 0.74; p: 0.001) and right lateral orbital frontal cortex (r = 0.45; p: 0.03). Linear regression showed a significant relationship between p-tau/t-tau ratio and left temporal pole (p = 0.01; r2: 0.60) and brain volume (p:0.002; r2: 0.56) after controlling for age and gender. CONCLUSIONS: Our data suggest that CSF biomarkers, especially p-tau/t-tau ratio, could play a role as prognostic factor in FTLD. Further longitudinal investigations are needed to confirm these findings.

Suicidal behavior in juvenile bipolar disorder and major depressive disorder patients: Systematic review and meta-analysis.

OBJECTIVE: To assess rates and lethality of suicidal behavior in studies of children and adolescents diagnosed with major depressive disorder (MDD) or bipolar disorder (BD). METHODS: This PROSPERO-registered protocol (CRD-42019159676) systematically reviewed reports on suicidal behavior among juveniles (age ≤ 18 years), and pooled data on risk (% of subjects) and rates (%/year), followed by random-effects meta-analysis and multivariable linear regression modeling. RESULTS: Included were 41 reports (1995-2020) from 15 countries involving 104,801 juveniles (102,519 diagnosed with MDD, 2282 with BD), at risk for 0.80-12.5 years. Meta-analytically pooled suicide attempter-rates averaged 7.44%/year [95%CI: 5.63-9.25] with BD and 6.27%/year [5.13-7.41] with MDD. Meta-analysis of 5 studies with both diagnostic groups found significantly greater attempt risk with BD vs. MDD (OR = 1.59 [1.24-2.05], p < 0.0001). In 6 studies, suicide rate with juvenile mood disorders averaged 125 [56.9-236]/100,000/year, similar to adult rates, >30-times greater than in the general juvenile population, and higher among older adolescents. The ratio of attempts/suicides (A/S) was 52.6 among mood-disordered juveniles, indicating greater lethality than among juveniles in the general population (A/S ≥ 250), but somewhat less than in the estimated adult general population (A/S ca. 30). CONCLUSIONS: Rates of suicide attempts in juveniles with a major mood disorder averaged 6580/100,000/year, were greater in BD versus MDD observed under the same conditions, and greater with shorter periods of observation. Lethality (fatalities per suicide attempt) was greater in juveniles diagnosed with major affective disorders than in the juvenile general population, but less than in adults.

Suspected Pituitary Apoplexy: Clinical Presentation, Diagnostic Imaging Findings and Outcome in 19 Dogs.

In human medicine, pituitary apoplexy (PA) is a clinical syndrome characterised by the sudden onset of neurological signs because of haemorrhage or infarction occurring within a normal or tumoral pituitary gland. The diagnosis is usually performed combining neurological signs and imaging findings. The aim of the present study is to describe the abnormal neurological signs, the diagnostic imaging findings, based on Computed Tomography (CT) and/or Magnetic Resonance Imaging (MRI), and the outcome in a population of dogs with suspected PA. Clinical cases were retrospectively reviewed. Nineteen cases of suspected PA were included. The majority of dogs showed behavioural abnormalities (11/19). Neurological signs more frequently identified were obtundation (7/19), vestibular signs (7/19) and epileptic seizures (6/19). The onset of neurological signs was per-acute in 14 out of 19 cases. Data regarding CT and MRI were available in 18 and 9 cases, respectively. Neurological signs resolved in less than 24 h in seven patients. The short-term prognosis was defined as favourable in the majority of our study population. The median survival time was of 7 months from the time of PA diagnosis. This is the first description of neurological signs, imaging findings and outcome in a large group of dogs with PA.

Characteristics Associated with Depression Severity in 270 Juveniles in a Major Depressive Episode.

Introduction: Severe depression is prevalent in young persons and can lead to disability and elevated suicidal risk. Objectives: To identify clinical and demographic factors associated with the severity of depression in juveniles diagnosed with a major mood disorder, as a contribution to improving clinical treatment and reducing risk of suicide. Methods: We analyzed factors associated with depression severity in 270 juveniles (aged 6-18 years) in a major depressive episode, evaluated and treated at the Bambino Gesù Children's Hospital of Rome. Depressive symptoms were rated with the revised Children's Depression Rating Scale (CDRS-R) and manic symptoms with the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (K-SADS-MRS). Bivariate comparisons were followed by multivariable linear regression modeling. Results: Depression severity was greater among females than males (55.0 vs. 47.2), with the diagnosis of a major depressive disorder (MDD) vs. bipolar disorder (BD; 53.8 vs. 49.3), and tended to increase with age (slope = 1.14). Some symptoms typical of mania were associated with greater depression severity, including mood lability, hallucinations, delusions, and irritability, whereas less likely symptoms were hyperactivity, pressured speech, grandiosity, high energy, and distractibility. Factors independently and significantly associated with greater depression severity in multivariable linear regression modeling were: MDD vs. BD diagnosis, female sex, higher anxiety ratings, mood lability, and irritability. Conclusions: Severe depression was significantly associated with female sex, the presence of some manic or psychotic symptoms, and with apparent unipolar MDD. Manic/psychotic symptoms should be assessed carefully when evaluating a juvenile depressive episode and considered in treatment planning in an effort to balance risks of antidepressants and the potential value of mood-stabilizing and antimanic agents to decrease the severity of acute episodes and reduce suicidal risk.

