Impact of Acute Dopamine Replacement on Cognitive Function in Parkinson's Disease.

BACKGROUND: PD causes striatal dopaminergic denervation in a posterior/dorsal to anterior/ventral gradient, leaving motor and associative cortico-striato-pallido-thalamic loops differentially susceptible to hyperdopaminergic effects with treatment. As the choice and titration of symptomatic PD medications are guided primarily by motor symptoms, it is important to understand their cognitive implications. OBJECTIVE: To investigate the effects of acute dopaminergic medication administration on executive function in Parkinson's disease (PD). METHODS: Participants with idiopathic PD were administered the oral Symbol Digit Modalities Test (SDMT; n = 181) and the Stroop test (n = 172) in the off-medication and "best on" medication states. ANCOVA was used to test for differences between off-medication and on-medication scores corrected for age and years of education. RESULTS: After administration of symptomatic medications, scores worsened on the SDMT (F = 11.70, P < 0.001, d = -0.13), improved on the Stroop color (F = 26.89, P < 0.001, d = 0.184), word (F = 6.25, P = 0.013, d = 0.09), and color-word (F = 13.22, P < 0.001, d = 0.16) test components, and the Stroop difference and ratio-based interference scores did not significantly change. Longer disease duration correlated with lower scores on the SDMT, Stroop color, word, and color-word scores; however, longer disease duration and higher levodopa-equivalents correlated with higher Stroop difference-based interference scores. CONCLUSIONS: Symptomatic medication differentially affects performance on two cognitive tests in PD. After acute treatment, core Stroop measures improved, Stroop interference was unchanged, and SDMT performance worsened, likely reflecting complex changes in processing speed and executive function related to acute treatment. When considering motor symptom therapies in PD, an individual's cognitive demands and expectations, especially regarding executive function, should be considered.

The Association of Antidepressant Use and Impulse Control Disorder in Parkinson's Disease.

OBJECTIVES: To examine whether initiation of an antidepressant is associated with the development of impulse control disorder (ICD) in patients with Parkinson's disease (PD). DESIGN: We performed a retrospective analysis utilizing data from the Parkinson's Progression Markers Initiative (PPMI). Two-sample Mann-Whitney tests were used for comparison of continuous variables and Pearson χ2 tests were used for categorical variables. Kaplan-Meier survival analysis and cox proportional hazards regression analysis was used to assess the hazard of ICD with antidepressant exposure. SETTING: The PPMI is a multicenter observational study of early PD with 52 sites throughout North America, Europe, and Africa. PARTICIPANTS: Participants in the current study were those in the PPMI PD cohort with a primary diagnosis of idiopathic PD. MEASUREMENTS: The presence of ICD was captured using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Antidepressant use was defined based on medication logs for each participant. Depressive symptoms were captured using the Geriatric Depression Scale (GDS). RESULTS: A total of 1,045 individuals were included in the final analysis. There was a significant increase in the probability of ICD in those exposed to serotonergic antidepressants compared to those not exposed (Log-rank p <0.001). Serotonergic antidepressant use was associated with a hazard ratio for ICD of 1.4 (95% CI 1.0-1.8, z-value 2.1, p = 0.04) after adjusting for dopamine agonist use, depression, bupropion use, MAOI-B use, amantadine use, LEDD, disease duration, sex, and age. CONCLUSIONS: Serotonergic antidepressant use appears to be temporally associated with ICD in patients with PD.

Examining the link between impulse control disorder and antidepressant use in Parkinson's disease.

