Toward More Accessible Fully Automated 3D Volumetric MRI Decision Trees for the Differential Diagnosis of Multiple System Atrophy, Related Disorders, and Age-Matched Healthy Subjects.

Differentiating multiple system atrophy (MSA) from related neurodegenerative movement disorders (NMD) is challenging. MRI is widely available and automated decision-tree analysis is simple, transparent, and resistant to overfitting. Using a retrospective cohort of heterogeneous clinical MRIs broadly sourced from a tertiary hospital system, we aimed to develop readily translatable and fully automated volumetric diagnostic decision-trees to facilitate early and accurate differential diagnosis of NMDs. 3DT1 MRI from 171 NMD patients (72 MSA, 49 PSP, 50 PD) and 171 matched healthy subjects were automatically segmented using Freesurfer6.0 with brainstem module. Decision trees employing substructure volumes and a novel volumetric pons-to-midbrain ratio (3D-PMR) were produced and tenfold cross-validation performed. The optimal tree separating NMD from healthy subjects selected cerebellar white matter, thalamus, putamen, striatum, and midbrain volumes as nodes. Its sensitivity was 84%, specificity 94%, accuracy 84%, and kappa 0.69 in cross-validation. The optimal tree restricted to NMD patients selected 3D-PMR, thalamus, superior cerebellar peduncle (SCP), midbrain, pons, and putamen as nodes. It yielded sensitivities/specificities of 94/84% for MSA, 72/96% for PSP, and 73/92% PD, with 79% accuracy and 0.62 kappa. There was correct classification of 16/17 MSA, 5/8 PSP, 6/8 PD autopsy-confirmed patients, and 6/8 MRIs that preceded motor symptom onset. Fully automated decision trees utilizing volumetric MRI data distinguished NMD patients from healthy subjects and MSA from other NMDs with promising accuracy, including autopsy-confirmed and pre-symptomatic subsets. Our open-source methodology is well-suited for widespread clinical translation. Assessment in even more heterogeneous retrospective and prospective cohorts is indicated.

Higher urate in LRRK2 mutation carriers resistant to Parkinson disease.

OBJECTIVE: LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers. METHODS: Banked plasma samples or urate levels were obtained for 3 cohorts of age- and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex. RESULTS: Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p < 0.001), with similar results for separate assessments of women (p < 0.02) and men (p < 0.001). A 2 mg/dL increment in urate concentration decreased the odds of having PD by approximately 50% (odds ratio = 0.48, p = 0.004). INTERPRETATION: These findings identify and substantiate urate as a biomarker of resistance to PD among LRRK2 mutation carriers. Ann Neurol 2019;85:593-599.

Ocular motor manifestations of movement disorders.

PURPOSE OF REVIEW: Impaired eye movements are frequently seen in ophthalmic and neurologic clinical practice, especially in individuals with movement disorders. Identification of the abnormal movement can aid initial diagnosis and improve understanding of the underlying disease pathophysiology. The present article reviews the ocular motor manifestations and recent research on them in common movement disorders. RECENT FINDINGS: Ocular motor manifestations and their pathophysiologic correlates are being defined. In particular, study of eye movements can help clarify the changing clinicopathologic spectrum of atypical parkinsonian disorders. The pathophysiology and natural history of blepharospasm are being elucidated. Recent research focuses on high-resolution imaging and other technological advances to improve the sensitivity of the ocular motility exam. Eye movements are being studied as biomarkers for diagnosis and progression in clinical care and trials. SUMMARY: The current review summarizes ocular motor manifestations in common movement disorders, and presents recent research investigating their cause and treatment.

Learning from history: Lord Brain and Hashimoto's encephalopathy.

We present two historic cases of severe encephalopathy associated with antithyroid antibodies. The first was published by Lord Brain of Eynsham, and the second was from our department's archives. Although both cases are from archival sources, they continue to inform current clinical care. We briefly review the poorly defined entity, Hashimoto's encephalopathy, and discuss diagnostic advances for autoimmune encephalopathy and for Creutzfeldt-Jakob disease. We advocate for giving a trial of corticosteroids to patients with 'encephalopathy, not otherwise specified' while awaiting antibody results or more definitive testing. Our case, initially diagnosed as having Creutzfeldt-Jakob disease, responded remarkably (with video evidence) to a trial of corticosteroids.

Designing the First Trials for Parkinson's Prevention.

