Daniel O Claassen

• MD, MS
• Professor (Associate) at Vanderbilt University

Dysregulated dopamine (DA) release in the mesocorticolimbic circuit is noted in Parkinson’s disease (PD) patients with impulsive and compulsive behaviors (ICBs). However, the effect of acute DA release on mood, the localization of this process, and the phenotypic differences in patients with ICB remain unknown. We applied a placebo-controlled dextr...

INTRODUCTION Action control may be impaired in essential tremor (ET). Disruptions in cerebello-thalamo-cortical networks are thought to underlie deficits in response inhibition, and previous studies have shown that beta band oscillations in the ventral intermediate nucleus (VIM) of the thalamus suppress behaviorally irrelevant information. While de...

Magnetic resonance imaging (MRI) sequences commonly used in simultaneous electroencephalogram (EEG)-MRI studies include blood oxygenation level-dependent (BOLD) and anatomical T 1 -weighted MRI. Safety and electrode heating profiles for these sequences have been well-characterized. However, recent improvements in EEG design may allow for additional...

Objective: Using a multi-informant approach, the authors assessed the psychiatric symptoms of adolescents and young adults with or without the huntingtin gene expansion and examined the association of psychiatric symptoms with cumulative disease exposure, a measure taking into account age and genetic data. Methods: The sample included 110 partic...

Background Central synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), involve alpha‐synuclein accumulation and dopaminergic cell loss in the substantia nigra (SN) and locus coeruleus (LC). Pure autonomic failure (PAF), a peripheral synucleinopathy, often precedes central synucl...

Background Huntington disease (HD) is a genetic neurodegenerative disorder. Given the focus on motor manifestations, nonmotor symptoms are frequently underappreciated in clinical evaluations, despite frequently contributing to primary functional impairment. Recent Findings A diagnosis of motor-onset as the definition of manifest symptoms misrepres...

Chorea is the primary manifestation of Huntington’s disease. Different clinicians pursue varied approaches to chorea management, and real-world evidence describing them is needed. The objective of this study was to assess the presence and severity of chorea, chorea pharmacotherapy, and treatment practice, and patterns in a large natural-history coh...

IntroductionIn a recently published Phase 3 trial (KINECT™-HD; NCT04102579), once-daily treatment with valbenazine significantly improved chorea versus placebo in adults with Huntington disease (HD). Individuals who completed KINECT-HD, along with de novo participants, were allowed to enroll in KINECT™-HD2 (NCT04400331), the first long-term study o...

Objective: Apathy is common in Huntington's disease (HD) and difficult to treat. Multiple recent calls have been made to increase understanding of apathy across the spectrum of HD severity. Functional status is an important outcome in HD trials; however, no consensus currently exists regarding the impact of apathy on functional status in HD. The a...

Intravenous arachnoid granulations (AGs) are protrusions of the arachnoid membrane into the venous lumen and function as contributors to the cerebrospinal fluid (CSF) flow circuit. Patients with Parkinson disease (PD) often present with accumulation of alpha synuclein. Previous works have provided evidence for neurofluid circulation dysfunction in...

Background/Aims Synthetic MRI (SynMRI) offers rapid data acquisition (5 min scan), which could reduce MRI time while providing versatile tissue contrasts for Huntington’s disease (HD) assessments. Broad application requires validation to ensure precise depiction of brain structural changes (especially striatum), as these are used to monitor HD prog...

Background/Aims Aberrant cerebrospinal fluid (CSF) flow and egress persist in many patients with Huntington’s disease (HD), and quantitation of these phenomena could inform mechanisms of disease progression and potentially assist with triaging patients for intrathecally-administered therapies. This work reports on the relevance of a recently-identi...

Background Children at risk for Huntington disease (HD) face significant stress while growing up in families impacted by HD. However, we do not fully understand the sources of stress in this population or the association between stress and psychological symptoms. Aims The aims of this study were to understand the types and characteristics of stres...

Background ANX005 is a humanized anti-complement C1q monoclonal antibody that blocks activation of the classical complement cascade. ANX005-HD-01 (HD-01; NCT04514367) was an open-label study of ANX005 in patients with manifest Huntington’s disease (HD). Enroll-HD is an ongoing, long-term observational registry study. HD-01b is a retrospective analy...

Background and Objectives: While historically cortico-basal ganglia-thalamocortical loops were believed to process limbic and sensorimotor data in parallel, there is now evidence to suggest that the two information streams can be processed in a single open loop. However, the limbic-motor interface remains insufficiently characterized. We sought to...