INTRODUCTION: Impulse control disorders (ICD) in Parkinson's disease (PD) and hypomanic episodes of bipolar disorder show overlapping symptoms, suggesting a shared neurobiology. To explore this, the following hypotheses are tested: (1) larger changes in affective symptoms from OFF to ON medication states will be associated with ICD, (2) antidepressant exposure will be associated with larger OFF to ON affective symptom changes, and (3) antidepressant exposure will be associated with ICD. METHODS: 200 participants (mean age 65, 61 % male) were evaluated in "off" and "on" dopamine states. Affective symptoms were captured using the Hamilton Anxiety and Depression Rating Scales. Differences in clinical outcomes were compared using two-sample Wilcoxon rank-sum tests and Pearson χ2 tests. We performed multivariable logistic regression to assess the association of antidepressant exposure on ICD. RESULTS: Participants with an ICD had higher anxiety and depressive scores in "on" and "off" states and larger changes in depressive symptoms from OFF to ON states compared to those without an ICD. Participants on antidepressants had higher anxiety scores in "on" and "off" states, higher depressive scores in the "off" state, and larger changes in anxiety symptoms from OFF to ON states than those not on an antidepressant. Antidepressant use was associated with a higher odds of an ICD (OR 2.3, CI [1.0-4.5], p-value 0.04). CONCLUSIONS: Affective symptom severity in "on" and "off" dopamine states is associated with ICD. Antidepressant therapy may be associated with ICD. Future prospective studies clarifying temporal associations between antidepressant initiation and ICD emergence are needed.

Cognitive Sequelae of Central-Variant Posterior Reversible Encephalopathy Syndrome (PRES).

INTRODUCTION: Although the posterior reversible encephalopathy syndrome (PRES) is often associated with headache and visual changes, central-variant PRES can be difficult to clinically diagnose in a patient with alteration of consciousness. Central-variant PRES has been previously described in the literature affecting subcortical white matter and the brainstem. Case Presentation. We describe a case presenting with hypertension (192/98) and altered level of consciousness requiring intubation. She was ultimately found to have extensive symmetric cortical and subcortical edema, with extensive involvement of bilateral thalami, consistent with central-variant PRES. Her mentation rapidly improved with blood pressure management. Confirmation of the diagnosis of central-variant PRES was made on repeat brain imaging. Our case is unique in demonstrating dramatic central white matter changes and their reversibility on repeat imaging six days later. Finally, persistent cognitive deficits at follow-up four months later are described. CONCLUSION: Atypical presentations of PRES, involving alterations in levels of consciousness, can be difficult to clinically diagnose. A thorough differential diagnosis is even more important in cases of PRES with atypical imaging. Recognition of the diagnostic patterns of PRES on brain imaging, with prompt reversal of the causative factors, is crucial for the appropriate care of these patients. The long-term sequelae, which could include cognitive deficits, are poorly studied and understood.

Indication of retrograde tau spreading along Braak stages and functional connectivity pathways.

PURPOSE: Tau pathology progression in Alzheimer's disease (AD) is explained through the network degeneration hypothesis and the neuropathological Braak stages; however, the compatibility of these models remains unclear. METHODS: We utilized [18F]AV-1451 tau-PET scans of 39 subjects with AD and 39 sex-matched amyloid-negative healthy controls (HC) in the ADNI (Alzheimer's Disease Neuroimaging Initiative) dataset. The peak cluster of tau-tracer uptake was identified in each Braak stage of neuropathological tau deposition and used to create a seed-based functional connectivity network (FCN) using 198 HC subjects, to identify healthy networks unaffected by neurodegeneration. RESULTS: Voxel-wise tau deposition was both significantly higher inside relative to outside FCNs and correlated significantly and positively with levels of healthy functional connectivity. Within many isolated Braak stages and regions, the correlation between tau and intrinsic functional connectivity was significantly stronger than it was across the whole brain. In this way, each peak cluster of tau was related to multiple Braak stages traditionally associated with both earlier and later stages of disease. CONCLUSION: We show specificity of healthy FCN topography for AD-pathological tau as well as positive voxel-by-voxel correlations between pathological tau and healthy functional connectivity. We propose a model of "up- and downstream" functional tau progression, suggesting that tau pathology evolves along functional connectivity networks not only "downstream" (i.e., along the expected sequence of the established Braak stages) but also in part "upstream" or "retrograde" (i.e., against the expected sequence of the established Braak stages), with pathology in earlier Braak stages intensified by its functional relationship to later disease stages.

