Estimation of Ambulation and Survival in Neurodegeneration with Brain Iron Accumulation Disorders.

BACKGROUND: Neurodegeneration with Brain Iron Accumulation (NBIA) disorder is a group of ultra-orphan hereditary diseases with very limited data on its course. OBJECTIVES: To estimate the probability of preserving ambulatory ability and survival in NBIA. METHODS: In this study, the electronic records of the demographic data and clinical assessments of NBIA patients from 2012 to 2023 were reviewed. The objectives of the study and factors impacting them were investigated by Kaplan-Meier and Cox regression methods. RESULTS: One hundred and twenty-two genetically-confirmed NBIA patients consisting of nine subtypes were enrolled. Twenty-four and twenty-five cases were deceased and wheelchair-bound, with a mean disease duration of 11 ± 6.65 and 9.32 ± 5 years. The probability of preserving ambulation and survival was 42.9% in 9 years and 28.2% in 15 years for classical Pantothenate Kinase-Associated Neurodegeneration (PKAN, n = 18), 89.4% in 7 years and 84.7% in 9 years for atypical PKAN (n = 39), 23% in 18 years and 67.8% in 14 years for Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN, n = 23), 75% in 20 years and 36.5% in 33 years for Kufor Rakeb Syndrome (KRS, n = 17), respectively. The frequencies of rigidity, spasticity, and female gender were significantly higher in deceased cases compared to surviving patients. Spasticity was the only factor associated with death (P value = 0.03). CONCLUSIONS: KRS had the best survival with the most extended ambulation period. The classical PKAN and MPAN cases had similar progression patterns to loss of ambulation ability, while MPAN patients had a slower progression to death. Spasticity was revealed to be the most determining factor for death.

Neurodegeneration with Brain Iron Accumulation Disorders and Retinal Neurovascular Structure.

BACKGROUND: The unique neurovascular structure of the retina has provided an opportunity to observe brain pathology in many neurological disorders. However, such studies on neurodegeneration with brain iron accumulation (NBIA) disorders are lacking. OBJECTIVES: To investigate NBIA's neurological and ophthalmological manifestations. METHODS: This cross-sectional study was conducted on genetically confirmed NBIA patients and an age-gender-matched control group. The thickness of retinal layers, central choroidal thickness (CCT), and capillary plexus densities were measured by spectral domain-optical coherence tomography (SD-OCT) and OCT angiography, respectively. The patients also underwent funduscopy, electroretinography (ERG), visual evoked potential (VEP), and neurological examination (Pantothenate-Kinase Associated Neurodegeneration-Disease Rating Scale [PKAN-DRS]). The generalized estimating equation model was used to consider inter-eye correlations. RESULTS: Seventy-four patients' and 80 controls' eyes were analyzed. Patients had significantly decreased visual acuity, reduced inner or outer sectors of almost all evaluated layers, increased CCT, and decreased vessel densities, with abnormal VEP and ERG in 32.4% and 45.9%, respectively. There were correlations between visual acuity and temporal peripapillary nerve fiber layer (positive) and between PKAN-DRS score and disease duration (negative), and scotopic b-wave amplitudes (positive). When considering only the PKAN eyes, ONL was among the significantly decreased retinal layers, with no differences in retinal vessel densities. Evidence of pachychoroid was only seen in patients with Kufor Rakeb syndrome. CONCLUSION: Observing pathologic structural and functional neurovascular changes in NBIA patients may provide an opportunity to elucidate the underlying mechanisms and differential retinal biomarkers in NBIA subtypes in further investigations. © 2023 International Parkinson and Movement Disorder Society.

Transcranial sonography in neurodegeneration with brain iron accumulation disorders.