For decades the greatest goal of Parkinson's disease (PD) research has often been distilled to the discovery of treatments that prevent the disease or its progression. However, until recently only the latter has been realistically pursued through randomized clinical trials of candidate disease-modifying therapy (DMT) conducted on individuals after they received traditional clinical diagnosis of PD (i.e., tertiary prevention trials). Now, in light of major advances in our understanding of the prodromal stages of PD, as well as its genetics and biomarkers, the first secondary prevention trials for PD are beginning. In this review, we take stock of DMT trials to date, summarize the breakthroughs that allow the identification of cohorts at high risk of developing a traditional diagnosis of PD, and describe key design elements of secondary prevention trials and how they depend on the prodromal stage being targeted. These elements address whom to enroll, what interventions to test, and how to measure secondary prevention (i.e., slowed progression during the prodromal stages of PD). Although these design strategies, along with the biological definition, subtype classification, and staging of the disease are evolving, all are driven by continued progress in the underlying science and integrated by a broad motivated community of stakeholders. While considerable methodological challenges remain, opportunities to move clinical trials of DMT to earlier points in the disease process than ever before have begun to unfold, and the prospects for PD prevention are nowtangible.

Short-term lipopolysaccharide treatment leads to astrocyte activation in LRRK2 G2019S knock-in mice without loss of dopaminergic neurons.

Background: The G2019S mutation of LRRK2, which enhances kinase activity of the protein, confers a substantial risk of developing Parkinson's disease (PD). However, the mutation demonstrates incomplete penetrance, suggesting the involvement of other genetic or environmental modulating factors. Here, we investigated whether LRRK2 G2019S knock-in (KI) mice treated with the inflammogen lipopolysaccharide (LPS) could model LRRK2 PD. Results: We found that short-term (2 weeks) treatment with LPS did not result in the loss of dopaminergic neurons in either LRRK2 G2019S KI or wild-type (WT) mice. Compared with WT mice, LRRK2 G2019S-KI mice showed incomplete recovery from LPS-induced weight loss. In LRRK2 G2019S KI mice, LPS treatment led to upregulated phosphorylation of LRRK2 at the autophosphorylation site Serine 1292, which is known as a direct readout of LRRK2 kinase activity. LPS treatment caused a greater increase in the activated astrocyte marker glial fibrillary acidic protein (GFAP) in the striatum and substantia nigra of LRRK2 G2019S mice than in those of WT mice. The administration of caffeine, which was recently identified as a biomarker of resistance to developing PD in individuals with LRRK2 mutations, attenuated LPS-induced astrocyte activation specifically in LRRK2 G2019S KI mice. Conclusions: Our findings suggest that 2 weeks of exposure to LPS is not sufficient to cause dopaminergic neuronal loss in LRRK2 G2019S KI mice but rather results in increased astrocyte activation, which can be ameliorated by caffeine.

Perspectives of People At-Risk on Parkinson's Prevention Research.

 The movement toward prevention trials in people at-risk for Parkinson's disease (PD) is rapidly becoming a reality. The authors of this article include a genetically at-risk advocate with the LRRK2 G2019 S variant and two patients with rapid eye movement sleep behavior disorder (RBD), one of whom has now been diagnosed with PD. These authors participated as speakers, panelists, and moderators in the "Planning for Prevention of Parkinson's: A Trial Design Forum" hosted by Massachusetts General Hospital in 2021 and 2022. Other authors include a young onset person with Parkinson's (PwP) and retired family physician, an expert in patient engagement in Parkinson's, and early career and veteran movement disorders clinician researchers. Several themes emerged from the at-risk participant voice concerning the importance of early intervention, the legitimacy of their input in decision-making, and the desire for transparent communication and feedback throughout the entire research study process. Challenges and opportunities in the current environment include lack of awareness among primary care physicians and general neurologists about PD risk, legal and psychological implications of risk disclosure, limited return of individual research study results, and undefined engagement and integration of individuals at-risk into the broader Parkinson's community. Incorporating the perspectives of individuals at-risk as well as those living with PD at this early stage of prevention trial development is crucial to success.

What to Test in Parkinson Disease Prevention Trials? Repurposed, Low-Risk, and Gene-Targeted Drugs.

Despite the sound epidemiologic and basic science rationales underpinning numerous "disease modification" trials in manifest Parkinson disease (PD), none has convincingly demonstrated that a treatment slows progression. Rapidly expanding knowledge of the genetic determinants and prodromal features of PD now allows realistic planning of prevention trials with initiation of putatively neuroprotective therapies earlier in the disease. In this article, we outline the principles of drug selection for PD prevention trials, focused on proof-of-concept opportunities that will help establish a methodological foundation for this fledgling field. We describe prototypical, relatively low-risk drug candidates for such trials (e.g., albuterol, ambroxol, caffeine, ibuprofen), tailored to specific at-risk populations ranging from pathogenic LRRK2 or GBA gene variant carriers to those defined by prodromal PD and α-synucleinopathy. Finally, we review gene-targeted approaches currently in development targeting clinically manifest PD for their potential in future prevention trials.

