MRI detection of brain gadolinium retention in multiple sclerosis: Magnetization transfer vs. T1-weighted imaging.

BACKGROUND AND PURPOSE: Evidence of brain gadolinium retention has affected gadolinium-based contrast agent usage. It is, however, unclear to what extent macrocyclic agents are retained and whether their in vivo detection may necessitate nonconventional MRI. Magnetization transfer (MT) could prove suitable to detect gadolinium-related signal changes since dechelated gadolinium ions bind to macromolecules. Therefore, this study aimed to investigate associations of prior gadolinium administrations with MT and T1 signal abnormalities. METHODS: A cohort of 23 persons with multiple sclerosis (MS) (18 females, 5 males, 57 ± 8.0 years) with multiple past gadolinium administrations (median 6, range 3-12) and 23 age- and sex-matched healthy controls underwent 1.5 Tesla MRI with MT, T1-weighted 2-dimensional spin echo, and T1-weighted 3-dimensional gradient echo. The signal intensity index was assessed by MRI in gadolinium retention predilection sites. RESULTS: There were dose-dependent associations of the globus pallidus signal on gradient echo (r = .55, p < .001) and spin echo (r = .38, p = .013) T1-weighted imaging, but not on MT. Relative to controls, MS patients had higher signal intensity index in the dentate nucleus on T1-weighted gradient echo (1.037 ± 0.040 vs. 1.016 ± 0.023, p = .04) with a similar trend in the globus pallidus on T1-weighted spin echo (1.091 ± 0.034 vs. 1.076 ± 0.014, p = .06). MT detected no group differences. CONCLUSIONS: Conventional T1-weighted imaging provided dose-dependent associations with gadolinium administrations in MS, while these could not be detected with 2-dimensional MT. Future studies could explore newer MT techniques like 3D and inhomogenous MT. Notably, these associations were identified with conventional MRI even though most patients had not received gadolinium administrations in the preceding 9 years, suggestive of long-term retention.

On Spinocerebellar Ataxia 21 as a Mimicker of Cerebral Palsy.

Objectives: Sporadic variants in ataxia genes may mimic cerebral palsy (CP). Spinocerebellar ataxia 21 (SCA21), a very rare autosomal dominant disease, was discovered to be associated with variants in the transmembrane protein 240 (TMEM240) gene in 2014. In this report, we present 2 patients with sporadic SCA21, one of them diagnosed with ataxic CP. Methods: Patients provided oral and written consent. Comprehensive clinical evaluation, neuroimaging studies, review of previous psychometric evaluations, and whole-genome sequencing were applied in both cases. Results: Both patients presented with early-onset ataxia and exhibited mild parkinsonian features. Patient 1 experienced motor and speech delay, autism, and dyslexia, whereas patient 2 experienced dyslexia. Neuroimaging was normal in both cases. In patient 1, the previously reported pathogenic c.509C>T (Pro170Leu) variant in TMEM240 was detected, whereas patient 2 harbored the novel c.182_188delinsGGAT (Val61_Pro63delinsGlyMet) variant in the same gene. Both genetic variants were sporadic. Discussion: Our findings support the notion that SCA21 is a neurodevelopmental syndrome and a mimicker of ataxic CP. Both lack of a family history of ataxia and congenital presentation were reasonable arguments to consider ataxic CP. However, lack of convincing perinatal incidents, progressive symptoms, and the common presence of cerebellar atrophy should alert neurologists about SCA21.

V374A KCND3 Pathogenic Variant Associated With Paroxysmal Ataxia Exacerbations.