BACKGROUND: Transcranial Sonography is a non-invasive technique that has been used as a diagnostic tool for a variety of neurodegenerative disorders. However, the utility and potential application of this technique in NBIA disorders is scarce and inconclusive. METHODS: In this cross-sectional retrospective case-control study, the echogenicity of Substantia Nigra (SN), Lentiform Nucleus (LN), and Diameter of the Third Ventricle (DTV) were assessed by TCS in genetically confirmed NBIA patients referring to the movement disorder clinic. The normal echogenicity area of SN was defined based on the 90th percentile of an age-and-gender-matched control group. NBIA patients underwent neurologic examination at each visit, but their brain magnetic resonance imaging and demographics were extracted from electronic records. RESULTS: Thirty-five NBIA patients of four subtypes with a mean disease duration of 10.54 years and 35 controls were enrolled. The normally defined SN echogenicity in controls was 0.23 cm2. DTV and SN echogenicity areas were significantly higher in patients compared to the controls (P = 0.002 and < 0.001, respectively). Around 85% and 63% of the patients showed LN and SN hyperechogenicity at least on one side, respectively. Disease duration was positively correlated with DTV (r = 0.422, p = 0.015). Cases with Pantothenate Kinase Associated Neurodegeneration (n = 23) also had significantly higher DTV and SN echogenicity area compared to the controls. CONCLUSION: Despite most NBIA patients displayed increased DVT and higher SN and LN hyperechogenicity than healthy controls, the discriminatory role of TCS on different NBIA subtypes remains to be determined.

Efficacy of Probiotics in Improving Motor Function and Alleviating Constipation in Parkinson's Disease: A Randomized Controlled Trial.

Background: Parkinson's disease (PD) is one of the common neurodegenerative diseases, and there has been an increasing interest in the potential role of intestinal dysbiosis in its pathogenesis and related gastrointestinal complications such as constipation. Objectives: This study aims to evaluate the effects of multi-strain probiotics on constipation and motor function in PD patients. Methods: This study was a blinded, randomized controlled trial (RCT) that involved 27 PD patients who were diagnosed with constipation according to the ROME IV criteria for functional constipation. The primary outcome measured before and after the intervention in both the placebo and probiotic groups was the frequency of defecation. Secondary outcomes evaluated were laxative use, sense of complete evacuation, Bristol Stool Scale for consistency, and Unified Parkinson's Disease Rating Scale (UPDRS) scale. The study lasted for eight weeks. Both groups also were educated about lifestyle modification. Results: Of 30 included patients (15 in each group), 13 were women, and 17 were men. Three patients dropped out of the study. Between-group analysis showed that the frequency of bowel movements significantly increased in the probiotic group 4 [3 - 5] in comparison with 2 [2 - 3] in placebo (P = 0.02). Stool consistency also improved in the probiotic group (P = 0.04). However, there were no significant differences in other outcomes. The within-group analysis showed improvement in stool consistency in both probiotics and placebo groups (P = 0.01 and P = 0.007, respectively), while stool frequency and sense of complete evacuation significantly improved only in the probiotic group (P < 0.05). Conclusions: This study demonstrated that multi-strain probiotics could improve frequency, consistency, and sense of complete evacuation in PD patients, while there was no significant effect on motor functions in 8 weeks. It is suggested that additional studies be conducted on longer-term effects.

Huntington's disease and neurovascular structure of retina.

BACKGROUND: Retinal biomarkers in neurodegenerative disorders have attracted much attention in recent years. Recent studies have reported visual dysfunction in Huntington's disease (HD). However, little is known about retinal structural changes in HD. METHODS: A total of 50 subjects, including 25 motor-manifest HD patients and 25 gender- and age-matched controls, were enrolled. Unified Huntington's Disease Rating Score-Motor part was assessed in HD patients. Spectral-domain Optical Coherence Tomography (SD-OCT) was used to evaluate the macular thickness and peripapillary retinal nerve fiber layer (pRNFL). Superficial and deep capillary plexus densities were measured using OCT angiography (OCTA). To account for inter-eye correlation, generalized estimating equation (GEE) model was used. RESULTS: HD patients had a significant reduction in macular thickness in both inner and outer superior sectors and the inferior outer sector. Inferior pRNFLs were significantly decreased in thickness. There was no significant difference in retinal capillary plexus density between the two groups. Age and disease duration were negatively correlated with macular thickness in HD patients. However, the severity of motor involvement was not correlated with SD-OCT or OCTA parameters. CONCLUSIONS: We observed attenuated pRNFL and macular retinal thickness in patients with HD, independent of macular capillary plexus parameters. It can support the hypothesis that the retina may be a potential biomarker for monitoring the neurodegenerative process in HD.

