A Comparative Study of Early and Late Onset Freezing of Gait in Parkinson's Disease.

BACKGROUND: Freezing of gait (FOG) is a common and debilitating symptom in Parkinson's disease (PD); the pathogenesis and natural course of which has not been fully understood. OBJECTIVES: This study was performed to evaluate patients with FOG in PD and ascertain factors contributing to an early onset of FOG in patients with PD. METHODOLOGY: A chart review of 100 patients with PD (FOG [+] 50, FOG [-]: 50) was performed. FOG (+) patients were subdivided by a median split of time from motor onset to development of FOG (median: 6 years) into early onset FOG (EOFOG [n = 24]) and late onset FOG (n = 26). RESULTS: The FOG (+) group had a significantly longer duration of motor symptoms, a higher Hoehn and Yahr stage, and greater severity of disease. Festination, falls, and wearing off were more prevalent in the FOG (+) group. Several nonmotor symptoms (NMS) such as constipation, psychosis, fatigue, weight loss, drooling, excessive sweating, depression, and postural giddiness were significantly higher in the FOG (+) group. The EOFOG group had a later age at onset of motor symptoms. There were no significant differences observed in the NMS, with the exception of fatigue in EOFOG. CONCLUSIONS: FOG is associated with longer disease duration and higher severity of disease. FOG (+) patients have distinct NMS which are contributory to disease morbidity. EOFOG might be associated with an accelerated disease progression and is linked with older patients and shorter disease duration.

Genetic analysis of the glucocerebrosidase gene in South Indian patients with Parkinson's disease.

BACKGROUND: Mutations in the glucocerebrosidase (GBA) gene have been associated with Parkinson's disease (PD). Several variants in the gene have been identified as risk factors for the development of PD, but there is difference in the prevalence of this mutation in various ethnic groups and countries. There is no published study related to this field on the Indian population. AIMS AND OBJECTIVES: The aim of the study was to investigate the frequency of mutations in the GBA gene in Indian patients with PD. MATERIALS AND METHODS: To perform the mutation analysis of the GBA gene, we amplified its entire coding region, spanning 11 exons and intron/exon junctions in three fragments, with a set of three primer pairs using the long polymerase chain reaction enzyme mix from Fermentas, Canada. RESULTS: We screened a total of 100 PD patients for mutations in the GBA gene. The sequence analysis identified the following five variants in this gene: IVS1 + 191G > C, IVS4 + 47G > A (rs. 2075569), IVS6 - 86A > G (rs. 114099990), IVS9 + 141A > G (rs. 28373017), and IVS10 + 3G > A. Of these, two variants IVS1 + 191G > C and IVS10 + 3G > A are novel, and the remaining three are known variants reported in the Single Nucleotide Polymorphism database (dbSNP). All the known variants were detected in homozygous as well as in heterozygous states. Both novel variants were identified in only one patient in a heterozygous state. CONCLUSION: GBA mutation may not be so common in Indian patients with PD as compared to the other ethnic populations. These findings need to be confirmed in larger studies.

Clinical utility of visualisation of nigrosome-1 in patients with Parkinson's disease.

OBJECTIVE: To determine the diagnostic characteristics of poor visualisation of nigrosome-1 as a neuroimaging biomarker in Parkinson's disease (PD) and to explore the relationship of poor visualisation of nigrosome-1 and clinical asymmetry. METHODS: High-resolution gradient-echo sequences of 67 patients with PD and 63 healthy controls were reviewed by two radiologists blinded to the clinical details. A three-tier classification system was used to categorise the scans based on the visualisation of nigrosome-1, and inter-rater reliability was calculated at each level of classification. Other diagnostic properties such as sensitivity, specificity and predictive values were calculated. The relationship between poor visualisation of nigrosome-1 and clinical asymmetry was also assessed. RESULTS: Poor visualisation of nigrosome-1 had high sensitivity (98.5%), specificity (93.6%), positive-predictive value (94.3%), negative-predictive value (98.3%), accuracy (96%) and inter-rater reliability (k = 0.75-0.92). Poorly visualised nigrosome-1 was significantly associated with higher motor asymmetry in the contralateral side in 64.8% of subjects (p = 0.004). CONCLUSIONS: Poor visualisation of nigrosome-1 in PD had good diagnostic properties as a neuroimaging biomarker in PD. There was also a significant agreement on clinical asymmetry and poor visualisation of nigrosome-1. KEY POINTS: • Nigrosome-1 represents the largest collection of dopaminergic neurons in dorso-lateral substantia nigra. • Loss of nigrosome-1 is being studied as a biomarker in Parkinson's disease. • Visualisation of nigrosome-1 had good diagnostic properties as a biomarker. • There was a contralateral relationship between nigrosome-1 lateralisation and clinical asymmetry. • We also highlight the potential limitations of nigrosome-1 visualisation as a biomarker.

