Ventral Striatal D2/3 Receptor Availability Is Associated with Impulsive Choice Behavior As Well As Limbic Corticostriatal Connectivity.

BACKGROUND: Low dopamine D2/3 receptor availability in the nucleus accumbens shell is associated with highly impulsive behavior in rats as measured by premature responses in a cued attentional task. However, it is unclear whether dopamine D2/3 receptor availability in the nucleus accumbens is equally linked to intolerance for delayed rewards, a related form of impulsivity. METHODS: We investigated the relationship between D2/3 receptor availability in the nucleus accumbens and impulsivity in a delay-discounting task where animals must choose between immediate, small-magnitude rewards and delayed, larger-magnitude rewards. Corticostriatal D2/3 receptor availability was measured in rats stratified for high and low impulsivity using in vivo [18F]fallypride positron emission tomography and ex vivo [3H]raclopride autoradiography. Resting-state functional connectivity in limbic corticostriatal networks was also assessed using fMRI. RESULTS: Delay-discounting task impulsivity was inversely related to D2/3 receptor availability in the nucleus accumbens core but not the dorsal striatum, with higher D2/3 binding in the nucleus accumbens shell of high-impulsive rats compared with low-impulsive rats. D2/3 receptor availability was associated with stronger connectivity between the cingulate cortex and hippocampus of high- vs low-impulsive rats. CONCLUSIONS: We conclude that delay-discounting task impulsivity is associated with low D2/3 receptor binding in the nucleus accumbens core. Thus, two related forms of waiting impulsivity-premature responding and delay intolerance in a delay-of-reward task-implicate an involvement of D2/3 receptor availability in the nucleus accumbens shell and core, respectively. This dissociation may be causal or consequential to enhanced functional connectivity of limbic brain circuitry and hold relevance for attention-deficit/hyperactivity disorder, drug addiction, and other psychiatric disorders

First Report of Tumor Treating Fields (TTFields) Therapy for Glioblastoma in Comorbidity with Multiple Sclerosis

Tumor Treating Fields (TTFields) therapy is FDA approved and has the CE mark for treatment of newly diagnosed and recurrent glioblastoma. To our knowledge, to date TTFields therapy remains unstudied in glioblastoma patients with multiple sclerosis (MS) as a comorbidity. Here, we present a patient who was diagnosed with MS at the age of 34. Treatment included several corticoid pulse treatments and therapies with interferon beta-1a and sphingosine-1-phosphate receptor modulator fingolimod. At the age of 52 the patient was diagnosed with glioblastoma, after experiencing worsening headaches which could not be attributed to the MS condition. After subtotal resection and concomitant radiochemotherapy, the patient received temozolomide in combination with TTFields therapy. For two years, the tumor condition remained stable while the patient showed high adherence to TTFields therapy with low-grade skin reactions being the only therapy-related adverse events. After two years, the tumor recurred. The patient underwent re-resection and radiotherapy and restarted TTFields therapy together with chemotherapy and is currently still on this therapy regime. Although having not been studied systematically, the case presented here demonstrates that TTFields therapy may be considered for newly diagnosed and recurrent glioblastoma patients with previously diagnosed multiple sclerosis

Identical patterns of cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A tract of interest-based MRI study

Background: There is an ongoing debate whether primary lateral sclerosis (PLS) should be regarded as an independent disease entity separate from amyotrophic lateral sclerosis (ALS) or as a slowly progressive variant of ALS. Objective: The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from PLS patients by a hypothesis-guided tract-of-interest-based approach compared with ‘classical’ ALS patients and healthy controls, in order to identify microstructural changes according to the neuropathologically defined ALS affectation pattern in vivo. Methods: DTI-based white matter mapping was performed both by an unbiased voxelwise statistical comparison and by a hypothesis-guided tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 50 PLS and 50 ALS patients vs 50 matched controls. Results: The analysis of white matter integrity by regional FA reductions demonstrated the characteristic alteration patterns along the CST and also in frontal and prefrontal brain areas in PLS patients and ALS patients. In the tract-specific analysis according to the ALS-staging pattern, PLS and ALS affectation patterns showed identical significant alterations of ALS-related tract systems when compared with controls and no differences when compared with each other. Conclusions: This DTI study showed the same microstructural affectation patterns in PLS patients as in ALS, in support of the hypothesis that PLS is a phenotypical variant of ALS. Keywords: Diffusion tensor imaging, Amyotrophic lateral sclerosis, Primary lateral sclerosis, Magnetic resonance imaging, Motor neuron disease