Manic and Depressive Symptoms in Children Diagnosed with Noonan Syndrome.

Noonan syndrome (NS) is a dominant clinically variable and genetically heterogeneous developmental disorder caused by germ-line mutations encoding components of the Ras-MAPK signaling pathway. A few studies have investigated psychopathological features occurring in individuals with NS, although they were poorly analyzed. The aim of the present work is to investigate the psychopathological features in children and adolescents with NS focusing on depressive and hypo-manic symptoms. Thirty-seven subjects with molecularly confirmed diagnosis were systematically evaluated through a psychopathological assessment. In addition, an evaluation of the cognitive level was performed. Our analyses showed a high recurrence of attention deficit and hyperactivity disorder symptoms, emotional dysregulation, irritability, and anxiety symptomatology. The mean cognitive level was on the average. The present study provides new relevant information on psychopathological features in individuals with NS. The implications for clinicians are discussed including the monitoring of mood disorders in a clinical evolution.

Suicidal behaviour and non-suicidal self-injury in children and adolescents seen at an Italian paediatric emergency department.

INTRODUCTION: Increasing rates of non-fatal self-harm amongst adolescents represent growing concern. The objective of the study is to describe non-fatal self-harm - including suicidal behaviour (SB), suicidal ideation (SI) and non-suicidal self-injury (NSSI) - observed at an Italian paediatric emergency department (ED). METHODS: Retrospective analysis of the clinical records of patients admitted to ED from 2011 to 2016, who underwent child psychiatry consultation (CPc). We analyzed: rates of CPc for SB, SI and NSSI; risk factors for SB and SI in patients admitted to the hospital's Child Psychiatry Unit after a CPc; and, correlations between NSSI and SB/SI. RESULTS: The rate of CPc for SB, SI and NSSI switched from 7.7% in 2011 to 19% in 2016, with a statistically significant increase over the years (p < 0.001), a 2.2:1 female/male ratio, and an average age of 15.5 ± 1.8 years. SB consisted mainly in drug poisoning (53%), with a significant prevalence in female. Mood disorder was identified in 82.5% of patients hospitalized for SB or SI. Substance abuse was more frequently found in patients admitted for SB when compared to the SI group. Almost half (48%) of the patients admitted for SB or SI reported a current or lifelong history of NSSI. In patients admitted for SB or SI, 3 factors were significantly and independently associated with NSSI: being female, substance abuse, and more severe depressive symptoms. CONCLUSIONS: Between 2011 and 2016, there was a significant growing need for CP consultations for suicidal behaviours, mainly in female adolescents. The subjects admitted for SI or SB, who also presented NSSI, were mainly substance abusers, and presented with more severe depressive symptoms.

Axial symptoms predict mortality in patients with Parkinson disease and subthalamic stimulation.

OBJECTIVE: To characterize how disease progression is associated with mortality in a large cohort of patients with Parkinson disease (PD) with long-term follow-up after subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: Motor and cognitive disabilities were assessed before and 1, 2, 5, and 10 years after STN-DBS in 143 consecutive patients with PD. We measured motor symptoms "off" and "on" levodopa and STN-DBS and recorded causes of death. We used linear mixed models to characterize symptom progression, including interactions between treatment conditions and time to determine how treatments changed efficacy. We used joint models to link symptom progression to mortality. RESULTS: Median observation time was 12 years after surgery, during which akinesia, rigidity, and axial symptoms worsened, with mean increases of 8.8 (SD 6.5), 1.8 (3.1), and 5.4 (4.1) points from year 1-10 after surgery ("on" dopamine/"on" STN-DBS), respectively. Responses to dopaminergic medication and STN-DBS were attenuated with time, but remained effective for all except axial symptoms, for which both treatments and their combination were predicted to be ineffective 20 years after surgery. Cognitive status significantly declined. Forty-one patients died, with a median time to death of 9 years after surgery. The current level of axial disability was the only symptom that significantly predicted death (hazard ratio 4.30 [SE 1.50] per unit of square-root transformed axial score). CONCLUSIONS: We quantified long-term symptom progression and attenuation of dopaminergic medication and STN-DBS treatment efficacy in patients with PD and linked symptom progression to mortality. Axial disability significantly predicts individual risk of death after surgery, which may be useful for planning therapeutic strategies in PD.