Atypical Variant of Guillain Barre Syndrome in a Patient with COVID-19.

OBJECTIVE: A rare variant Miller Fisher Syndrome overlap with Guillain Barre Syndrome is described in an adult patient with SARS-COV-2 infection. CASE PRESENTATION: The clinical course of a 45-year-old immunosuppressed man is summarized as a patient who developed ataxia, ophthalmoplegia, and areflexia after upper respiratory infection symptoms began. A nasopharyngeal swab was positive for COVID-19 polymerase chain reaction. He progressed to acute hypoxemic and hypercapnic respiratory failure requiring intubation and rapidly developed tetraparesis. Magnetic resonance imaging of the spine was consistent with Guillain Barre Syndrome. However, the clinical symptoms, along with positive anti-GQ1B antibodies, were consistent with Miller Fisher Syndrome and Guillain Barre Syndrome overlap. The patient required tracheostomy and had limited improvement in his significant neurological symptoms after several months. CONCLUSIONS: The case demonstrates the severe neurological implications, prolonged recovery and implications in the concomitant respiratory failure of COVID-19 patients with neurological symptoms on the spectrum of disorders of Guillain Barre Syndrome.

Intrathecal blood injection: a case report of a rare complication of an epidural blood patch.

BACKGROUND: Intrathecal injection is a rare complication of spinal anesthesia and an underreported complication of epidural blood patches. Although there are other reported cases of intrathecal blood injection, these cases lack confirmatory imaging and others report injection of mixed blood with other agents. CASE PRESENTATION: We present a case report of post-laminectomy cerebrospinal fluid leak who underwent epidural blood patch placement. CT and MRI brain imaging was obtained, depicting intrathecal blood products. The patient had subsequent seizures and respiratory distress, received supportive care, and returned to baseline after several days. CONCLUSION: The patient's clinical course illustrates the potential complications of blood products within CSF, including seizures and respiratory distress, which improved with supportive care in this case. Importantly, to our knowledge, this is the only report that clearly depicts injection of purely blood products, without other confounding agents (such as gadolinium), into intrathecal space and with diffuse spread through the CSF as visualized on CT and MRI imaging.

Overlapping and distinct neural metabolic patterns related to impulsivity and hypomania in Parkinson's disease.

Impulsivity and hypomania are common non-motor features in Parkinson's disease (PD). The aim of this study was to find the overlapping and distinct neural correlates of these symptoms in PD. Symptoms of impulsivity and hypomania were assessed in 24 PD patients using the Barratt Impulsiveness Scale (BIS-11) and Self-Report Manic Inventory (SRMI), respectively. In addition, fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for each individual was performed. We conducted two separate multiple regression analyses for BIS-11 and SRMI scores with FDG-PET data to identify the brain regions that are associated with both impulsivity and hypomania scores, as well as those exclusive to each symptom. Then, seed-based functional connectivity analyses on healthy subjects identified the areas connected to each of the exclusive regions and the overlapping region, used as seeds. We observed a positive association between BIS-11 and SRMI scores and neural metabolism only in the prefrontal areas. Conjunction analysis revealed an overlapping region in the middle frontal gyrus. Regions exclusive to impulsivity were found in the medial part of the right superior frontal gyrus and regions exclusive to hypomania were in the right superior frontal gyrus, right precentral gyrus and right paracentral lobule. Connectivity patterns of seeds exclusively related to impulsivity were different from those for hypomania in healthy brains. These results provide evidence of both overlapping and distinct regions linked with impulsivity and hypomania scores in PD. The exclusive regions for each characteristic are connected to specific intrinsic functional networks.

Networks of tau distribution in Alzheimer's disease.

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimer's disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimer's disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer's disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer's disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer's disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer's disease.