Association of the Area Deprivation Index With Dementia Basic Workup and Diagnosis in Central and Western Virginia: A Cross-Sectional Study.

Background and Objectives: The Area Deprivation Index (ADI) provides a validated and multidimensional metric of areal disadvantage. Our goals were to determine if the ADI influences the likelihood of receiving workup based on published guidelines and an etiologic diagnosis of dementia in Central and Western Virginia. Methods: We collected deidentified data from the electronic health record of individuals aged 50-105 years diagnosed with dementia at the University of Virginia (UVA) Medical Center (2016-2021) and at Carillion Clinic (2018-2021). Visit-specific ICD-10 codes were used to classify each dementia diagnosis as "disease-specific" (e.g., Alzheimer disease) or "general" (e.g., unspecified dementia). Following the American Academy of Neurology guidelines, we considered the evaluation performed as "adequate" if patients had vitamin B12, thyroid-stimulating hormone, and brain CT or magnetic resonance imaging within 6 months of the initial diagnosis. Census tract ADI was linked to study participants using the unique census tract identifier derived from the participants' home addresses at the time of diagnosis. Statistical modeling occurred under a Bayesian paradigm implemented using a standard code in R. Results: The study included 13,431 individuals diagnosed with dementia at UVA (n = 7,152) and Carillion Clinic (n = 6,279). Of those, 32.5% and 20.4% received "disease-specific" diagnoses at UVA and Carillion Clinic and 8.2% and 20.4% underwent "adequate" workup, respectively. The adjusted relationship between census tract ADI and the likelihood of a disease-specific diagnosis was U-shaped: Residence in moderately disadvantaged areas was associated with the lowest likelihood of disease-specific diagnosis. Discussion: Most patients diagnosed with dementia did not receive an adequate evaluation or an etiologic diagnosis. Those living in locations just above the national median ADI levels had the lowest likelihood of receiving an etiologic diagnosis, lower than those in the least and most deprived areas. Renewed awareness efforts among providers are needed to increase compliance with diagnostic guidelines.

Primary Palliative Care in Huntington's Disease.

Background: Palliative care practices, including communication about patient-centered goals of care and advance care planning (ACP), have the potential to enhance care throughout the course of Huntington's disease (HD) and related disorders. The goal of our project was to develop a pilot program that integrates primary palliative care practices with interdisciplinary care for HD. Objectives: (1) To train HD team members to facilitate goals of care and ACP conversations at all stages of HD; (2) To create materials for care planning in HD focused on patient-centered goals of care and health-related quality of life; and (3) To modify clinic workflow to include goals of care and ACP discussions. Methods: We defined planning domains to expand care planning beyond end-of-life concerns. We created a patient and family guide to advance care planning in HD. We conducted VitalTalk communications training with the HD team. We modified the interdisciplinary clinic workflow to include ACP and developed an EMR template for documentation. Results: After communication training, more team members felt well prepared to discuss serious news (12.5% to 50%) and manage difficult conversations (25% to 62.5%). The proportion of clinic visits including advance care planning discussions increased from 12.5% to 30.6% during the pilot phase. Conclusions: Provision of primary palliative care for HD in an interdisciplinary clinic is feasible. Integration of palliative care practices into HD specialty care requires additional training and modification of clinic operations.

Practical Considerations in the Administration of Aducanumab for the Neurologist.

Aducanumab (Aduhelm), developed by the biotechnology firm Biogen in Cambridge, MA, was approved using the less common accelerated approval pathway by the Federal Drug Administration (FDA) reserved for treatments that fill a significant unmet need.1 Its approval on June 7, 2021, has been met with an outpouring of opinions from prescribers, insurers, advocacy groups, and hospital systems regarding its risk-benefit profile.2-4 Originally approved for all forms of Alzheimer disease (AD), the FDA updated aducanumab's labeling on July 8, 2021, for "treatment in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials."5 With 6 million people nationally in the United States who suffer from AD and an anticipated one-third of those who may now fulfill the criteria under the revised labeling, the implications of aducanumab's approval continue to generate national interest.6.