Cerebral Microstructural Alterations after Radiation Therapy in High-Grade Glioma: A Diffusion Tensor Imaging-Based Study

ObjectiveTo investigate radiation therapy-induced microstructural damage of white matter in patients with high-grade glioma by diffusion tensor imaging (DTI).MethodsDTI was performed in 18 patients with high-grade glioma (WHO grades III and IV) and 13 healthy controls. DTI images were cross-sectionally aligned for the calculation of baseline fractional anisotropy (FA). Interhemispheric FA values in patients with high-grade glioma before or without brain radiation therapy were compared with the interhemispheric FA values in patients after radiation therapy and in healthy controls. In a subgroup without any clinical or diagnostic evidence of tumor progression, serial DTI data (5–11 scans) before and after radiation therapy were collected and longitudinal interhemispheric FA changes were assessed and compared to longitudinal data from the control group.In addition, interhemispheric axial, mean, and radial diffusivity was assessed.ResultsGlobal interhemispheric FA reductions could be detected cross-sectionally in patients after radiation therapy; these were significantly different from global interhemispheric FA differences both in patients without radiation and in healthy controls. Longitudinal scans in patients with radiation therapy confirmed these findings and revealed progressive microstructural white matter damage after partial brain radiotherapy. The additional DTI metrics axial diffusion, mean diffusivity, and radial diffusion confirmed interhemispheric differences in patients without or before radiation therapy, which were lower than the differences in patients after radiation therapy, although not reaching significance.ConclusionInterhemispheric global FA differences could potentially serve as a biological marker for irradiation-induced microstructural white matter damage

The spectrum and differential diagnosis of acquired ocular motor nerve palsies: a clinical study of 502 patients

Background!#!Ocular motor nerve palsies (OMNP) frequently cause patients to present in an emergency room. In the following study, we report the differential diagnosis of OMNP by use of magnetic resonance imaging (MRI) and CSF examination as a standard.!##!Method!#!We performed a data analysis of N = 502 patients who presented with oculomotor, trochlear, and/or abducens nerve palsy in the emergency room of the Department of Neurology, University of Ulm, between January 2006 and December 2019. We report clinical and MRI scan findings in all patients; furthermore, the CSF of 398 patients has been analysed.!##!Results!#!Abducens nerve palsies were most common (45%), followed by palsies of the oculomotor (31%) (CNP III) and trochlear nerve (15%). Multiple OMNPs were seen in 9% of our cohort. The most common causes included inflammations (32.7%), space-occupying lesions, such as aneurysms or neoplasms (17.3%), diabetes mellitus (13.3%), and brainstem infarctions (11%). Still 23.4% of the patients could not be assigned to any specific cause after differential diagnostic procedures and were described as idiopathic. One of three patients with an inflammation and 39% of the patients with space-occupying lesions showed additional cranial nerve deficits.!##!Conclusion!#!Inflammation and space-occupying processes were the most frequent causes of OMNP, although brainstem infarctions also play a significant role, in particular in CNP III. The presence of additional CNPs increases the probability of an inflammatory or space-occupying cause

Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer

Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental. Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis. Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm. Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%. Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental

A Prospective Validation Study of the Functional Bedside Aspiration Screen with Endoscopy: Is It Clinically Applicable in Acute Stroke?

The purpose of this study was to investigate the reliability of the novel Functional Bedside Aspiration Screen (FBAS) to predict aspiration risk in acute stroke and to guide initial therapy needs. We conducted a prospective validation study of the FBAS 10-point scale in 101 acute ischemic stroke patients. Outcome measures were compared with the Penetration Aspiration Scale (PAS) via the Flexible Endoscopic Swallowing Study. Correlations with the Functional Oral Intake Scale (FOIS) and the Therapy Requirement Scale (TRS) were analyzed. We observed a 65.8% sensitivity and 70.2% specificity (p = 0.004) for predicting penetration risk (for PAS score ≥ 3) and a 73% sensitivity and 62% specificity for predicting aspiration risk (PAS score ≥ 6). For patients with a modified ranking scale 0–2 (n = 44) on admission, the predictive measurements of the FBAS yielded sensitivity and specificity values of 66.7% and 88.6% (p = 0.011). A significant negative correlation was found with PAS measurements, whereas a positive correlation was observed regarding FOIS. Significantly lower FBAS scores were observed in patients with high requirements for therapeutic interventions and dietary modification. FBAS may be regarded as an alternative time-efficient clinical support tool in settings in which instrumentation is not directly accessible. Further studies including a larger cohort of acute stroke patients with more severe neurological deficits are necessary

Cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A two-centre tract of interest-based DTI analysis

Background: After the demonstration of a corticoefferent propagation pattern in amyotrophic lateral sclerosis (ALS) by neuropathological studies, this concept has been used for in vivo staging of individual patients by diffusion tensor imaging (DTI) techniques, both in `classical` ALS and in restricted phenotypes such as primary lateral sclerosis (PLS). Objective: The study was designed to investigate that microstructural changes according to the neuropathologically defined ALS alteration pattern in PLS patients could be confirmed to be identical to ´classical´ ALS patients. The novelty in this approach is that the results were independent of the subject samples and the data acquisition parameters (as was validated in two samples from two different centres). That way, reproducibility across (international) centres in addition to harmonisation/standardisation of data analysis has been addressed, for the possible use of MRI-based staging to stratify patients in clinical trials. Methods: Tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern was applied to DTI data (pooled from two ALS centres) of 88 PLS patients and 88 ALS patients with a ‘classical’ phenotype in comparison to 88 matched controls in order to identify white matter integrity alterations. Results: In the tract-specific analysis, alterations were identical for PLS and ALS in the tract systems corresponding to the ALS staging pattern, independent of the subject samples and the data acquisition parameters. The individual categorisation into ALS stages did not differ between PLS and ALS patients. Conclusions: This DTI study in a two-centre setting demonstrated that the neuropathological stages can be mapped in vivo in PLS with high reproducibility and that PLS-associated cerebral propagation, although showing the same corticofugal patterns as ALS, might have a different time course of neuropathology, in analogy to its much slower clinical progression rates. Keywords: Diffusion tensor imaging, Amyotrophic lateral sclerosis, Primary lateral sclerosis, Magnetic resonance imaging, Motor neuron diseas

sj-docx-1-tan-10.1177_17562864241239123 – Supplemental material for Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer

Supplemental material, sj-docx-1-tan-10.1177_17562864241239123 for Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer by Rebecca Kassubek, Marc-Andre G. R. Winter, Jens Dreyhaupt, Mona Laible, Jan Kassubek, Albert C. Ludolph and Jan Lewerenz in Therapeutic Advances in Neurological Disorders</p

The spectrum of KIAA0196 variants, and characterization of a murine knockout: implications for the mutational mechanism in hereditary spastic paraplegia type SPG8

International audienceBackground : The hereditary spastic paraplegias (HSPs) are rare neurodegenerative gait disorders which are genetically highly heterogeneous. For each single form, eventual consideration of therapeutic strategies requires an understanding of the mechanism by which mutations confer pathogenicity. SPG8 is a dominantly inherited HSP, and associated with rather early onset and rapid progression. A total of nine mutations in KIAA0196, which encodes the WASH regulatory complex (SHRC) member strumpellin, have been reported in SPG8 patients so far. Based on biochemical and cell biological approaches, they have been suggested to act via loss of function-mediated haploinsufficiency.Methods : We generated a deletion-based knockout allele for E430025E21Rik, i.e. the murine homologue of KIAA0196. The consequences on mRNA and protein levels were analyzed by qPCR and Western-blotting, respectively. Motor performance was evaluated by the foot-base angle paradigm. Axon outgrowth and relevant organelle compartments were investigated in primary neuron cultures and primary fibroblast cultures, respectively. A homemade multiplex ligation-dependent probe amplification assay enabling identification of large inactivating KIAA0196 deletion alleles was applied to DNA from 240 HSP index patients. Results : Homozygous but not heterozygous mice showed early embryonic lethality. No transcripts from the knockout allele were detected, and the previously suggested compensation by the wild-type allele upon heterozygosity was disproven. mRNA expression of genes encoding other SHRC members was unaltered, while there was evidence for reduced SHRC abundance at protein level. We did, however, neither observe HSP-related in vivo and ex vivo phenotypes, nor alterations affecting endosomal, lysosomal, or autophagic compartments. KIAA0196 copy number screening excluded large inactivating deletion mutations in HSP patients. The consequences of monoallelic KIAA0196/E430025E21Rik activation thus differ from those observed for dominant HSP genes for which a loss-of-function mechanism is well established. Conclusions : Our data do not support the current view that heterozygous loss of strumpellin/SHRC function leads to haploinsufficiency and, in turn, to HSP. The lethality of homozygous knockout mice, i.e. the effect of complete loss of function, also argues against a dominant negative effect of mutant on wild-type strumpellin in patients. Toxic gain-of-function represents a potential alternative explanation. Confirmation of this therapeutically relevant hypothesis in vivo, however, will require availability of appropriate knockin models