Shweta Prasad

Three‐dimensional neuromelanin‐sensitive magnetic resonance imaging of the substantia nigra in Parkinson's disease

The aim was to investigate the diagnostic utility of signal intensity measurement of the substantia nigra pars compacta (SNc) using three‐dimensional (3D) neuromelanin‐sensitive magnetic resonance imaging (MRI), for discrimination of patients with Parkinsons disease (PD) from healthy controls.

Motor asymmetry and neuromelanin imaging: Concordance in Parkinson's disease

BACKGROUNDnThe onset of motor symptoms in Parkinsons disease (PD) is characteristically asymmetric and correlates with dopaminergic deficit of contralateral basal ganglia. This study explored the concordance between motor asymmetry and changes of substantia nigra pars compacta (SNc) using neuromelanin-sensitive imaging.nnnMETHODSnForty-four subjects with PD and fifteen healthy controls were included in this study. Clinical laterality (CL) was based on the motor sub scores of the Unified Parkinsons Disease Rating Scale-Part III. All subjects underwent neuromelanin-sensitive imaging and imaging laterality (IL) was based on the differences between contrast ratios of the right and left lateral SNc. Concordance was evaluated by correlating CL and IL.nnnRESULTSnMotor asymmetry at disease onset was reported in 97.72% of subjects with PD, of which 65.90% reported right-sided onset. Forty-three subjects were right-handed and 68.18% reported onset of symptoms on dominant side. Right CL was observed in 59.09%, left CL in 40.90%, right IL in 11.36% and left IL in 88.63%. Concordance was established in 61.36%, majority of whom had a combination of right CL and left IL. In healthy controls, a significantly lower contrast ratio of the left lateral SNc was also noted.nnnCONCLUSIONSnHandedness may correlate with motor asymmetry and left hemisphere may have a predilection for neurodegeneration. The finding of significant neuronal loss of left SNc in controls warrants further evaluation for better understanding of motor asymmetry in PD. Neuromelanin sensitive imaging can be a useful tool to study the relationship between motor asymmetry and nigrostriatal dysfunction.

When time is of the essence: Managing care in emergency situations in Parkinson's disease

A movement disorder emergency is an acute or sub-acutely evolving neurological illness predominated by a primary movement disorder. Although Parkinsons disease (PD) is a chronic, progressive disorder, patients may present with a variety of acute symptoms. Timely diagnosis and management is crucial to reduce mortality and morbidity. The underlying causes of an emergency in PD may be attributable to either disease related emergencies which occur as a direct consequence of the disease pathophysiology or secondary to anti-parkinsonian medications, such as Parkinsonism-hyperpyrexia syndrome, acute psychosis, etc. Indirect disease related emergencies, are those which not directly associated with the disease but occur secondary to deficits produced by the disease, e.g. falls and pneumonia. Emergencies in patients with PD may also be related to deep brain stimulation or systemic illnesses which are unrelated to PD. Complications may also occur during the surgical management of patients with PD owing to the effects of the disease on cardiovascular and respiratory functions or interactions of PD medication with anesthetic agents. Additionally, although motor complications are expected to form a majority of ER admissions in PD, several studies have reported indirect or non-PD related complications as the predominant primary reason for emergency admissions. The present article aims to review emergencies encountered in patients with PD with focus on the identification and management of these emergencies.

