Abnormal Brain Iron Accumulation is a Rare Finding in Down Syndrome Regression Disorder.

BACKGROUND: Down syndrome regression disorder (DSRD) is characterized by the sudden loss of adaptive function, cognitive-executive function, and language with abnormal sleep and/or motor control. METHODS: Clinical, laboratory, and imaging data from three individuals with DSRD and iron on brain imaging were reviewed. RESULTS: Three patients with Down syndrome presented with new onset of flat affect, depression, reduced speech, and other neurological symptoms consistent with DSRD. Magnetic resonance imaging showed abnormal iron accumulation in the basal ganglia, as well as calcification in two cases. Molecular diagnostic testing for neurodegeneration with brain iron accumulation was negative in the two individuals tested. CONCLUSIONS: These individuals presented suggest that a subset of individuals with DSRD have abnormal brain iron accumulation. Motor control symptoms reported in DSRD, such as stereotypies and parkinsonism, may reflect this basal ganglia involvement. The presence of abnormal brain iron should not delay or preclude diagnosis and treatment for DSRD.

Towards Precision Therapies for Inherited Disorders of Neurodegeneration with Brain Iron Accumulation.

Background: Neurodegeneration with brain iron accumulation (NBIA) disorders comprise a group of rare but devastating inherited neurological diseases with unifying features of progressive cognitive and motor decline, and increased iron deposition in the basal ganglia. Although at present there are no proven disease-modifying treatments, the severe nature of these monogenic disorders lends to consideration of personalized medicine strategies, including targeted gene therapy. In this review we summarize the progress and future direction towards precision therapies for NBIA disorders. Methods: This review considered all relevant publications up to April 2021 using a systematic search strategy of PubMed and clinical trials databases. Results: We review what is currently known about the underlying pathophysiology of NBIA disorders, common NBIA disease pathways, and how this knowledge has influenced current management strategies and clinical trial design. The safety profile, efficacy and clinical outcome of clinical studies are reviewed. Furthermore, the potential for future therapeutic approaches is also discussed. Discussion: Therapeutic options in NBIAs remain very limited, with no proven disease-modifying treatments at present. However, a number of different approaches are currently under development with increasing focus on targeted precision therapies. Recent advances in the field give hope that novel strategies, such as gene therapy, gene editing and substrate replacement therapies are both scientifically and financially feasible for these conditions. Highlights: This article provides an up-to-date review of the current literature about Neurodegeneration with Brain Iron Accumulation (NBIA), with a focus on disease pathophysiology, current and previously trialed therapies, and future treatments in development, including consideration of potential genetic therapy approaches.

Brain MRI Pattern Recognition in Neurodegeneration With Brain Iron Accumulation.

Most neurodegeneration with brain iron accumulation (NBIA) disorders can be distinguished by identifying characteristic changes on magnetic resonance imaging (MRI) in combination with clinical findings. However, a significant number of patients with an NBIA disorder confirmed by genetic testing have MRI features that are atypical for their specific disease. The appearance of specific MRI patterns depends on the stage of the disease and the patient's age at evaluation. MRI interpretation can be challenging because of heterogeneously acquired MRI datasets, individual interpreter bias, and lack of quantitative data. Therefore, optimal acquisition and interpretation of MRI data are needed to better define MRI phenotypes in NBIA disorders. The stepwise approach outlined here may help to identify NBIA disorders and delineate the natural course of MRI-identified changes.

4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN.

Pantothenate kinase-associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease-vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4'-phosphopantetheine, normalized levels of the CoA-, iron-, and dopamine-related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4'-phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron-sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4'-phosphopantetheine as a candidate therapeutic for PKAN.

Assessment of an Objective Method of Dyskinesia Measurement in Parkinson's Disease.

BACKGROUND: The goal of this study was to validate an objective method of measuring levodopa induced dyskinesia in Parkinson's disease (PD). METHODS: To characterize agreement between the clinician-based measure and a force plate, we assessed dyskinesia in PD subjects participating in a randomized and blinded clinical trial of an adenosine A2A anatagonist. Convergent validity and intra-class correlations were evaluated between the objective force plate measure and clinician assessments. RESULTS: All measures correlated across time and detected differences in treatments. CONCLUSION: Our results indicate that objective measure from a force plate is in scale agreement with clinical ratings of dyskinesia severity, indicating it as a reliable method to measure LID objectively but with greater resolution to detect changes in LID.

Neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A2-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor-Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). Together, these genes account for disease in approximately 85% of patients diagnosed with an NBIA disorder. New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.

Neurodegeneration with brain iron accumulation: diagnosis and management.