Association between plasma PCSK9 levels and lipid profile in patients with Parkinson's disease and comparison with healthy subjects.

Background: Up to know, limited and contradictory results have been published about the role of prognostic values of lipid profile and proprotein convertase subtilisin/kexin type 9 (PCSK9) in Parkinson's disease (PD). The aim of the present study is to investigate the role of lipid profile and PCSK9 in patients with PD and compare it with healthy individuals. Methods: In this case-control study, 31 individuals diagnosed with PD were compared with 31 healthy individuals. The lipid profile and PCSK9 of research participants were measured and the resulting data were analyzed using SPSS software. The P-values smaller than 0.05 were considered significant. Results: The mean age of participants in the PD and control group was 56.9 ± 8.8 and 53.7 ± 10.1 years, respectively (P > 0.050). 27 individuals (87.1%) in the PD group and 13 individuals (41.9%) in the control group were men. Low-density lipoprotein (LDL) level (84.2 ± 24.9 ml/dl vs. 105.5 ± 16.8, P < 0.001), high-density lipoprotein (HDL) level (45.5 ± 8.7 ml/dl vs. 51.1 ± 9.5 ml/dl, P < 0.001), and total cholesterol (155.3 ± 31.2 ml/dl vs. 192.8 ± 32.5 ml/dl, P < 0.001) were lower and triglyceride (TG) level was higher in the PD group (133.3 ± 79.3 ml/dl vs. 131.2 ± 58.6 ml/dl, P = 0.900) compared with the control group. PCSK9 level was higher in the PD group, but no significant difference was found (141.6 ± 70.0 vs. 129.7 ± 51.0 ng/ml, P = 0.500) compared to healthy subjects. Moreover, there was no relation between PCSK9 and severity of PD. Conclusion: Our findings showed that individuals with PD had lower levels of HDL, LDL, and total cholesterol compared with the control group. However, higher concentrations of PCSK9 were observed in patients with PD compared with healthy volunteers.

Long term follow-up results of deep brain stimulation of the Globus pallidus interna in pediatric patients with DYT1-positive dystonia.

OBJECTIVES: Primary generalized dystonia (PGD) due to heterozygous torsin 1A (TOR1A) gene mutation (DYT1) is a childhood onset dystonia with rapid deterioration of symptoms, leading to severe disability in adolescence. Globus pallidus interna deep brain stimulation (GPi-DBS) has been shown to provide significant improvement in these cases. METHODS: This was a retrospective study of TOR1A mutation positive dystonia patients, conducted at a university hospital from 2006 to 2018. Burke-Fahn-Marsden Dystonia Rating Scale (BFM-DRS) was used to evaluate dystonia severity before and after surgery. Emergence of postsurgical parkinsonian symptoms was evaluated using the Unified Parkinson Disease Rating Scale (UPDRS) part III. Montreal Cognitive Assessment (MOCA) was applied to assess cognitive dysfunction. SPSS version 18 was used for data analysis. RESULTS: Eleven patients entered for analysis with an average age of 22.36 (±3.35) years (range: 18-28). Seven patients (63.6 %) were female. Mean follow-up period was 8.72 (±0.87). Difference between baseline and most recent BFM scores was significant (disability: 10.5 ±4.52 versus 2.09 (±3.20), P: 0.001; severity: 48.45 (±17.88) versus 9.36 (±10.47), P<0.001). The mean MOCA and UPDRS III scores after 7-9 years of DBS were 27.18 (±2.99), and 6.09 (±4.15), respectively. CONCLUSION: Our experience confirms that GPi-DBS in pediatric patients with DYT1 dystonia is overall successful, with significant and long-lasting positive effects on motor and cognitive functions. There was no prominent side effect in long-term follow up.