Path to Parkinson Disease Prevention: Conclusion and Outlook.

Tremendous progress in our understanding of the pathophysiology and clinical manifestations of the prodromal phase of Parkinson disease (PD) offers a unique opportunity to start therapeutic interventions as early as possible to slow or even stop the progression to clinically manifest motor PD. A Parkinson's Prevention Conference, "Planning for Prevention of Parkinson's: A trial design symposium and workshop" was convened to discuss all issues that need to be addressed before the launch of the first PD prevention study. In this review, we summarize the major opportunities and challenges in designing prevention trials in PD, organized by the following critical trial design questions: Who (should be enrolled)? What (to test)? How (to measure prevention)? and the pivotal question, When during the prodromal disease (should we start these trials)? We outline the implications of these questions and their meaning for a responsible, sustainable, and fruitful further planning for prevention trials. Despite the great progress that has been made, it needs to be acknowledged that several queries remain to be carefully considered and addressed because prevention trials are being planned and become a reality.

Planning for Prevention of Parkinson Disease: Now Is the Time.

Parkinson disease (PD) is a chronic progressive neurodegenerative disease with increasing worldwide prevalence. Despite many trials of neuroprotective therapies in manifest PD, no disease-modifying therapy has been established. Over the past several decades, a series of breakthroughs have identified discrete populations at substantially increased risk of developing PD. Based on this knowledge, now is the time to design and implement PD prevention trials. This endeavor builds on experience gained from early prevention trials in Alzheimer disease and Huntington disease. This article first reviews prevention trial precedents in these other neurodegenerative diseases before focusing on the critical design elements for PD prevention trials, including whom to enroll for these trials, what therapeutics to test, and how to measure outcomes in prevention trials. Our perspective reflects progress and remaining challenges that motivated a 2021 conference, "Planning for Prevention of Parkinson: A Trial Design Symposium and Workshop."

Chasing Protection in Parkinson's Disease: Does Exercise Reduce Risk and Progression?

Exercise may be the most commonly offered yet least consistently followed therapeutic advice for people with Parkinson's disease (PD). Epidemiological studies of prospectively followed cohorts have shown a lower risk for later developing PD in healthy people who report moderate to high levels of physical activity, and slower rates of motor and non-motor symptom progression in people with PD who report higher baseline physical activity. In animal models of PD, exercise can reduce inflammation, decrease α-synuclein expression, reduce mitochondrial dysfunction, and increase neurotrophic growth factor expression. Randomized controlled trials of exercise in PD have provided clear evidence for short-term benefits on many PD measurements scales, ranging from disease severity to quality of life. In this review, we present these convergent epidemiological and laboratory data with particular attention to translationally relevant features of exercise (e.g., intensity requirements, gender differences, and associated biomarkers). In the context of these findings we will discuss clinical trial experience, design challenges, and emerging opportunities for determining whether exercise can prevent PD or slow its long-term progression.

Association of caffeine and related analytes with resistance to Parkinson disease among LRRK2 mutation carriers: A metabolomic study.

OBJECTIVE: To identify markers of resistance to developing Parkinson disease (PD) among LRRK2 mutation carriers (LRRK2+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the LRRK2 mutation. METHODS: Plasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 LRRK2+/PD+, 115 LRRK2+/UC, 70 LRRK2-/PD+, and 65 LRRK2-/UC, and CSF available from 68 of them, were analyzed by liquid chromatography with mass spectrometry. For 282 analytes quantified in plasma and CSF, we assessed differences among the 4 groups and interactions between LRRK2 and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with p value corrections for multiple comparisons. RESULTS: Plasma caffeine concentration was lower in patients with PD vs UC (p < 0.001), more so among LRRK2+ carriers (by 76%) than among LRRK2- participants (by 31%), with significant interaction between LRRK2 and PD status (p = 0.005). Similar results were found for caffeine metabolites (paraxanthine, theophylline, 1-methylxanthine) and a nonxanthine marker of coffee consumption (trigonelline) in plasma, and in the subset of corresponding CSF samples. Dietary caffeine was also lower in LRRK2+/PD+ compared to LRRK2+/UC with significant interaction effect with the LRRK2+ mutation (p < 0.001). CONCLUSIONS: Metabolomic analyses of the LCC samples identified caffeine, its demethylation metabolites, and trigonelline as prominent markers of resistance to PD linked to pathogenic LRRK2 mutations, more so than to idiopathic PD. Because these analytes are known both as correlates of coffee consumption and as neuroprotectants in animal PD models, the findings may reflect their avoidance by those predisposed to develop PD or their protective effects among LRRK2 mutation carriers.