Paroxysmal Hypothermia With Prominent Parkinsonian Features After Suprachiasmatic Tumor Resection.

Paroxysmal hypothermia (PH) is a rare syndrome of stereotyped episodes of hypothermia, bradycardia, and altered mental status occurring in patients with hypothalamic lesions. Prior cases have mentioned bradykinesia, ataxia, and dysarthria, but parkinsonism has not been described as a specific feature of PH. We report two patients, an adult and a child, who developed PH after suprachiasmatic tumor resection, both with clinical presentations notable for prominent parkinsonian features despite no evidence of parkinsonism during the intervening months and years. We propose a diagnostic algorithm and scoring tool to aid in the clinical diagnosis of PH presenting as parkinsonism.

Multi-Dimensional, Short-Timescale Quantification of Parkinson's Disease and Essential Tremor Motor Dysfunction.

Introduction: Parkinson's disease (PD) is a progressive movement disorder characterized by heterogenous motor dysfunction with fluctuations in severity. Objective, short-timescale characterization of this dysfunction is necessary as therapies become increasingly adaptive. Objectives: This study aims to characterize a novel, naturalistic, and goal-directed tablet-based task and complementary analysis protocol designed to characterize the motor features of PD. Methods: A total of 26 patients with PD and without deep brain stimulation (DBS), 20 control subjects, and eight patients with PD and with DBS completed the task. Eight metrics, each designed to capture an aspect of motor dysfunction in PD, were calculated from 1-second, non-overlapping epochs of the raw positional and pressure data captured during task completion. These metrics were used to generate a classifier using a support vector machine (SVM) model to produce a unifying, scalar "motor error score" (MES). The data generated from these patients with PD were compared to same-day standard clinical assessments. Additionally, these data were compared to analogous data generated from a separate group of 12 patients with essential tremor (ET) to assess the task's specificity for different movement disorders. Finally, an SVM model was generated for each of the eight patients with PD and with DBS to differentiate between their motor dysfunction in the "DBS On" and "DBS Off" stimulation states. Results: The eight metrics calculated from the raw positional and force data captured during task completion were non-redundant. MES generated by the SVM analysis protocol showed a strong correlation with MDS-UPDRS-III scores assigned by movement disorder specialists. Analysis of the relative contributions of each of the eight metrics showed a significant difference between the motor dysfunction of PD and ET. Much of this difference was attributable to the homogenous, tremor-dominant phenotype of ET motor dysfunction. Finally, in individual patients with PD with DBS, task performance and subsequent SVM classification effectively differentiated between the "DBS On" and "DBS Off" stimulation states. Conclusion: This tablet-based task and analysis protocol correlated strongly with expert clinical assessments of PD motor dysfunction. Additionally, the task showed specificity for PD when compared to ET, another common movement disorder. This specificity was driven by the relative heterogeneity of motor dysfunction of PD compared to ET. Finally, the task was able to distinguish between the "DBS On" and "DBS Off" states within single patients with PD. This task provides temporally-precise and specific information about motor dysfunction in at least two movement disorders that could feasibly correlate to neural activity.

Response to Letter to the Editor.

In Response To: Walker RH. Reply to: Tardive dyskinesia-like syndrome due to drugs that do not block dopamine receptors: rare or non-existent: literature review. Tremor Other Hyperkinet Mov. 2019; 9. doi: 10.7916/3rez-p096 Original Article: D'Abreu A, Friedman JH. Tardive dyskinesia-like syndrome due to drugs that do not block dopamine receptors: rare or non-existent: literature review. Tremor Other Hyperkinet Mov. 2018; 8. doi: 10.7916/D8FF58Z9.

Is Diffusion Tensor Imaging a Good Biomarker for Early Parkinson's Disease?

