Kelly A. Mills

An Update and Review of the Treatment of Myoclonus

Recent advances in medications and surgical therapy for neurological disorders may offer new therapeutic options for the treatment of myoclonus. Appropriate therapy for myoclonus depends on the etiology, and in some cases, myoclonus can improve when the provoking cause is eliminated. When the underlying cause for the movements is not immediately reversible, localization, disease pathophysiology, and etiology may each play a role in determining the most appropriate symptomatic treatment of disabling myoclonic jerks. While the use of many agents is still based on small, open-label case series and anecdotes, there is a growing body of evidence from head-to-head comparative trials in several types of myoclonus that may help guide therapy. New therapies for refractory myoclonus, including sodium oxybate and even deep brain stimulation, are also being explored with increasing enthusiasm.

Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients

INTRODUCTION Gait impairment in Parkinsons Disease (PD) is often severely disabling, yet frequently remains refractory to treatment. The locus coeruleus (LC) has diffuse noradrenergic projections that are thought to play a role in gait function. Enhancement of norepinephrine transmission may improve gait in some PD patients. We hypothesized that the severity of PD pathology, and more specifically, Lewy bodies and neuronal loss in the LC, would correlate with the severity of gait dysfunction in PD. METHODS Autopsy data from 51 patients, collected through the Morris K. Udall Parkinsons Disease Research Center, were correlated with clinical gait-related measures, including individual Unified Parkinsons Disease Rating Scale (UPDRS) Part II and III questions, total UPDRS Part III scores, and timed up-and-go speed (TUG). RESULTS Neither the presence nor degree of Lewy body pathology in the LC on autopsy was associated with a higher UPDRS part III gait score. LC tau deposition and frontal Lewy body deposition were not correlated with any of the assessed gait measures. The degree of Lewy body pathology, independent of Braak stage, was positively associated with the severity of motor symptoms overall (UPDRS Part III total score). CONCLUSION Neither the degree of Lewy body nor tau pathology in the LC is associated with severity of gait disorders in PD. This finding may have implications for targeted noradrenergic therapies in patients with refractory gait disorders.

Dopamine transporter availability reflects gastrointestinal dysautonomia in early Parkinson disease

BACKGROUND Constipation is a prodromal feature of Parkinsons disease (PD) and the gastrointestinal (GI) tract is implicated in the pathogenesis of PD. However, no studies have demonstrated ante-mortem relationships between nigrostriatal dysfunction and GI dysautonomia in PD. METHODS The Scale for Outcomes in Parkinsons disease for Autonomic Symptoms (SCOPA-AUT) assesses dysautonomia in the multi-center Parkinsons Progression Marker Initiative (PPMI). We used linear mixed-effects models and reliable change indices (RCIs) to examine longitudinal associations between dysautonomia and dopamine transporter (DAT) striatal binding ratios (SBRs) measured by single-photon emission computerized tomography in PPMI participants over four years (n = 397 at baseline). RESULTS Adjusted mixed-models of longitudinal data showed that constipation-but not orthostatic hypotension or urinary dysfunction-was associated with reduced SBR in both caudate (P < 0.001) and putamen (P = 0.040). In both regions, SBR reductions between baseline and 4-year follow-up were significant and measurable (P < 0.0001), with larger decline and variance in the caudate nucleus. Four-year change in caudate-but not putaminal-SBR was significantly associated with RCI-indicated progression of GI dysautonomia (P = 0.031), but not other types of dysautonomia. These associations remained after adjusting for the use of medications or supplements to control constipation. Consistent with prior PPMI reports, motor impairment progression was not associated with SBR reduction. CONCLUSIONS GI dysautonomia correlates with reductions in DAT availability; constipation is most closely associated with caudate-DAT reduction. Worsening GI-dysautonomia and reduced bowel movements may accompany advancing nigral degeneration or changes in nigrostriatal dopamine function.

Neuropsychological predictors of patient-reported cognitive decline after deep brain stimulation in Parkinson’s disease

ABSTRACT Background: Deep brain stimulation (DBS) is effective for treatment of motor complications of dopaminergic therapy in Parkinson’s disease (PD) but occasionally has been associated with multidomain cognitive decline. Patient- and caregiver-reported cognitive decline are clinically meaningful and increasingly recognized as important to consider when evaluating therapeutic interventions for PD. Objective: The objective was to assess presurgical neuropsychological and clinical factors associated with PD patient- and caregiver-reported cognitive decline in two or more domains after DBS. Method: A single telephone survey was used to assess patient- and caregiver-reported cognitive decline in five domains at both one and four months after DBS surgery. Decline in two or more domains was considered multidomain cognitive decline (MDCD). Baseline demographic, clinical, and neuropsychological factors were compared in those with or without MDCD. Preoperative neuropsychological measures were evaluated as risk factors and regressed on the presence of MDCD, with demographic covariates, using multiple logistic regression. Results: Preoperative performance in verbal recognition memory, language knowledge, and verbal processing decline were associated with postoperative, patient-reported MDCD in the first four weeks. MDCD at four months after DBS was associated with worse preoperative verbal reasoning, verbal recall, and semantic verbal fluency. Caregiver-reported MDCD one month after DBS was associated with poorer baseline verbal memory recognition accuracy/discriminability, visuospatial problem solving, and constructional praxis. Conclusion: Poor presurgical performance in verbal memory recognition, language processing, and visuospatial performance is associated with patient- or caregiver-reported decline following DBS surgery. Posterior cortical dysfunction seems to portend significant self-reported cognitive decline following deep brain stimulation.