OBJECTIVE: Ataxia channelopathies share common features such as slow motor progression and variable degrees of cognitive dysfunction. Mutations in potassium voltage-gated channel subfamily D member 3 (KCND3), encoding the K+ channel, Kv4.3, are associated with spinocerebellar ataxia (SCA) 19, allelic with SCA22. Mutations in potassium voltage-gated channel subfamily C member 3 (KCNC3), encoding another K+ channel, Kv3.3, cause SCA13. First, a comprehensive phenotype assessment was carried out in a family with autosomal dominant ataxia harboring 2 genetic variants in KCNC3 and KCND3. To evaluate the physiological impact of these variants on channel currents, in vitro studies were performed. METHODS: Clinical and psychometric evaluations, neuroimaging, and genotyping of a family (mother and son) affected by ataxia were carried out. Heterozygous and homozygous Kv3.3 A671V and Kv4.3 V374A variants were evaluated in Xenopus laevis oocytes using 2-electrode voltage-clamp. The influence of Kv4 conductance on neuronal activity was investigated computationally using a Purkinje neuron model. RESULTS: The main clinical findings were consistent with adult-onset ataxia with cognitive dysfunction and acetazolamide-responsive paroxysmal motor exacerbations in the index case. Despite cognitive deficits, fluorodeoxyglucose (FDG)-PET displayed hypometabolism mainly in the severely atrophic cerebellum. Genetic analyses revealed the new variant c.1121T>C (V374A) in KCND3 and c.2012T>C (A671V) in KCNC3. In vitro electrophysiology experiments on Xenopus oocytes demonstrated that the V374A mutant was nonfunctional when expressed on its own. Upon equal co-expression of wild-type (WT) and V374A channel subunits, Kv4.3 currents were significantly reduced in a dominant negative manner, without alterations of the gating properties of the channel. By contrast, Kv3.3 A671V, when expressed alone, exhibited moderately reduced currents compared with WT, with no effects on channel activation or inactivation. Immunohistochemistry demonstrated adequate cell membrane translocation of the Kv4.3 V374A variant, thus suggesting an impairment of channel function, rather than of expression. Computational modeling predicted an increased Purkinje neuron firing frequency upon reduced Kv4.3 conductance. CONCLUSIONS: Our findings suggest that Kv4.3 V374A is likely pathogenic and associated with paroxysmal ataxia exacerbations, a new trait for SCA19/22. The present FDG PET findings contrast with a previous study demonstrating widespread brain hypometabolism in SCA19/22.

Validation of Rapid Magnetic Resonance Myelin Imaging in Multiple Sclerosis.

OBJECTIVE: Magnetic resonance imaging (MRI) is essential for multiple sclerosis diagnostics but is conventionally not specific to demyelination. Myelin imaging is often hampered by long scanning times, complex postprocessing, or lack of clinical approval. This study aimed to assess the specificity, robustness, and clinical value of Rapid Estimation of Myelin for Diagnostic Imaging, a new myelin imaging technique based on time-efficient simultaneous T1 /T2 relaxometry and proton density mapping in multiple sclerosis. METHODS: Rapid myelin imaging was applied using 3T MRI ex vivo in 3 multiple sclerosis brain samples and in vivo in a prospective cohort of 71 multiple sclerosis patients and 21 age/sex-matched healthy controls, with scan-rescan repeatability in a subcohort. Disability in patients was assessed by the Expanded Disability Status Scale and the Symbol Digit Modalities Test at baseline and 2-year follow-up. RESULTS: Rapid myelin imaging correlated with myelin-related stains (proteolipid protein immunostaining and Luxol fast blue) and demonstrated good precision. Multiple sclerosis patients had, relative to controls, lower normalized whole-brain and normal-appearing white matter myelin fractions, which correlated with baseline cognitive and physical disability. Longitudinally, these myelin fractions correlated with follow-up physical disability, even with correction for baseline disability. INTERPRETATION: Rapid Estimation of Myelin for Diagnostic Imaging provides robust myelin quantification that detects diffuse demyelination in normal-appearing tissue in multiple sclerosis, which is associated with both cognitive and clinical disability. Because the technique is fast, with automatic postprocessing and US Food and Drug Administration/CE clinical approval, it can be a clinically feasible biomarker that may be suitable to monitor myelin dynamics and evaluate treatments aiming at remyelination. ANN NEUROL 2020;87:710-724.

Correction to: Cognitive dysfunction and subjective symptoms in patients with arachnoid cyst before and after surgery.

Incorrect family name of Åsa Bergendal.

Cognitive dysfunction and subjective symptoms in patients with arachnoid cyst before and after surgery.