Objectives: To assess white matter abnormalities in Parkinson's disease (PD). Methods: A hundred and thirty-two patients with PD (mean age 60.93 years; average disease duration 7.8 years) and 137 healthy controls (HC; mean age 57.8 years) underwent the same MRI protocol. Patients were assessed by clinical scales and a complete neurological evaluation. We performed a TBSS analysis to compare patients and controls, and we divided patients into early PD, moderate PD, and severe PD and performed an ROI analysis using tractography. Results: With TBSS we found lower FA in patients in corpus callosum, internal and external capsule, corona radiata, thalamic radiation, sagittal stratum, cingulum and superior longitudinal fasciculus. Increased AD was found in the corpus callosum, fornix, corticospinal tract, superior cerebellar peduncle, cerebral peduncle, internal and external capsules, corona radiata, thalamic radiation and sagittal stratum and increased RD were seen in the corpus callosum, internal and external capsules, corona radiata, sagittal stratum, fornix, and cingulum. Regarding the ROIs, a GLM analysis showed abnormalities in all tracts, mainly in the severe group, when compared to HC, mild PD and moderate PD. Conclusions: Since major abnormalities were found in the severe PD group, we believe DTI analysis might not be the best tool to assess early alterations in PD, and probably, functional and other structural analysis might suit this purpose better. However it can be used to differentiate disease stages, and as a surrogate marker to assess disease progression, being an important measure that could be used in clinical trials. HIGHLIGHTS DTI is not the best tool to identify early PDDTI can differentiate disease stagesDTI analysis may be a useful marker for disease progression.

Tardive Dyskinesia-like Syndrome Due to Drugs that do not Block Dopamine Receptors: Rare or Non-existent: Literature Review.

Background: Although tardive dyskinesia (TD) is most commonly defined as a movement disorder caused by chronic exposure to dopamine-receptor-blocking drugs (DRBDs), it has also been thought to result from exposure to some non-DRBDs. Methods: We critiqued many reviews making the association between non-DRBDs and a TD-like syndrome and almost all case reports. We checked whether cases met criteria for the diagnosis of TD-like syndrome and whether DRBDs had been excluded. Results: We found that both tricyclic antidepressants and selective serotonin reuptake inhibitor antidepressants may unmask or exacerbate TD after prior exposure to or with concurrent use of DRBDs. We found support for its existence outside of this context to be extremely weak. Discussion: There is little evidence that drugs other than DRBDs by themselves cause a TD syndrome; most reported cases appear to occur as a result of a "priming" effect induced by a DRBD, which is later unmasked.

Parkinson's disease: A Quick Update.

Parkinson's disease is a neurodegenerative disorder characterized by motor and non-motor symptoms. Although the diagnosis still relies on the presence of motor signs, new diagnostic criteria have been proposed to incorporate recent observations in order to improve accuracy. The cornerstone of therapy remains dopamine replacement with L-Dopa. However, new therapies, with different modes of action, or administration have become available to improve management.

Tardive dyskinesia: Epidemiology.

The term tardive syndrome (TS) encompasses a few different phenomenologic conditions, some of which occur in isolation and others in association with each other. This, along with the unusual confound for a drug side effect, in which increased use of the drug improves the problem, and the need for most patients to continue taking the offending drug, makes understanding the epidemiology difficult and unreliable. While the change from the "first generation" to the "second generation" of antipsychotic drugs is generally believed to have reduced the incidence of TS, prospective research studies have not supported that contention. Published reports have found point prevalences of 13% with second generation antipsychotics and 32% with first, yet others have found no differences. One study found increasing rates of TS with a 68% prevalence by 25 years, while another found a decreased prevalence over time, due presumably to masking effects of the antipsychotic drugs. Regardless of the possible differences, it is clear that TS remains a significant and common problem associated with almost all antipsychotic drugs. There have also been scattered reports of TS caused by drugs not known to inhibit dopamine receptors. These are reviewed and were found to be often of dubious reliability.