Background: Huntington's disease (HD) is a neurodegenerative disorder marked by cognitive impairment, movement abnormalities, and behavioral disturbances. The Stroop Color Word Test (SCWT) is a widely used tool to detect cognitive decline in HD. Variations in SCWT formats-horizontal (original) and vertical (Golden)-may influence performance, given...

Background Parkinson’s disease is characterized by dopamine-responsive symptoms as well as aggregation of α-synuclein protofibrils. New diagnostic methods assess α-synuclein aggregation characteristics from cerebrospinal fluid (CSF) and recent pathophysiologic mechanisms suggest that CSF circulation disruptions may precipitate α-synuclein retention...

Background: Huntington's disease (HD) is a neurodegenerative disease that presents families with significant numbers of stressful events. However, relatively little empirical research has characterized the stressors encountered by members of HD-affected families and their correlations with psychological symptoms. Objective: This study examined f...

Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia (TD) and chorea associated with Huntington disease (HD). To enhance detection of safety signals across individual trials, integrated safety analyses of deutetrabenazine in TD and HD chorea were conducted. For TD, safety data were integrated from two 1...

Background: Huntington's disease (HD) is a neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene, resulting in the production of mutant huntingtin proteins (mHTT). Previous research has identified urea as a key metabolite elevated in HD animal models and postmortem tissues of HD patients. Howev...

Background The choroid plexus functions as the blood-cerebrospinal fluid (CSF) barrier, plays an important role in CSF production and circulation, and has gained increased attention in light of the recent elucidation of CSF circulation dysfunction in neurodegenerative conditions. However, methods for routinely quantifying choroid plexus volume are...

Background Peri-sinus structures such as arachnoid granulations (AG) and the parasagittal dural (PSD) space have gained much recent attention as sites of cerebral spinal fluid (CSF) egress and neuroimmune surveillance. Neurofluid circulation dysfunction may manifest as morphological changes in these structures, however, automated quantification of...

Individuals with Tourette syndrome (TS) have poorer quality of life (QoL) than their peers, yet factors contributing to poor QoL in this population remain unclear. Research to date has predominantly focused on the impact of tics and psychiatric symptoms on QoL in TS samples. The aim of this cross-sectional, multi-informant study was to identify psy...

Antiamyloid antibodies have been used to reduce cerebral amyloid-beta (Aβ) load in patients with Alzheimer's disease. We applied focused ultrasound with each of six monthly aducanumab infusions to temporarily open the blood-brain barrier with the goal of enhancing amyloid removal in selected brain regions in three participants over a period of 6 mo...

While colloquially recognized for its role in pleasure, reward, and affect, dopamine is also necessary for proficient action control. Many motor studies focus on dopaminergic transmission along the nigrostriatal pathway, using Parkinson's disease as a model of a dorsal striatal lesion. Less attention to the mesolimbic pathway and its role in motor...

We express our gratitude to Dr Watanabe¹ for the editorial comment regarding our review article² and the thought-provoking discussion concerning the origins of neuromelanin (NM)-MRI contrast. Considering the increasing clinical interest in NM-MRI, gaining a profound understanding of the contrast mechanisms responsible for this signal is crucial, as...

Limbic and motor integration is enabled by a mesial temporal to motor cortex network. Parkinson disease (PD) is characterized by a loss of dorsal striatal dopamine but relative preservation of mesolimbic dopamine early in disease, along with changes to motor action control. Here, we studied 47 patients with PD using the Simon conflict task and [¹⁸F...

Impulsivity is a behavioral trait that is elevated in many neuropsychiatric disorders. Parkinson’s disease (PD) patients can exhibit a specific pattern of reward-seeking impulsive-compulsive behaviors (ICBs), as well as more subtle changes to generalized trait impulsivity. Prior studies in healthy controls (HCs) suggest that trait impulsivity is re...

Introduction Deutetrabenazine is approved for treatment of Huntington disease (HD)-related chorea and tardive dyskinesia (TD) in adults. Factors associated with deutetrabenazine persistence and adherence are not well understood. Methods Claims data from the Symphony Health Solutions Integrated Dataverse (2017-2019) were analyzed to identify real-w...

Background: The choroid plexus functions as the blood-cerebrospinal fluid barrier, plays an important role in neurofluid production and circulation, and has gained increased attention in light of the recent elucidation of neurofluid circulation dysfunction in neurodegenerative conditions. However, methods for routinely quantifying choroid plexus vo...

Disruptions to dopamine and noradrenergic neurotransmission are noted in several neurodegenerative and psychiatric disorders. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) offers a non-invasive approach to visualize and quantify the structural and functional integrity of the substantia nigra and locus coeruleus. This method may aid in...