Letter Specific Dysgraphia: A Silent Stutter: Letter Specific Dysgraphia

Dysgraphia refers to impaired handwriting due to abnormal orthographic coding or finger sequencing and can be broadly categorized into central and peripheral dysgraphia. The former involves spelling retrieval, assembly, and the generation of an abstract graphemic representation. The latter involves the process of externalizing a graphemic representation (i.e., handwriting, oral spelling, typing, or letter arranging). The processes involved in the production of handwriting are complex. First, graphemes (i.e., letters or letter groups) are set up via the lexical look-up or phoneme-to-grapheme correspondence rules. Second, features such as letter shape, case, and stroke sequence are specified by effector-independent allographs. Last, the written trace is generated by the activation of effectorspecific motor programs, which indicate muscle activation patterns for the graphemes. Impairment at any stage in this process will lead to dysgraphia. This report describes an unusual case of dysgraphia, wherein the patient had difficulty writing a specific letter. Although the concept of dysgraphia has been commonly described, the involvement of a single letter has not been previously reported. A 40-year-old man presented at our movement disorders clinic with a 12-year history of difficulty writing. The symptom was insidious in onset and restricted to writing the letter “t” in Bengali ( ). The patient described the difficulty as a momentary hesitation associated with tremulousness of hand while attempting to write the initial segment of the letter, after which he was able to write fluently. This problem persisted irrespective of the position of the letter in a word. He denied the presence of a similar difficulty with other letters in Bengali or while writing in English. The patient had no other complaints and had an unremarkable medical and family history. On examination, the patient was able to write the English alphabet in upper and lower case and numbers fluently with no evidence of hesitancy or tremulousness (Video 1, Segment 1). Upon writing the Bengali alphabet, an abnormality was observed while the patient wrote the letter (Video 1, Segment 1). There was no abnormality observed while writing the other letters. The abnormality was restricted to the initial segment of the letter when a rapid, jerky movement of the hand with increased activity of the wrist extensors and flexors was observed, after which the rest of the letter was executed flawlessly (Video 1, Segment 2). A similar abnormality was also observed with the number “ ” (i.e., the number 3, which is structurally similar to the letter ). The patient was also made to write the word “tota” in Bengali and the hesitancy with writing the letter was once again observed (Video 1, Segment 2). Dysgraphia was also observed for the letter when a random string of letters and numbers were dictated to the patient. The patient was able to copy the letter and verbalize the letter normally. No dystonic posturing of either hand was observed, and the rest of his neurological examination was unremarkable. A computed tomography scan of the brain was normal. The video of the patient was taken after obtaining written informed consent. We evaluated the kinematics of this dysgraphia and hesitancy by utilizing a digitizing tablet (Wacom Intuos PTH-860) with a non-inking stylus. Data were collected and analyzed using NeuroScript’s MovAlyzeR (v.6.1.0.0). We used a healthy, age and education-matched control to confirm the presence of abnormal kinematics. A real-time recording of the patient writing the letter (Video 1, Segment 3) clearly demonstrates the presence of an initial hesitancy while executing the letter. Comparison of the kinematic properties of the letter , between the patient and control, revealed a significantly lower absolute velocity in the patient (0.97 ± 0.31 cm/s vs. 4.44 ± 1.59 cm/s, p < 0.01; Fig. 1). There was no significant difference in the axial pressure (556.73 ± 91.07 z-unit vs. 472.63 ± 94.72 z-unit, p > 0.05). The act of writing has been functionally and anatomically localized to the parietal cortex, in particular, the posterior parietal cortex and occipitotemporal junction and to a region of the middle temporal gyrus termed the Exner’s area or the graphemic/ motor frontal area. Depending on the site involved and the step of handwriting production affected, focal brain damage can affect handwriting in different ways, with symptoms ranging from dysgraphia to agraphia. For instance, Kapur et al. had reported a case with a left occipital space occupying lesion, who had dysgraphia for the letters H and B. In the current patient, the neurological examination was unremarkable except for the dysgraphia. Hence, the dysgraphia observed in this patient is unlikely to be

SUMOylation: One small modification for proteins, multiple giant problems for mankind: SUMOylation of α-Synuclein In PD

SUMOylation and ubiquitination are important post-translational modifications that play pivotal roles in several crucial biological processes. Ubiquitination is critical in mediating proteasomedependent degradation of proteins by the binding of ubiquitin protein via ligases. SUMOylation involves covalent attachment of a small ubiquitin-like modifier (SUMO) protein to a lysine residue. In contrast to ubiquitination, SUMOylation enhances the stability of proteins. a-Synuclein is the main protein constituent of Lewy bodies, the pathological hallmarks of Parkinson’s disease (PD). The accumulation and aggregation of a-synuclein is attributed to aberrations in degradation mechanisms — proteasomal, lysosomal, or autophagic pathways. The E3 ubiquitinligase seven in absentia homolog (SIAH) and the Nedd4 ubiquitin ligase have been reported to be vital in the degradation of a-synuclein. Studies have demonstrated the presence of a-synuclein bound to SUMO at lysines and increased a-synuclein aggregation by SUMOylation on proteasomal inhibition. However, further progress in understanding the implications of a-synuclein SUMOylation was restricted as the endogenous a-synuclein SUMO ligase was unknown. Although SUMOylation had been implicated in the pathogenesis of PD, Alzheimer’s disease, and amyotrophic lateral sclerosis, the evidence was lacking. Rott et al filled this gaping knowledge gap by identifying SUMOylation as a major regulator of a-synuclein degradation and pathological accumulation. They demonstrated that SUMOylation increases a-synuclein by 2 mechanisms: (1) a-synuclein is SUMOylated by PIAS2, which leads to a-synuclein accumulation, aggregation, and increased levels; and (2) a-synuclein ubiquitination via SIAH and Nedd4 is blocked, leading to further aggregation. Furthermore, to explore the relevance of a-synuclein SUMOylation, Rott et al used ginkgolic acid, an E1 SUMO inhibitor and demonstrated a reduction in a-synuclein levels. SUMOylation of the a-synuclein disease mutants A30P, A53T, and E46K was also reported to be significantly higher than the wild-type a-synuclein. Levels of PIAS2 were 3-fold higher in the substantia nigra (SN) of patients with PD. Finally, the total levels of SUMOylated proteins were found to be 2-fold higher in the SN of patients with PD compared with controls, which demonstrated a causal relationship underlying upregulation of a-synuclein SUMOylation in PD. This study unequivocally demonstrates the role of SUMOylation in the pathological aggregation of a-synuclein in PD. The suggestion of SUMOylation blockers as a strategy to prevent intracellular a-synuclein accumulation, aggregation, and spread throws open a new playing field in the domain of preventive strategies in PD.