Association of freezing of gait with nigral iron accumulation in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: The objective of this work was to investigate whether patients with and without freezing of gait (FOG) in Parkinson's disease (PD) have differences in iron accumulation in substantia nigra using R2* relaxometry. MATERIALS AND METHODS: This study included seventeen PD patients with FOG [FOG (+)], equal number of age and gender matched patients without FOG [FOG (-)] and 34 healthy controls (HC). T2* images were obtained from a 3-Tesla MRI system using multi-echo sequence. R2* values were extracted from Substantia Nigra (SN) and red nucleus and were compared among the three groups and correlated with clinical findings. RESULTS: R2* values were increased in PD group as a whole compared to HC in rostral and caudal segments of Substantia Nigra pars compacta (SNc) and in Substantia Nigra pars reticulata (SNr) but not in red nucleus. Within PD subgroups, FOG (+) group had increased iron accumulation in SNc compared to FOG (-) and HC. FOG score positively correlated with R2* values in the caudal region of SNc in FOG (+) group. CONCLUSIONS: Our study reveals higher nigral iron content in FOG (+) compared to FOG (-) and HCs. In addition, we observed positive correlation of FOG score with iron accumulation in SNc. Results of this study emphasize possible role of higher nigral iron content in the pathogenesis of FOG in PD.

Altered Brain Wiring in Parkinson's Disease: A Structural Connectome-Based Analysis.

Parkinson's disease (PD) is a neurodegenerative disorder that predominantly affects the motor system. Diffusion magnetic resonance imaging (MRI) has demonstrated deficits in anisotropy as well as increased diffusivity in the sub-cortical structures, primarily in the substantia nigra in PD. However, the clinical spectrum of PD is not limited to motor symptoms; rather, it encompasses several nonmotor symptoms such as depression, psychosis, olfactory dysfunction, and cognitive impairment. These nonmotor symptoms underscore PD as a complex neurological disorder arising from dysfunction of several network components. Therefore, to decipher the underlying neuropathology, it is crucial to employ novel network-based methods that can elucidate associations between specific network changes. This study aimed at assessing the large-scale structural network changes in PD. Structural connectomes were computed by using probabilistic fiber tracking on diffusion MRI between 86 regions of interest. Graph theoretic analysis on the connectome was carried out at several levels of granularity: global, local (nodal), lobar, and edge wise. Our findings demonstrate lower network clustering capability, overall lower neural connectivity, and significantly reduced nodal influence of the hippocampus in PD. In addition, extensive patterns of reduced connectivity were observed within and between the temporal, parietal, and occipital areas. In summary, our findings corroborate widespread structural disconnectivity that can be potentially linked to the nonmotor symptoms in PD.

Imaging biomarker correlates with oxidative stress in Parkinson's disease.

BACKGROUND: While oxidative stress (OS) may be one of the crucial factors determining the initiation and progression of Parkinson's disease (PD), its correlation with gray matter (GM) atrophy is not known. AIMS: To determine the GM volume (GMV) changes using voxel-based morphometry (VBM) and correlation with OS marker serum malondialdehyde (MDA) in PD. MATERIALS AND METHODS: Seventy-two patients with PD were clinically evaluated and underwent magnetic resonance imaging (MRI) on a 3T MRI scanner using a 32-channel head coil. Lipid peroxidation product MDA levels were measured by spectrophotometry. MDA levels and regional GM differences using VBM were compared with 72 healthy controls. RESULTS: The mean age of the patients was 51.3 ± 10.6 years and that of controls was 50.8 ± 10.4 years. The mean age of onset of symptoms in PD was 45.2 ± 11.3 years. In PD, serum MDA level was significantly higher than that in controls (0.592 ± 0.89 µmol/l vs. 0.427 ± 0.055 µmol/l; P < 0.0001). Compared to controls, patients had greater regional GM atrophy in all the brain lobes (P < 0.001, uncorrected). A significant positive correlation was found between GMV and MDA in the caudate nucleus (CN) and posterior cingulate gyrus (PC) in the patient group (P < 0.001, uncorrected). CONCLUSIONS: We observed GM atrophy in all major brain lobes of patients when compared to controls. Only in the patient group, a significant positive correlation was observed in CN and PC with MDA. These findings suggest that, even though the whole brain is affected in PD, some of the non-substantia nigra regions of the brain, such as CN, may have some differential compensatory mechanism, which are preserved from oxidative damage.

Role of altered cerebello-thalamo-cortical network in the neurobiology of essential tremor.

INTRODUCTION: Essential tremor (ET) is the most common movement disorder among adults. Although ET has been recognized as a mono-symptomatic benign illness, reports of non-motor symptoms and non-tremor motor symptoms have increased its clinical heterogeneity. The neural correlates of ET are not clearly understood. The aim of this study was to understand the neurobiology of ET using resting state fMRI. METHODS: Resting state functional MR images of 30 patients with ET and 30 age- and gender-matched healthy controls were obtained. The functional connectivity of the two groups was compared using whole-brain seed-to-voxel-based analysis. RESULTS: The ET group had decreased connectivity of several cortical regions especially of the primary motor cortex and the primary somatosensory cortex with several right cerebellar lobules compared to the controls. The thalamus on both hemispheres had increased connectivity with multiple posterior cerebellar lobules and vermis. Connectivity of several right cerebellar seeds with the cortical and thalamic seeds had significant correlation with an overall score of Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) as well as the subscores for head tremor and limb tremor. CONCLUSION: Seed-to-voxel resting state connectivity analysis revealed significant alterations in the cerebello-thalamo-cortical network in patients with ET. These alterations correlated with the overall FTM scores as well as the subscores for limb tremor and head tremor in patients with ET. These results further support the previous evidence of cerebellar pathology in ET.