Exploratory structural assessment in craniocervical dystonia: Global and differential analyses.

INTRODUCTION: Our goal was to investigate the cortical thickness and subcortical volume in subjects with craniocervical dystonia and its subgroups. METHODS: We studied 49 subjects, 17 with cervical dystonia, 18 with blepharospasm or oromandibular dystonia, and 79 healthy controls. We performed a whole group analysis, followed by a subgroup analysis. We used Freesurfer software to measure cortical thickness, subcortical volume and to perform a primary exploratory analysis in the craniocervical dystonia group, complemented by a region of interest analysis. We also performed a secondary analysis, with data generated from Freesurfer for subgroups, corrected by false discovery rate. We then performed an exploratory generalized linear model with significant areas for the previous steps using clinical features as independent variables. RESULTS: The primary exploratory analysis demonstrated atrophy in visual processing regions in craniocervical dystonia. The secondary analysis demonstrated atrophy in motor, sensory, and visual regions in blepharospasm or oromandibular dystonia, as well as in limbic regions in cervical dystonia. Cervical dystonia patients also had greater cortical thickness than blepharospasm or oromandibular dystonia patients in frontal pole and medial orbitofrontal regions. Finally, we observed an association between precuneus, age of onset of dystonia and age at the MRI exam, in craniocervical dystonia; between motor and limbic regions and age at the exam, clinical score and time on botulinum toxin in cervical dystonia and sensory regions and age of onset and time on botulinum toxin in blepharospasm or oromandibular dystonia. CONCLUSIONS: We detected involvement of visual processing regions in craniocervical dystonia, and a pattern of involvement in cervical dystonia and blepharospasm or oromandibular dystonia, including motor, sensory and limbic areas. We also showed an association of cortical thickness atrophy and younger onset age, older age at the MRI exam, higher clinical score and an uncertain association with longer time on botulinum toxin.

Nonmotor Symptoms in Parkinson's Disease.

Nonmotor symptoms (NMSs) in Parkinson's disease (PD) have become increasingly recognized as major determinants of quality of life across cultures worldwide. Behavioral symptoms include dementia, depression, anxiety, apathy, and fatigue. Somatic symptoms include hypotension, constipation, diaphoresis, and pain. However, somatic symptoms may also be intrinsic, such as dementia, and iatrogenic, such as compulsive disorders. The authors address some of the more common disorders, yet few have been the target of clinical trials.

Cerebellar Gray Matter Alterations in Huntington Disease: A Voxel-Based Morphometry Study.

Neuropathological and neuroimaging studies in Huntington disease (HD) have suggested a role for the cerebellum. Our goal was to perform a detailed evaluation of cerebellar morphology. We performed the Unified HD rating scale (UHDRS) and Montreal cognitive assessment (MOCA) in 26 HD patients and 26 healthy controls. We created a two-sample test to analyze cerebellar gray matter (GM) differences between groups and another to correlate GM alterations with UHDRS and MOCA, corrected for age, expanded cytosine-adenine-guanine repeats, and disease duration using the spatially unbiased atlas template (SUIT)-SPM-toolbox which preserves anatomical detailing. We found increased GM density in the anterior cerebellum compared to controls. Higher GM density in the postero-superior lobe correlated with mood symptoms. Worse motor function and better cognitive function correlated with GM changes in the posterior cerebellum (false discovery rate (FDR) correction p < 0.05 and k > 100 voxels). In this detailed study of the in vivo cerebellar morphology in HD, we observed GM changes in regions involved in sensorimotor integration, motor planning, and emotional processing, supporting cerebellar involvement in the neuropathological process of HD.

Fatigue and Its Associated Factors in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.