Levodopa-Induced Dyskinesia: “TRAP”ping the Culprit

Levodopa-induced dyskinesia (LID) is a commonly observed complication of pharmacotherapy in Parkinson’s disease (PD). The most favored hypothesis for LID implicates a crucial role of striatal neurons, and several compelling studies support this hypothesis. Alcacer and colleagues performed direct pathway stimulation with Gs-coupled Designer Receptors Exclusively Activated by Designer Drugs in order to mimic the signaling events recruited by L-dopa in these neurons and induced an appreciable dyskinesia in 6-OHDA-lesioned mice. Immediateearly genes, such as c-Fos and FosB, have also been reported to be upregulated in the striatum of animals with LID. However, the primary motor cortex (M1) and primary somatosensory cortex (S1) have also been implicated in LID, and the presence of interconnections between these regions confounds the origins of this aberrant activity. The recent study by Girasole and colleagues has demonstrated the role of a distinct subset of striatal direct pathway neurons in the production of LID and demonstrated a reduction of LID by inhibiting this subset of neurons. To investigate which regions and cell types produced the LID, they used a transgenic mouse tool known as targeted recombination in active populations (TRAP), in combination with an established mouse model of LID. TRAP is a technique that aids in obtaining genetic access to neurons activated by defined stimuli. Using Fos-driven CreER, TRAP permits identification and subsequent manipulation of activated neurons, which are captured during a time window defined by tamoxifen administration. They demonstrated the presence of LID-associated neurons in several brain regions, including M1, S1, and striatum. Furthermore, confocal imaging revealed direct pathway medium spiny neurons (dMSNs) to be primarily involved in LID. Although at a lower severity when compared to L-dopa, optogenetic reactivation in the absence of L-dopa produced dyskinesia only when the striatal dMSNs were activated. No dyskinesia was observed when cells of the M1 and S1 were optogenetically activated. Finally, optogenetic inhibition of the striatal neurons was also found to ameliorate LID. This study utilizes TRAP and optogenetics to demonstrate a significant causal relationship between LID and a distinct subgroup of striatal direct pathway neurons. Further studies based on this observation may help in the identification of new pharmacological targets for the prevention and management of LIDs.

DTI in essential tremor with and without rest tremor: Two sides of the same coin?: DTI in ET with and Without Rest Tremor