Efficacy and tolerability of antidepressants in Parkinson's disease: A systematic review and network meta-analysis

To systematically review and analyze the efficacy and tolerability of different antidepressant pharmacologic treatments for depressive symptoms in Parkinsons disease (PD)

Domain-specific cognitive impairment in non-demented Parkinson's disease psychosis

In Parkinsons disease (PD), psychosis is associated with cognitive impairment that may be more profound in particular cognitive domains. Our goal was to determine whether psychosis in non‐demented PD participants is associated with domain‐specific cognitive impairment on the Mini‐Mental State Exam (MMSE).

Changes in Verbal Fluency in Parkinson's Disease

The test for semantic verbal fluency is quick and easy to administer. Decreases in semantic verbal fluency would suggest executive dysfunction among individuals with Parkinsons disease (PD).

Molecular imaging in neuropsychiatry

This volume, entitled ‘Molecular Imaging in Neuropsychiatry’, focuses on state of the art molecular imaging methods, as applied to the most challenging diagnostic and therapeutic issues in psychology and neurology, and demonstrates the critical role of molecular brain imaging in understanding neurobiological mechanisms and in potentially informing the development of more effective treatments. The topics range from neurodevelopmental to mood disorders, addictions, to the non-motor symptoms of movement disorders. The past two decades have witnessed remarkable advances in radiotracer chemistry for positron emission tomography (PET), as well as methodological advances for magnetic resonance spectroscopy (MRS) that provides complementary information to PET imaging. Radiotracer development has made possible the investigation of enzymes, neurotransmitter synthesis/metabolism, transporters, and receptors for a variety of neurotransmitters and neuromodulators (including second messengers and neuropeptides) in the living brain. A major focus over the past decade has been in vivo imaging of neurodegenerative disease mechanisms that previously could be studied only at post-mortem examination, including inflammation, betaamyloid, and Tau proteins (Hammoud, 2016; Mathis, Lopresti, Ikonomovic, & Klunk, 2017). MRS provides a unique opportunity to study amino acid neurotransmitters (GABA, glutamate), and measures of neuronal metabolism and oxidative stress. Recent advances include edited MRS, which has resulted in more precise quantification of neurotransmitters and metabolites at lower field strength that can be performed even in multi-site studies, as well as high field strength MRS imaging (Godlewska, Clare, Cowen, & Emir, 2017; Mikkelsen et al., 2017). In parallel to advances in PET radiotracer chemistry, developments in instrumentation have substantially improved the spatial resolution of PET. The highresolution research tomograph is a dedicated human brain PET scanner with a resolution of 2.3–3.4mm (de Jong et al., 2007; Wienhard et al., 2002). The development of dual modality imaging has been another major innovation in instrumentation, including PET/ computed tomography scanners and PET/magnetic resonance imaging (MRI) scanners. Sequential imaging of structure and function (PET/CT, PET/MRI) and, more recently, simultaneous acquisition of structure/circuitry and function (PET/MRI; Bailey et al., 2017). Simultaneous PET/MRI is an important opportunity to study pharmacologic and/or behaviour induced changes in neural circuitry and specific neurobiological mechanisms. The review by Hwang, Mohamed, and Brasic (2017) describes the complementary contributions of PET and MRS to the understanding of the pathophysiology of autism spectrum disorders (ASD), where molecular imaging studies are critical to inform the development of treatments for cognitive dysfunction and neuropsychiatric symptoms. The authors discuss the challenges of conducting neuroimaging research in ASD. They present the major MRS and PET neuroimaging findings, including their own important contributions. MRS studies of GABA and glutamate and PET studies of dopamine, serotonin, glucose metabolism, and cerebral blood flow are reviewed. The results presented underscore the need to understand the neurobiology of ASD across the lifespan, as well as to relate the molecular imaging findings to symptomatology in larger patient samples. While chronic schizophrenia has been a major focus of the molecular imaging research, the study of individuals at clinical high risk for schizophrenia has been more limited. Schifani et al. (2017) have performed innovative molecular imaging studies of early psychosis, including studying individuals at clinical high risk for schizophrenia and first episode psychosis. This challenging area of research is critical to identify molecular targets that may alter the early course of psychosis and may have implications for understanding the co-morbidity between psychosis and substance use that may have a negative impact on psychosis risk and course. In their review, the authors focus on imaging of extra-striatal dopamine, neuroinflammation, glutamate, GABA, and endocannabinoids. Importantly, they discuss future applications to study novel mechanisms such as other endocannabinoid targets, synaptic density, and nociceptin receptors, based on recent advances in radiotracer chemistry. The role of the hypothalamic-pituitary-adrenocortical (HPA) axis is well established in post-traumatic stress disorder (PTSD), and has been appreciated recently in substance use disorders and their co-morbidity with PTSD. As PET radiotracer development for the HPA axis has been challenging, human studies have focused