Role of Corpus Callosum Volumetry in Differentiating the Subtypes of Progressive Supranuclear Palsy and Early Parkinson's Disease.

BACKGROUND AND OBJECTIVE: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder. Classic PSP or Richardson-Steele phenotype (PSP-RS) and parkinsonian phenotype (PSP-P) are the common subtypes of PSP. At the early stage, differentiating the subtypes of PSP as well as differentiating PSP from other parkinsonian disorders, especially Parkinson's disease (PD) is challenging. Microstructural abnormalities of corpus callosum (CC) have been reported both in PSP and PD. The objective of this study was to compare the volumes of various segments of CC between patients with PSP-P, PSP-RS, and early PD. METHODOLOGY: This study included 32 patients with PSP (RS: 18, P: 14), 20 patients with early PD, and 25 controls. All subjects underwent 3-Tesla MRI. An automated surface-based analysis package (FreeSurfer) was used to divide CC into five segments: anterior (CC1), midanterior (CC2), central (CC3), midposterior (CC4), and posterior (CC5). Volumes of these segments were compared among the four groups. RESULTS: The PSP-RS group had significantly lower CC volume in all segments except in CC1 and CC5, whereas the volumes of the five segments of CC were comparable among PSP-P, PD and controls. The PSP-RS group had lower CC3 volume compared to the PSP-P group, and the PSP-RS group had lower volume of both CC2 and CC3 compared to the PD group. CONCLUSIONS: The lower volume of the central segment of CC (CC3) might help in differentiating PSP-RS from PSP-P. There is no significant difference in the pattern of CC atrophy in PSP-P and early PD. Studies with higher sample sizes are warranted to confirm the results of our study.

A preliminary study of the neuroanatomical correlates of primary writing tremor: role of cerebellum.

INTRODUCTION: To explore the neuroanatomical correlates of primary writing tremor (PWT) and the role of cerebellum, using advanced structural neuroimaging. Till date, there are no studies exploring the gray and white matter changes using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) in PWT. METHODS: Ten male patients with PWT were evaluated clinically and with magnetic resonance imaging. VBM and DTI images of patients were compared with that of 10 healthy male subjects. Spatially unbiased infra-tentorial template (SUIT) analysis was done to investigate the alterations of cerebellar gray matter. Region-of-interest analysis was performed on regions observed to be significantly different on DTI analysis. RESULTS: The mean duration of illness and mean age of the patients were 3.5 ± 1.9 and 51.7 ± 8.6 years, respectively. On VBM analysis, the cluster of gray matter atrophy was found in bilateral cerebellar areas of culmen and left declive, right superior and medial frontal gyrus, bilateral middle frontal gyrus, bilateral anterior cingulate gyrus, and bilateral parahippocampal gyrus. DTI showed significantly reduced fractional anisotrophy of the anterior thalamic radiation, cingulum, and inferior fronto-occipital fasciculus in PWT patients compared to controls. The axial diffusivity, mean diffusivity, and radial diffusivity maps did not reveal any significant differences. On SUIT analysis, significant atrophy was found in right uvula and semilunar lobule in patients with PWT compared to controls. CONCLUSIONS: Our study found that patients with PWT had predominant gray matter atrophy in parts of cerebellum and frontal lobe along with white matter changes of the cingulum and frontal lobe connections.

Freezing of gait in Parkinson's disease is associated with altered functional brain connectivity.

BACKGROUND: Patients with Parkinson's disease (PD) may develop several gait disturbances during the course of illness and Freezing of gait (FOG) is one of them. Several neuroimaging studies have been conducted to identify the neural correlates of FOG but results have not been uniform. Resting state functional MRI (rs-fMRI) is relatively less explored in PD patients with FOG. This study aims to compare the whole brain resting state connectivity of PD patients with and without FOG using rs-fMRI. METHODS: rs-fMRI was obtained for 28 PD patients (15 with and 13 patients without FOG) who were matched for various demographic and clinical characteristics. Seed to voxel analysis was performed at whole brain level and compared between the two groups. RESULTS: When compared to patients without FOG, the patients with FOG had reduced functional connectivity across multiple seeds. Major finding was reduced inter-hemispheric connectivity of left parietal opercular cortex with multiple regions of the brain primarily involving the primary somatosensory and auditory areas, which also negatively correlated with the FOGQ scores. CONCLUSION: Our findings suggest that alterations in the resting state functional connectivity of the opercular parietal cortex may be one of the substrates of FOG. Reduced interhemispheric connectivity probably is the reason for impairment of control and coordination in bilateral leg movements while walking.