Essential tremor (ET) is a movement disorder characterized by an action tremor of the bilateral upper limbs, and a rest tremor (RT) is reported in 2% to 46% of cases. The phenotype of ET with rest tremor (ETR) produces a diagnostic dilemma because it resembles tremor-dominant Parkinson’s disease (TDPD). Despite the importance of this conundrum, there are surprisingly few studies comparing ETR and ET without a rest tremor (ETWR). 3 In most studies exploring ET, ETWR and ETR have been evaluated as a single group, because of which the pathophysiology and neuroimaging correlates of RT in ET remain uncertain. Connectivity-based neuroimaging studies have reported common alterations of the cerebello-thalamo-cortical network in ETWR and ETR, with additional damage to the motor network in ETR. No differences were observed in cerebellar diffusion tensor imaging (DTI) metrics of ETWR and ETR, suggesting the possible role of other structures in ETR. 6 We used whole-brain tract-based spatial statistics (TBSS) analysis and cerebellar gray matter (GM) and white matter (WM) analysis to investigate microstructural changes between ETWR and ETR (see supplementary material for detailed methodology and results). Except for a lower Mini Mental Status Examination score in ET, no demographic differences were observed between subgroups (Table 1). TBSS analysis comparing ET (n = 40) and healthy controls (n = 40) revealed widespread abnormalities, whereas comparison between ETWR (n = 21) and ETR (n = 19) showed no differences (Supplementary Figs. 1 and 2). Lower fractional anisotropy of the corpus callosum and corticospinal tract were observed in ETR compared with healthy controls (Supplementary Fig 3). There were no significant cerebellar GM abnormalities between ET, subgroups, and health controls (Supplementary Table 1). ET and ETR had higher mean diffusivity of total cerebellar, right hemispheric, and left hemispheric WM compared with controls. A consistent pattern suggestive of higher WM microstructural damage was observed in the ETR subgroup (Supplementary Table 2). There were no cerebellar GM orWMdifferences between ETWR and ETR. Few studies have used the whole-brain TBSS approach, and none have compared ETWR and ETR. 7 Our findings concur with voxel-based morphometry and cerebellar TBSS studies, which reported no differences between ETWR and ETR. Contrary to Novellino et al, we found no cerebellar GM abnormalities. However, we observed significant cerebellar WM abnormalities, patterns of which are suggestive that ETR could be a severe variant of ET. Although neuroimaging studies fail to demonstrate differences between ETWR and ETR, significant differences in structural and functional connectivity have been reported.. The involvement of the globus pallidus interna (GPi) in ETR, confounds the pathogenesis of this phenotype. The GPi is

Shaky and unsteady: Dynamic posturography in essential tremor

BACKGROUNDnThe spectrum of symptoms exhibited by patients with essential tremor (ET) extends far beyond the classical tremor. This study aims to explore and establish the presence of subtle balance abnormalities in ET using dynamic posturography (DP).nnnMETHODSnDP was performed on 18 patients with ET and 26 controls. Diagnosis of ET was based on the Consensus Statement of the Movement Disorder Society on Tremor. Dynamic stability which included the overall balance index, anterior-posterior index and mediolateral index, and limits of stability were measured.nnnRESULTSnPatients with ET had significantly impaired balance indices. Impairment of dynamic stability revealed poor static balance control in all directions. Lower limits of stability scores indicated a smaller range of motion prior to which patients have to shift foot balance. No correlations were observed between age at evaluation, age at onset, duration of illness and the balance indices.nnnCONCLUSIONSnDynamic posturography reveals significant balance impairment in patients with ET which is unrelated to the age at onset, age at evaluation or duration of illness. This finding concurs with pre-existing reports and adds to the growing body evidence of cerebellar involvement in ET.

Impaired frontal lobe functions in patients with Parkinson’s disease and psychosis

INTRODUCTIONnPatients with Parkinsons disease (PD) may develop several non-motor symptoms (NMS). Psychosis is one of the debilitating NMS of PD. The neurobiology of psychosis is not fully understood. This study aims to compare the frontal lobe functions of PD patients with and without psychosis using the Frontal Assessment Battery (FAB).nnnMETHODOLOGYnThis study included 69 patients with PD; 34 with psychosis (PD-P) and 35 without psychosis (PD-NP). Mini Mental Status Examination (MMSE) was used to screen for cognitive impairment. Unified Parkinsons disease Rating scale part-III (UPDRS-III) was used to measure the severity and Hoehn and Yahr score (H&Y) was used to measure the stage of PD. Frontal lobe functions were assessed by FAB.nnnRESULTSnThe PD-P and PD-NP groups were comparable for age (58.7±8.4 vs 55.7±8.2, p=0.14), age at onset of symptoms (51.4±8.1 vs 50.0±8.8, p=0.48), gender distribution (men: 88%vs 80%, p=0.51), MMSE (28.2±1.9 vs 28.7±1.2 p=0.12), levodopa equivalent dose/day (736.0±376.3 vs 625.2±332.2, p=0.19), UPDRS-III OFF-score (36.7±8.8 vs 35.4±13.2, p=0.64), UPDRS-III ON-score (13.2±5.4 vs 12.4±6.6, p=0.44) and H&Y stage (2.3±0.3 vs 2.3±0.3, p=0.07). PD-P group had lower total FAB score compared to PD-NP group (13.9±2.2 vs 16.5±1.8, p<0.01). On the FAB, PD-P group had lower scores compared to PD-NP in lexical fluency (FAB-2), programming (FAB-3), sensitivity to interference (FAB-4) and inhibitory control (FAB-5).nnnCONCLUSIONnPatients with PD-P had significant frontal lobe dysfunction compared to PD-NP. FAB may be a simple and useful bedside tool to assess frontal dysfunction in patients with PD in a busy neurological set up.