Postprandial hypotension (PPH) is highly prevalent in Parkinson Disease (PD) and is defined as a sudden and substantial decrease (>20 mm Hg or >10 mm hg) in blood pressure within two hours after ingesting a meal. This condition is associated with syncope and falls. Eating a meal induces significant blood sequestration in the splanchnic circulation...

Postprandial hypotension (PPH) is defined as a sudden and substantial decrease (>20 mmHg or >10 mmHg) in blood pressure (BP) within two hours post meal intake; This condition is highly prevalent in neurogenic orthostatic hypotension (nOH) and is associated with pre-syncopal symptoms and postprandial syncope. We studied factors contributing to PPH i...

BACKGROUND: Parkinson’s disease is characterized by dopamine-responsive symptoms as well as aggregation and accumulation of a-synuclein protofibrils. New diagnostic methods assess a-synuclein aggregation characteristics from cerebrospinal fluid and recent pathophysiologic mechanisms suggest that cerebrospinal fluid circulation disruptions may preci...

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that predominantly impacts a Caucasian population, but few efforts have explored racial differences in presentation and progression. Objective: The aim was to assess the presentation and progression of HD across race groups using the Enroll-HD longitudinal o...

Background: Essential tremor (ET) and Parkinson's disease (PD) are the most common tremor disorders and are common indications for deep brain stimulation (DBS). In some patients, PD and ET symptoms overlap and diagnosis can be challenging based on clinical criteria alone. The objective of this study was to identify structural brain differences bet...

Objectives: To describe the characteristics of patients receiving a clinical referral for neuropsychological evaluation in two Huntington's Disease Society of America Centers of Excellence (HDSA COE). In this exploratory pilot study, we used an empirically supported clinical neuropsychological battery to assess differences in cognitive performance...

Background Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics. Objective To assess the safety and efficacy of deutetrabenazine, a vesicular monoamine transporter 2 inhibitor, in children and adolescents with TS. Methods ARTISTS OLE (NCT03567291) was a 54‐week, global, phase 3, open‐label extension study...

Objective: Investigations of cerebrospinal fluid (CSF) flow aberrations in Huntington's disease (HD) are of growing interest as impaired CSF flow may contribute to mutant Huntington (mHTT) retention and observed heterogeneous responsiveness to intrathecally administered therapies. Method: We assessed net cerebral aqueduct CSF flow and velocity i...

Objective: Antisocial behaviors are common and problematic among patients with behavioral variant frontotemporal dementia (bvFTD). In the present study, the investigators aimed to validate an informant-based questionnaire developed to measure the extent and severity of antisocial behaviors among patients with dementia. Methods: The Social Behavi...

Cognitive impairment (CI) is the most frequent non-motor symptom in Parkinson’s disease and is associated with deficits in a number of cognitive functions including working memory. However, the pathophysiology of Parkinson’s disease CI is poorly understood. Beta oscillations have previously been shown to play an important role in cognitive function...

Background Impulsivity is a common clinical feature of Huntington disease (HD), but the underlying cognitive dynamics of impulse control in this population have not been well-studied. Objective To investigate the temporal dynamics of action impulse control in HD patients using an inhibitory action control task. Methods Sixteen motor manifest HD p...

Background: Families in which a parent has Huntington's disease (HD) are faced with significant stressors that can contribute to difficulties in communicating together about illness-related concerns. Family members who use more disengagement coping strategies, including denial and avoidance, to deal with illness-related stressors may have the grea...

Background: Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease. Metho...

OBJECTIVES/GOALS: To identify an electroencephalographic (EEG) signature of SOR in adults with TS METHODS/STUDY POPULATION: We will recruit 60 adults with CTD and 60 sex- and age-matched healthy controls to complete scales assessing severity of SOR (Sensory Gating Inventory, SGI), tics, and psychiatric symptoms. Subjects will then be monitored on d...

One of the pathological hallmarks of Alzheimer’s and related diseases is the increased accumulation of protein amyloid-β in the brain parenchyma. As such, recent studies have focused on characterizing protein and related clearance pathways involving perivascular flow of neurofluids, but human studies of these pathways are limited owing to limited m...

Background: Dyskinetic cerebral palsy (DCP), a lifelong neurological disorder beginning in early childhood, manifests with hyperkinetic movements and dystonia. The Movement Disorder-Childhood Rating Scale (MD-CRS) is a clinician-reported outcome measure assessing the intensity of movement disorders and their effect on daily life in pediatric patie...

Background and objectives The clinical diagnosis of Huntington disease (HD) is typically made once motor symptoms and chorea are evident. Recent reports highlight the onset of cognitive and psychiatric symptoms before motor manifestations. These findings support further investigations of cognitive function across the lifespan of HD sufferers. Meth...