Neurodegeneration with brain iron accumulation (NBIA) encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia. The genetic basis of ten forms of NBIA is now known. The clinical features of NBIA range from rapid global neurodevelopmental regression in infancy to mild parkinsonism with minimal cognitive impairment in adulthood, with wide variation seen between and within the specific NBIA sub-type. This review describes the clinical presentations, imaging findings, pathologic features, and treatment considerations for this heterogeneous group of disorders.

The effect of deep brain stimulation randomized by site on balance in Parkinson's disease.

BACKGROUND: The effect of the surgical site of DBS on balance and gait in Parkinson's Disease (PD) is uncertain. This is the first double-blind study of subjects randomized to either the STN (N = 14) or GPi (N = 14) who were assessed on a range of clinical balance measures. METHODS: Balance testing occurred before and 6 months postsurgery. A control PD group was tested over the same period without surgery (N = 9). All subjects were tested on and off medication and DBS subjects were also tested on and off DBS. The Postural Instability and Gait Disability items of the UPDRS and additional functional tests, which we call the Balance and Gait scale, were assessed. Activities of Balance Confidence and Activities of Daily Living questionnaires were also recorded. RESULTS: Balance was not different between the best-treated states before and after DBS surgery for both sites. Switching DBS on improved balance scores, and scores further improved with medication, compared to the off state. The GPi group showed improved performance in the postsurgery off state and better ratings of balance confidence after surgery, compared to the STN group. CONCLUSIONS: Clinical measures of balance function for both the STN and GPi sites showed that balance did not improve beyond the best medically treated state before surgery. Both clinical balance testing in the off/off state and self-reported balance confidence after surgery showed better performance in the GPi than the STN group.

ß-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

Effects of deep brain stimulation in the subthalamic nucleus or globus pallidus internus on step initiation in Parkinson disease: laboratory investigation.

OBJECT: Difficulty with step initiation, called "start hesitation," is related to gait bradykinesia and is an early hallmark of gait freezing in Parkinson disease (PD). Authors of this study investigated the effects of deep brain stimulation (DBS) and levodopa on step initiation before and 6 months after DBS surgery in 29 patients with PD who were randomized to either the bilateral subthalamic nucleus (STN) or globus pallidus internus (GPi) as the DBS site. METHODS: The authors measured the amplitude and duration of anticipatory postural adjustments (APAs), the feed-forward postural preparation that precedes the onset of voluntary step initiation, based on center-of-pressure displacements on a force plate. They also measured the length and velocity of the first step using a motion analysis system to study kinematics. Some of the patients (22) were from a large, multicenter, double-blind clinical trial, and all patients in the study (29, PD-DBS group) were randomized to DBS in either the bilateral STN (15 patients) or bilateral GPi (14 patients). Differences in step initiation were investigated in 2 conditions before surgery (off/on levodopa) and in 4 conditions after surgery (off/on levodopa combined with off/on DBS). Twenty-eight elderly healthy control volunteers (CTRL group) were also tested, and 9 control volunteers with PD who met the criteria for DBS (PD-C group) were tested at baseline and 6 months later. RESULTS: Patients in the PD-DBS group had smaller amplitudes and longer durations of APAs compared with those in the 28 healthy control volunteers in all conditions. Before surgery, APAs improved with levodopa. After surgery, the APAs were significantly worse than in the best-treatment state before surgery (DOPA condition), and responsiveness to levodopa decreased. No differences in APAs were detected between the STN and GPi groups. A comparison with PD control volunteers who did not undergo DBS surgery confirmed that a deterioration in step preparation was not related to disease progression. Step length and velocity were smaller in the PD-DBS group than in controls in all conditions. Before surgery, levodopa improved the length and velocity of the first step. Both step length and velocity were unchanged in the best-treatment state before surgery (DOPA condition) as compared with after surgery (DBS+DOPA), with only step velocity in the STN group getting worse after surgery. CONCLUSIONS: Six months of DBS in the STN or GPi impaired anticipatory postural preparation for step initiation, the opposite effect as with levodopa. Deep brain stimulation disrupted postural preparation more than step execution, suggesting independent motor pathways for preparation and execution of gait. Although turning the stimulators on after surgery combined with levodopa benefited the postural preparation to step, a comparison of pre- and postsurgery conditions suggests that either the surgery itself or 6 months of continuous stimulation may lead to an alteration of circuits or plastic changes that impair step initiation.

The effects of subthalamic and pallidal deep brain stimulation on postural responses in patients with Parkinson disease.