Impact of anticholinergic drugs withdrawal on motor function in patients with Parkinson's disease.

OBJECTIVES: Physicians have prescribed anticholinergic agents as monotherapy or adjuvant therapy in patients with Parkinson's disease for decades. However, these medications can cause many adverse effects including gait freezing and falling. Herein we assessed the effects of anticholinergic medications on motor function, freezing of gait and falling in a group of patients with PD. PATIENTS AND METHODS: This prospective study evaluated the effect of gradual discontinuation of anticholinergics on motor function in 131 outpatients with Parkinson's disease. We assessed patients' motor function at baseline six and twelve months later using the UPDRS-III. We also evaluated freezing of gait and falling in patients using UPDRS-II part 14 and 13 respectively. The anticholinergics were tapered and gradually discontinued and additional levodopa doses were added as patients needed. RESULTS: 131patients successfully discontinued their anticholinergic medications. Stopping anticholinergics significantly improved the motor symptoms in PD patients as reflected in the change between the mean (±SD) UPDRS-III score of 36.85(±11.5) at the baseline to 32.51(±11.4) and 31.43 (±11.3) after six and twelve months (P < 0.001). The mean (±SD) scores of freezing of gait (FOG)significantly changed from 1.34(±1) to 1.17(±1) and 0.6(±0.7) and for falling down from 0.62(±0.8) to 0.5 (±0.8) and 0.29(±0.5) respectively (p-value of <0.001). CONCLUSION: Our finding demonstrated an improvement in motor function and FOG and falling incidences in PD patients, after discontinuation of anticholinergic drugs. As motor complications adversely affect the quality of life in PD patients, clinicians must be careful with the unnecessary use of anticholinergic drugs in their treatment strategies.

Tongue Protrusion Dystonia in Pantothenate Kinase-Associated Neurodegeneration.

BACKGROUND: Tongue protrusion dystonia is an uncommon focal dystonia involving the lingual muscles. Causes of tongue protrusion dystonia include tardive dystonia, posthypoxic dystonia, neuroacanthocytosis, pantothenate kinase-associated neurodegeneration, and Lesch-Nyhan syndrome. METHOD: We summarize three children with pantothenate kinase-associated neurodegeneration and tongue protrusion dystonia. All three patients underwent careful neurological examination, brain magnetic resonance imaging, and genetic testing. RESULTS: Tongue protrusion dystonia was a prominent and disabling symptom in all three patients. Brain magnetic resonance imaging revealed a typical eye of the tiger sign in all patients. Two patients had the same genetic mutation (c.1168 A>T mutation, p.I390F). CONCLUSIONS: Tongue protrusion dystonia may be a clue to the underlying etiology of dystonia, including hereditary forms of dystonia. Among them, pantothenate kinase-associated neurodegeneration is an important cause, especially in children.

Parkinsonism management issues in a patient with exhausted subthalamic deep brain stimulation battery, stricken by severe acute respiratory syndrome coronavirus 2.

Background: Nowadays, many neurological conditions, including Parkinson's disease (PD), are treated with deep brain stimulation (DBS). Life-threatening consequences can occur from DBS hardware failure or sudden implantable pulse generator (IPG) battery depletion. This issue may potentially worsen in concomitance with medical or infectious conditions, requiring stronger emergency management. Methods: We present here a 58 year-old PD patient with DBS, whose IPG replacement surgery was complicated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and we report management of this patient along with recommendations for patients with similar situation. Results: As the newly-emerged coronavirus disease 2019 (COVID-19) is now announced to be pandemic, new protocols and specific measures for each individual group of patients with chronic diseases seem obligatory. Regarding our recent experience with a patient suffering from PD, on DBS treatment, who needed hospitalization, we felt useful to share our experience as a recommended protocol for similar patients in the time of current pandemic. Conclusion: Close monitoring of laboratory and clinical signs should be warranted in patients with PD awaiting IPG replacement in order to be prepared in these novel conditions that may precipitate an akinetic crisis/dystonic storm and to prevent life-threatening complications during the current pandemic.