Objective: The cerebellum has been identified as the key brain region that modulates reward processing in animal models. Consistently, we recently found that people with cerebellar ataxia have impulsive and compulsive behaviors (ICBs), the main symptoms related to abnormal reward processing. Due to the lack of a validated scale to quantitatively m...

Objective: MRI-guided low-intensity focused ultrasound (FUS) has been shown to reversibly open the blood-brain barrier (BBB), with the potential to deliver therapeutic agents noninvasively to target brain regions in patients with Alzheimer's disease (AD) and other neurodegenerative conditions. Previously, the authors reported the short-term safety...

The choroid plexus (ChP) comprises a collection of modified ependymal cells that play an important role in the production of brain cerebrospinal fluid (CSF), and ChP perfusion aberrations have been implicated in a range of cerebrovascular and neurodegenerative disorders. To provide an exemplar for the growing interest in ChP activity, we evaluated...

Purpose of review: Patients with multiple system atrophy (MSA) can present with diverse clinical manifestations, and the clinical care required is complex and requires a thoughtful approach to emerging symptoms and treatment decisions. Recent findings: Even though it is a rare disease, MSA is often encountered in clinical practice. New developme...

Background ANX005 is a humanized monoclonal antibody designed to inhibit C1q. Aims Report final results of ANX005-HD-01: a Phase 2 study of patients with or at risk of manifest HD. Methods/Techniques Eligible patients (CAP>400) received intravenous ANX005 every 2 weeks (wk) through wk22 (NCT04514367). Endpoints were assessed on-treatment through...

Introduction While Huntington’s disease (HD) disproportionately impacts those of European descent, greater awareness has encouraged increased counseling and diagnoses in Black, Hispanic, and Asian patients. This study aims to identify indices of disease burden and progression in HD among race groups. Methods Data from Enroll-HD periodic data set 5...

SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington’s disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP,...

Cognitive impairment (CI) is the most frequent nonmotor symptom in Parkinsons Disease (PD) and is associated with deficits in executive functions such as working memory. Previous studies have demonstrated that caudate beta power is involved in learning and working memory. Decreased dopamine in motor cortico-striato-thalamo-cortical (CSTC) circuits...

The importance of metal biology in neurodegenerative diseases such as Huntingtin Disease is well documented with evidence of direct interactions between metals such as copper, zinc, iron and manganese and mutant Huntingtin pathobiology. To date, it is unclear whether these interactions are observed in humans, how this impacts other metals, and how...

(R)‐[18F]MH.MZ ([18F]MH.MZ) is a promising positron emission tomography (PET) radiotracer for in vivo study of the 5‐HT2A receptor. To facilitate clinical trials a fully automated radiosynthesis procedure for [18F]MH.MZ was developed using commercially available materials on the iPhase Flexlab module. The overall synthesis time was 100 minutes with...

Background and Objectives Individuals with cerebellar ataxia (CA) can develop impulsive behavioral symptoms, often resulting in negative interpersonal consequences, detrimentally impacting their quality of life. Limited evidence exists concerning impulsivity in CA and its associated behavioral changes. We assessed impulsive traits in CA using the B...

Although researchers have recognized the need to better account for the heterogeneous perceptual speech characteristics among talkers with the same disease, guidance on how to best establish such dysarthria subgroups is currently lacking. Therefore, we compared subgroup decisions of two data-driven approaches based on a cohort of talkers with Hunti...

Impulsivity is inherent to behavioral disorders such as substance abuse and binge eating. While the role of dopamine in impulse behavior is well established, γ-aminobutyric acid (GABA) therapies have promise for the treatment of maladaptive behaviors. In Parkinson disease (PD), dopaminergic therapies can result in the development of impulsive and c...

Abstract Background Recent studies have suggested alternative cerebrospinal fluid (CSF) clearance pathways for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of these pathways is the anatomic region surrounding the superior sagittal sinus, which has been shown to have relevance to trans-arachnoid...

Background: Anosognosia can manifest as an unawareness of neurobehavioral symptoms in individuals with Huntington disease (HD). Measurement of anosognosia is challenging, but the Anosognosia Scale (AS) represents a brief option with promising findings in small samples. Objective: To replicate application of the AS in a larger HD sample than prev...

Objective: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by neuropsychiatric symptoms (e.g., anxiety and depression), where individuals suffer high levels of stress from the social, physical, and cognitive burden of the disease. The present study examined two factors associated with increased risk for s...