OBJECT: The effect of deep brain stimulation (DBS) for Parkinson disease (PD) on balance is unclear. The goal of this study was to investigate how automatic postural responses (APRs) were affected in patients randomized to either subthalamic nucleus (STN) or globus pallidus internus (GPi) surgery. METHODS: The authors tested 24 patients with PD who underwent bilateral DBS, 9 control patients with PD who did not undergo DBS, and 17 age-matched control volunteers. The electrode placement site was randomized and blinded to the patients and to the experimenters. Kinematic, kinetic, and electromyographic recordings of postural responses to backward disequilibrium via forward translations of the standing surface were recorded in the week prior to surgery while the patients were off (OFF) and on (ON) antiparkinsonian medication (levodopa), and then 6 months after surgery in 4 conditions: 1) off medication with DBS switched off (OFF/OFF); 2) off medication with DBS on (DBS); 3) on medication with DBS off (DOPA); and 4) with both medication and DBS on (DBS+DOPA). Stability of the automatic postural response (APR) was measured as the difference between the displacement of the center of pressure and the projected location of the center of body mass. RESULTS: Patients with PD had worse APR stability than controls. Turning the DBS on at either site improved APR stability compared with the postoperative OFF condition by lengthening the tibialis response, whereas medication did not show an appreciable effect. The STN group had worse APR stability in their best functional state (DBS+DOPA) 6 months after the DBS procedure compared with their best functional state (ON levodopa) before the DBS procedure. In contrast, the GPi group and the PD control group showed no change over 6 months. The APR stability impairment in the STN group was associated with smaller tibialis response amplitudes, but there was no change in response latency or coactivation with gastrocnemius. CONCLUSIONS: Turning the DBS current on improved APR stability for both STN and GPi sites. However, there was a detrimental DBS procedural effect for the STN group, and this effect was greater than the benefit of the stimulating current, making overall APR stability functionally worse after surgery for the STN group.

Site of deep brain stimulation and jaw velocity in Parkinson disease.

OBJECT: While deep brain stimulation (DBS) has proven to be an effective treatment for many symptoms of Parkinson disease (PD), a deterioration of axial symptoms frequently occurs, particularly for speech and swallowing. These unfavorable effects of DBS may depend on the site of stimulation. The authors made quantitative measures of jaw velocity to compare the relative effectiveness of DBS in the globus pallidus internus (GPi) or the subthalamic nucleus (STN). This was a randomized, double-blind, and longitudinal study, with matched healthy controls. METHODS: The peak velocities of self-scaled and externally scaled jaw movements were studied in 27 patients with PD before and after 6 months of bilateral DBS in the GPi or the STN. A mixed-effects model was used to identify differences in jaw velocity before DBS surgery (baseline) while off and on levodopa therapy, and after 6 months of DBS (postoperative) during 4 treatment conditions (off- and on-levodopa states with and without DBS). RESULTS: Self-scaled jaw velocity was impaired by the DBS procedure in the STN; velocity was significantly decreased across all postoperative conditions compared with either the off- or on-levodopa baseline conditions. In contrast, the postoperative velocity in the GPi group was generally faster than the baseline off-levodopa state. Turning the DBS off and on had no effect on jaw velocity in either group. Unlike baseline, levodopa therapy postoperatively no longer increased jaw velocity in either group, and this lack of effect was not related to postoperative changes in dose. The externally scaled jaw velocity was little affected by PD, but DBS still slightly affected performance, with the STN group significantly slower than the GPi group for most conditions. CONCLUSIONS: The authors' results suggest that either the electrode implant in STN or the subsequent period of continuous STN stimulation negatively affected voluntary jaw velocity, including the loss of the preoperative levodopa-induced improvement. While the GPi group showed some improvement in voluntary jaw velocity postoperatively, their performance during the combination of DBS and levodopa was not different from their best medical management presurgery. The results have implications for DBS target selection, particularly for those patients with oromotor dysfunctions.

OFF-off rebound dyskinesia in subthalamic nucleus deep brain stimulation of Parkinson's disease.

A 61-year-old man with Parkinson's disease (PD), motor fluctuations, and dyskinesias underwent bilateral implantation of deep brain stimulation (DBS) electrodes in the subthalamic nucleus (STN). One month after surgery, DBS was optimized to bilateral monopolar settings at the most proximal electrode just superior to the STN, which improved motor fluctuations and dyskinesias. At several postoperative evaluations off medications overnight, both stimulators were turned off and within 60 seconds he developed severe dyskinesias. When the stimulators were turned back on, the dyskinesias soon resolved. This article is a first report of a unique pattern of rebound-type dyskinesia that occurred in the off medication state produced by stopping STN DBS.