Fatigue has been described in several neurodegenerative diseases, reducing quality of life. A systematic evaluation of this clinical feature is lacking in SCA3/MJD. The aim of this study was to evaluate the frequency and the factors associated with fatigue in SCA3/MJD. Patients with SCA3/MJD and matched healthy controls answered the Modified Fatigue Impact Scale (MFIS), Beck Inventory Depression (BDI) and Epworth Sleepiness Scale (ESS). Scale for the assessment and rating of ataxia (SARA) was used to determine ataxia severity. We used Mann-Whitney and Fisher exact tests to compare mean scores and proportions between groups. Linear regression analyses were employed to investigate factors associated with fatigue in SCA3/MJD. Seventy-four patients were included with a mean age and disease duration of 47.2 ± 12.8 and 9.5 ± 6.37 years, respectively. There were 38 men and 36 women. Mean (CAG)n was 72.2 ± 3.8. Mean MFIS score was higher in patients with SCA3/MJD (41.4 ± 16.2 vs 18.4 ± 12.9, p < 0.001). According to BDI scores, relevant depressive symptoms were found in 69.4 % of patients but only in 10.4 % of controls (p < 0.001). The proportion of patients with ESS scores indicating excessive daytime somnolence was also higher than controls (37.5 vs 22.3 %, p = 0.05). In the multiple regression analysis, both BDI and ESS scores were associated with fatigue (r = 0.67, p < 0.001 and p = 0.01). Fatigue is frequent and strongly associated with depression and excessive daytime somnolence in SCA3/MJD.

Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes.

Friedreich's ataxia (FDRA) is the most common inherited ataxia worldwide, caused by homozygous GAA expansions in the FXN gene. Patients usually have early onset ataxia, areflexia, Babinski sign, scoliosis and pes cavus, but at least 25 % of cases have atypical phenotypes. Disease begins after the age of 25 in occasional patients (late-onset Friedreich ataxia (LOFA)). Little is known about the frequency and clinical profile of LOFA patients. One hundred six patients with molecular confirmation of FDRA and followed in three Brazilian outpatient centers were enrolled. General demographics, GAA expansion size, age at onset, cardiac, endocrine, and skeletal manifestations were evaluated and compared between LOFA and classic FDRA (cFDRA) groups. We used Mann-Whitney and Fisher tests to compare means and proportions between groups; p values <0.05 were considered significant. LOFA accounted for 17 % (18/106) and cFDRA for 83 % (88/106) of the patients. There were 13 and 48 women in each group, respectively. LOFA patients were significantly older and had smaller GAA expansions. Clinically, LOFA group had a tendency toward lower frequency of diabetes/impaired glucose tolerance (5.8 vs. 17 %, p = 0.29) and cardiomyopathy (16.6 vs. 28.4 %, p = 0.38). Skeletal abnormalities were significantly less frequent in LOFA (scoliosis 22 vs. 61 %, p = 0.003, and pes cavus 22 vs.75 %, p < 0.001) as were spasticity and sustained reflexes, found in 22 % of LOFA patients but in none of the cFDRA patients (p = 0.001). LOFA accounts for 17 % of Brazilian FDRA patients evaluated herein. Clinically, orthopedic features and spasticity with retained reflexes are helpful tips to differentiate LOFA from cFDRA patients.

Differential Pattern of Cerebellar Atrophy in Tremor-Predominant and Akinetic/Rigidity-Predominant Parkinson's Disease.