A Classification System for Assessment and Home Monitoring of Tremor in Patients with Parkinson's Disease.

BACKGROUND: Tremor is one of the most common symptoms of Parkinson's disease (PD), which is widely being used in the diagnosis procedure. Accurate estimation of PD tremor based on Unified PD Rating Scale (UPDRS) provides aid for physicians in prescription and home monitoring. This article presents a robust design of a classification system to estimate PD patient's hand tremors and the results of the proposed system as compared to the UPDRS. METHODS: A smartphone accelerometer sensor is used for accurate and noninvasive data acquisition. We applied short-time Fourier transform to time series data of 52 PD patients. Features were extracted based on the severity of PD patients' hand tremor. The wrapper method was employed to determine the most discriminative subset of the extracted features. Four different classifiers were implemented for achieving best possible accuracy in the estimation of PD hand tremor based on UPDRS. Of the four tested classifiers, the Naive Bayesian approach proved to be the most accurate one. RESULTS: The classification result for the assessment of PD tremor achieved close to 100% accuracy by selecting an optimum combination of extracted features of the acceleration signal acquired. For home health-care monitoring, the proposed algorithm was also implemented on a cost-effective embedded system equipped with a microcontroller, and the implemented classification algorithm achieved 93.8% average accuracy. CONCLUSIONS: The accuracy result of both implemented systems on MATLAB and microcontroller is acceptable in comparison with the previous works.

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

The association between fear of falling and quality of life for balance impairments based on hip and ankle strategies in the drug On- and Off-phase of patients with idiopathic Parkinson' disease.

Background: Despite the negative effect of fear of falling during functioning and social participation of patients with Parkinson' disease, so far, only few studies have investigated its effect on the quality of life in these patients. We aimed to investigate the association between fear of falling and quality of life controlling for balance impairments based on hip and ankle strategy in drug On- and Off-phase of patients with idiopathic Parkinson' disease. Methods: In this non-experimental cross-sectional study, 139 patients with idiopathic Parkinson' disease (100 male, 39 female) by mean± SD age of 60.2±12.27 years, mean±SD time since diagnosis of 6.7±5.53 years and mean±SD Hoehn and Yahr stage of 2.8±1.49 were selected by a simple non-probability method. Balance function was measured by a functional reach test with hip and ankle strategy. The Persian version of the selfcompleted Fall Efficacy Scale-International and Parkinson's disease quality of life questionnaire was used to evaluate fear of falling and quality of life, respectively. Results: The results showed that the score of all dimensions of quality of life (i.e., mobility, activities of daily living, emotional wellbeing, stigma, social support, cognition, communication and bodily discomfort) were significantly affected by the intensity of fear of falling. Multiple regression analysis indicated a significant association between fear of falling and quality of life in a way that fear of falling explained 11% to 47% and 12% to 43% of variance in drug On-phase, as well as 8% to 45% and 9% to 48% of variance in the drug Off-phase in dimensions of quality of life after controlling for balance function based on hip and ankle strategy, respectively. In the drug On-phase, the strongest association (R=0.85, p<0.001) was found between fear of falling and mobility dimension of quality of life. In the drug Off-phase, the strongest relation was observed between fear of falling and mobility (R=0.82, p<0.001) as well as activities of daily living (R=0.78-0.79, p<0.001) dimensions. Conclusion: This study found that fear of falling affects the quality of life of patients with Parkinson' disease beyond its relationship with balance impairments based on the hip and ankle strategy in both drug On- and Off-phase.