Introduction: Chorea is characterized by sudden, involuntary movements that interfere with quality of life (QOL). Utility values measure preferences for different health states and reflect societal perceived disease severity. To date, no studies have reported utility values specifically for Huntington's disease (HD) chorea. We estimated impact on...

Impulsive-compulsive behaviors manifest in a substantial proportion of persons with Parkinson disease. Reduced ventral striatum dopamine receptor availability, and increased dopamine release is noted in patients with these symptoms. Prior studies of impulsivity suggest that midbrain D2 autoreceptors regulate striatal dopamine release in a feedback...

IntroductionChorea, a common clinical manifestation of Huntington’s disease (HD), involves sudden, involuntary movements that interfere with daily functioning and contribute to the morbidity of HD. Tetrabenazine and deutetrabenazine are FDA-approved to treat chorea associated with HD. Compared to tetrabenazine, deutetrabenazine has a unique pharmac...

Background Sensory over-responsivity (SOR) refers to excessively intense and/or prolonged behavioral responses to environmental stimuli typically perceived as non-aversive. SOR is prevalent in several neurodevelopmental disorders, including chronic tic disorders (CTDs) and obsessive-compulsive disorder (OCD). Few studies have examined the extent an...

Background: Recent studies have suggested the importance of a glymphatic clearance pathway for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of this pathway is the anatomic region surrounding the superior sagittal sinus, which has been hypothesized to encompass lymphatic vessels. This so-called...

The stop-signal task is a well-established assessment of response inhibition, and in humans, proficiency is linked to dorsal striatum D2 receptor availability. Parkinson's disease (PD) is characterized by changes to efficiency of response inhibition. Here, we studied 17 PD patients (6 female and 11 male) using the stop-signal paradigm in a single-b...

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for H...

Background: The COVID-19 pandemic has increased the need for remote healthcare options among patients with Huntington's disease (HD). However, since not every HD patient is suitable for telehealth, it is important to differentiate who can be seen virtually from who should remain as in-person. Unfortunately, there are no clinical guidelines on how...

Objective: The importance of metal biology in neurodegenerative diseases such as Huntingtin Disease is well documented with evidence of direct interactions between metals such as copper, zinc, iron and manganese and mutant Huntingtin pathobiology. To date, it is unclear whether these interactions are observed in humans, how this impacts other metal...

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics; treatments for tics are associated with safety concerns. Deutetrabenazine is a selective vesicular monoamine transporter 2 inhibitor approved for the treatment of chorea associated with Huntington disease and tardive dyskinesia...

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities. Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dysk...

Deficits in cognition, reward processing, and motor function are clinical features relevant to both aging and depression. Individuals with late-life depression often show impairment across these domains, all of which are moderated by the functioning of dopaminergic circuits. As dopaminergic function declines with normal aging and increased inflamma...

Unlawful behaviors have been reported in association with Huntington's disease (HD), although their overall prevalence and clinical significance remain unknown. Recognition of problematic behavior is limited by stigma and lack of routine clinical assessment, as well as the absence of validated screening measures. We performed a retrospective chart...

Objective: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that presents significant challenges to family communication. The investigators examined observations of communication between parents with HD and their offspring talking about the challenges of HD and explored potential correlates of their communication. Meth...

Background: Chorea is recognized as a prototypic motor feature of Huntington’s disease (HD), but its effect on health-related quality of life (HRQoL) has not been fully explored. This study describes the impact of chorea on HRQoL in patients with HD. Objective: To determine the impact of HD-related chorea on employment, self-care activities, activi...

Background: Chorea is recognized as a prototypic motor feature of Huntington’s disease (HD), but its effect on health-related quality of life (HRQoL) has not been fully explored. This study describes the impact of chorea on HRQoL in patients with HD. Objective: To determine the impact of HD-related chorea on employment, self-care activities, activi...

Objective To determine the impact of photophobia on persons with Progressive Supranuclear Palsy (pwPSP) by determining the functional impact of light sensitivity using methods established in migraine research. Methods All 60 participants (pwPSP=15, Parkinson Disease (PD)=15, Older adults=30) completed a series of questionnaires designed to assess...

Background Reduced diffusion along perivascular spaces in adults with Alzheimer’s-disease-related-dementias has been reported and attributed to reduced glymphatic flow. Objectives To apply quantitative measures of diffusion along, and orthogonal to, perivascular spaces in a cohort of older adults with and without clinical symptoms of alpha-synucle...

IntroductionDopamine medication withdrawal in Parkinson’s disease (PD) is commonly employed in clinical practice and can be required for participation in research studies. When asked to withdraw from medications, participants often enquire as to what symptoms they should expect.Objectives This study sought to improve the informed consent process by...