Parkinson's disease (PD) is an akinetic-rigid disorder characterized by basal ganglia dysfunction and a possible cerebello-thalamo-cortical circuit involvement. This study aims to investigate the pattern of cerebellar involvement in PD and to assess whether it correlates with clinical parameters. MRI scans were acquired from 50 healthy controls (HC) and 63 patients; 44 were classified as tremor-predominant-PD (PDT) and 19 as akinetic/rigidity-predominant-PD (PDAR). We designed an analysis of covariance including the three groups and contrasted as follows: (1) all 63 PD vs HC, (2) PDT vs HC, (3) PDAR vs HC, and (4) PDT vs PDAR. For a precise evaluation of the cerebellum, we used the SUIT tool for voxel-based morphometry. Applying p = 0.001 and extent threshold = 20 voxels, the overall PD group vs HC showed decreased gray matter (GM) in the left lobules VI and crus I. The PDT group showed decreased cerebellar GM when compared with HC at left lobules VI, VIIb, and VIIIa; at right lobules Crus I, VIIb, and VIIIb; and vermal lobules VI and VIIIa. When compared with PDAR, PDT also showed a decrease in the left lobules VIIIa (p < 0.001). There were small clusters of both positive and negative correlation between disease duration and PDT group. The PDAR group showed no cerebellar changes. Our findings support the growing evidence of cerebellar involvement in the pathogenesis of the resting tremor.

Does Side of Onset Influence the Pattern of Cerebral Atrophy in Parkinson's Disease?

BACKGROUND: Imaging studies have revealed widespread neurodegeneration in Parkinson's disease (PD), but only a few considered the issue of asymmetrical clinical presentations. OBJECTIVE: To investigate if the side of onset influences the pattern of gray matter (GM) atrophy in PD. METHODS: Sixty patients (57.87 ± 10.27 years) diagnosed with idiopathic PD according to the U.K. Brain Bank criteria, 26 with right-sided disease onset (RDO) and 34 with left-sided disease onset (LDO), were compared to 80 healthy controls (HC) (57.1 ± 9.47 years). We acquired T1-weighted images on a 3 T scanner. Images were processed and analyzed with VBM8 (SPM8/Dartel) on Matlab R2012b platform. Statistic assessments included a two-sample test (family-wise error p < 0.05) with extent threshold of 20 voxels. RESULTS: Compared to HC, LDO patients had GM atrophy in the insula, putamen, anterior cingulate, frontotemporal cortex, and right caudate, while the RDO group showed atrophy at the anterior cingulate, insula, frontotemporal, and occipital cortex. CONCLUSION: This study revealed widespread GM atrophy in PD, predominantly in the left hemisphere, regardless of the side of onset. Future investigations should also consider handedness and side of onset to better characterize cerebral involvement and its progression in PD.

Pattern of Reduced Functional Connectivity and Structural Abnormalities in Parkinson's Disease: An Exploratory Study.

BACKGROUND: MRI brain changes in Parkinson's disease (PD) are controversial. OBJECTIVES: We aimed to describe structural and functional changes in PD. METHODS: Sixty-six patients with PD (57.94 ± 10.25 years) diagnosed according to the UK Brain Bank criteria were included. We performed a whole brain analysis using voxel-based morphometry (VBM-SPM 8 software), cortical thickness (CT) using CIVET, and resting-state fMRI using the Neuroimaging Analysis Kit software to compare patients and controls. For VBM and CT we classified subjects into three groups according to disease severity: mild PD [Hoehn and Yahr scale (HY) 1-1.5], moderate PD (HY 2-2.5), and severe PD (HY 3-5). RESULTS: We observed gray matter atrophy in the insula and inferior frontal gyrus in the moderate PD and in the insula, frontal gyrus, putamen, cingulated, and paracingulate gyri in the severe groups. In the CT analysis, in mild PD, cortical thinning was restricted to the superior temporal gyrus, gyrus rectus, and olfactory cortex; in the moderate group, the postcentral gyrus, supplementary motor area, and inferior frontal gyrus were also affected; in the severe PD, areas such as the precentral and postentral gyrus, temporal pole, fusiform, and occipital gyrus had reduced cortical thinning. We observed altered connectivity at the default mode, visual, sensorimotor, and cerebellar networks. CONCLUSION: Subjects with mild symptoms already have cortical involvement; however, further cerebral involvement seems to follow Braak's proposed mechanism. Similar regions are affected both structurally and functionally. We believe the combination of different MRI techniques may be useful in evaluating progressive brain involvement and they may eventually be used as surrogate markers of disease progression.