INTRODUCTION: Arachnoid cysts are congenital, benign lesions in the brain and are often incidental radiological findings. Frequently, the arachnoid cysts are left untreated; however, recent studies have shown that arachnoid cysts can cause cognitive dysfunction that affect quality of life. Moreover, the function can improve after surgical decompression. Hence, there is controversy regarding symptomatology and treatment effects of arachnoid cysts. The aim of the study was to analyse if arachnoid cysts can cause cognitive impairment and subjective symptoms and if these impairments are reversible after surgical treatment. MATERIAL AND METHODS: Twenty-one consecutive patients with radiologically confirmed supratentorial arachnoid cysts were cognitively evaluated using a battery of seven neuropsychological tests. Twelve of these patients underwent surgery and were evaluated before and after surgery. The patients were also evaluated with neuropsychological testing after surgery. Further information was extracted from the medical records. The cognitive test results were compared to standard population values using z-test, and the test results from the surgically treated patients were compared before and after surgery using paired t-test. RESULTS: The surgically treated patients had a statistically significant improvement of neurocognitive test results after surgery in six out of the seven tests (p < 0.05). The total patient group showed lower mean values in all tests when compared to standard population. Statistical significance was, however, only detected in two of the seven tests. All surgically treated patients reported diminished symptoms after surgery. CONCLUSIONS: The patients with arachnoid cysts presented with cognitive dysfunction compared to the normal population which improved after surgical decompression. Arachnoid cysts should not be considered asymptomatic unless thoroughly evaluated with clinical and neuropsychological work-up.

Lesion accumulation is predictive of long-term cognitive decline in multiple sclerosis.

OBJECTIVE: To investigate the long-term progression of cognitive dysfunction and its neuroanatomical correlates and predictors in multiple sclerosis (MS). METHODS: A cohort of 37 MS patients reflecting five decades of disease duration and all subtypes was followed over 17.5 years. Matched controls were recruited at the last follow-up. Global cognitive functioning was assessed using a principal component cognitive index based on comprehensive neuropsychological testing. During the last 8.5 years of the study, brain MRI was performed to analyze normalized volumetrics of three global tissue compartments (white and gray matter, lesions) and strategic regions (corpus callosum, thalamus, hippocampus). RESULTS: Cognitive decline progressed continuously throughout the study paralleled by atrophy and lesion accumulation. The cognitive index partly correlated with Expanded Disability Status Scale (ρ = -0.47, p < 0.001) and was mainly associated with the lesion fraction (ß = -0.48, p < 0.001) and callosal fraction (ß = 0.39, p = 0.002) in multiple linear regression analysis. The lesion fraction was an independent predictor of the cognitive performance 8.5 years later (ß = -0.35, p = 0.008). Symbol Digit Modalities Test was most frequently abnormal (40%), while Rey-Osterrieth Complex Figure Test was more sensitive to detect cognitive decline. CONCLUSIONS: Cognitive impairment progresses continuously in MS, associated with atrophy and lesion accumulation, suggesting that interventions targeting these processes could be beneficial at all disease stages. Widespread cognitive functions are more profoundly affected, associated with lesions and corpus callosal atrophy, supporting the idea of an underlying disconnection mechanism for cognitive decline in MS.

Novel Features and Abnormal Pattern of Cerebral Glucose Metabolism in Spinocerebellar Ataxia 19.

Spinocerebellar ataxia type 19 (SCA19), allelic with spinocerebellar ataxia type 22 (SCA22), is a rare syndrome caused by mutations in the KCND3 gene which encodes the potassium channel Kv4.3. Only 18 SCA19/22 families and sporadic cases of different ethnic backgrounds have been previously reported. As in other SCAs, the SCA19/22 phenotype is variable and usually consists of adult-onset slowly progressive ataxia and cognitive impairment; myoclonus and seizures; mild Parkinsonism occurs in some cases. Here we describe a Swedish SCA19/22 family spanning five generations and harboring the T377M mutation in KCND3. For the first time for this disease, 18F-fluorodeoxyglucose PET was assessed revealing widespread brain hypometabolism. In addition, we identified white matter abnormalities and found unusual features for SCA19/22 including early age of onset and fast rate of progression in the late course of disease in the oldest patient of this family.