Clinical pathologic case report: A 70-year-old man with inflammatory cerebral amyloid angiopathy causing headache, cognitive impairment, and aphasia.

A 70-year-old man presented with two months of worsening cognitive impairment, hallucinations, and difficulty speaking, with superimposed headaches. Cerebrospinal fluid analysis was notable for lymphocytic pleocytosis and elevated protein. Imaging studies revealed multiple acute and subacute infarcts with cortical microhemorrhages. The patient underwent a stereotactic brain biopsy. In this article, we discuss the patient's differential diagnosis, pathologic findings, ultimate diagnosis, and clinical outcome.

Targeting urate to reduce oxidative stress in Parkinson disease.

Oxidative stress has been implicated as a core contributor to the initiation and progression of multiple neurological diseases. Genetic and environmental factors can produce oxidative stress through mitochondrial dysfunction leading to the degeneration of dopaminergic and other neurons underlying Parkinson disease (PD). Although clinical trials of antioxidants have thus far failed to demonstrate slowed progression of PD, oxidative stress remains a compelling target. Rather than prompting abandonment of antioxidant strategies, these failures have raised the bar for justifying drug and dosing selections and for improving study designs to test for disease modification by antioxidants. Urate, the main antioxidant found in plasma as well as the end product of purine metabolism in humans, has emerged as a promising potential neuroprotectant with advantages that distinguish it from previously tested antioxidant agents. Uniquely, higher urate levels in plasma or cerebrospinal fluid (CSF) have been linked to both a lower risk of developing PD and to a slower rate of its subsequent progression in numerous large prospective epidemiological and clinical cohorts. Laboratory evidence that urate confers neuroprotection in cellular and animal models of PD, possibly via the Nrf2 antioxidant response pathway, further strengthened its candidacy for rapid clinical translation. An early phase trial of the urate precursor inosine demonstrated its capacity to safely produce well tolerated, long-term elevation of plasma and CSF urate in early PD, supporting a phase 3 trial now underway to determine whether oral inosine dosed to elevate urate to concentrations predictive of favorable prognosis in PD slows clinical decline in people with recently diagnosed, dopamine transporter-deficient PD.

Identification of distinct phenotypes of locally advanced pancreatic adenocarcinoma.

BACKGROUND: A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease. Optimal treatment remains controversial. We sought to analyze the clinical course of locally advanced pancreatic adenocarcinoma (LAPC) in order to identify potential distinct clinical phenotypes. METHODS: Patients (pts) diagnosed with LAPC who survived >2 months were identified from institutional databases. Clinical details were collected. Sequential re-staging scans were reviewed. Progression-free survival (PFS), time from progression to death (TTD), and overall survival (OS) were estimated with Kaplan-Meier method and compared with log-rank test. RESULTS: Between 2005 and 2011, 40 pts were identified. Median age was 66 yrs (range, 43-74) and 60 % (n=24) were male. All pts received chemotherapy. Median OS was 11.3 months. Twenty patients (50 %) had local progression only (LP) and 16 (40 %) had metastatic progression (MP) at first documentation of progression, while four patients (10 %) had stable disease. PFS was 4.0 vs 5.6 months (hazard ratio (HR) 0.97; 95 % CI 0.49-1.93, p=0.94) for LP and MP, respectively. Three of the patients with LP (15 %) eventually developed metastatic disease after a median of 4.2 months (3.7-9.6). For MP patients, five had concurrent local progression. Sites of disease were lung (eight), peritoneum (five), liver (three), and bone (one). TTD for LP and MP was 5.6 vs 1.4 months (HR 0.62; 95 % CI 0.28-1.39, p=0.24) and OS was 13.2 vs 8.0 months (HR 0.59; 95 % CI 0.28-1.25, p=0.017), respectively. CONCLUSIONS: We identified two subgroups of LAPC with distinctive behavior, one local dominant progression with low predilection for metastases and another with rapid metastatic development and worse survival. Early recognition of these phenotypes might allow a more tailored treatment approach to improve outcome.