Genetic Risk for Alzheimer Disease and Plasma Tau Are Associated With Accelerated Parietal Cortex Thickness Change in Middle-Aged Adults

Plasma tau, particularly when combined with genetic stratification for AD risk, can be a useful indicator of brain change in midlife.

source: Neuro Genetics

Summary

[Posted 3/Mar/2023]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: Plasma tau, particularly when combined with genetic stratification for AD risk, can be a useful indicator of brain change in midlife. Accelerated inferior parietal cortex changes in midlife may be an important factor to consider as a marker of AD-related brain alterations.

BACKGROUND: Neuroimaging and biomarker studies in Alzheimer disease (AD) have shown well-characterized patterns of cortical thinning and altered biomarker concentrations of tau and ß-amyloid (A ß). However, earlier identification of AD has great potential to advance clinical care and determine candidates for drug trials. The extent to which AD risk markers relate to cortical thinning patterns in midlife is unknown. The first objective of this study was to examine cortical thickness change associated with genetic risk for AD among middle-aged military veterans. The second objective was to determine the relationship between plasma tau and A ß and change in brain cortical thickness among veterans stratified by genetic risk for AD.

DETAILS: Participants consisted of post-9/11 veterans (N = 155) who were consecutively enrolled in the Translational Research Center for TBI and Stress Disorders prospective longitudinal cohort and were assessed for mild traumatic brain injury (TBI) and posttraumatic disorder (PTSD). Genome-wide polygenic risk scores (PRSs) for AD were calculated using summary results from the International Genomics of Alzheimer's Disease Project. T-tau and A ß40 and A ß42 plasma assays were run using Simoa technology. Whole-brain MRI cortical thickness change estimates were obtained using the longitudinal stream of FreeSurfer. Follow-up moderation analyses examined the AD PRS × plasma interaction on change in cortical thickness in AD-vulnerable regions. Higher AD PRS, signifying greater genetic risk for AD, was associated with accelerated cortical thickness change in a right hemisphere inferior parietal cortex cluster that included the supramarginal gyrus, angular gyrus, and intraparietal sulcus. Higher tau, but not A ß42/40 ratio, was associated with greater cortical thickness change among those with higher AD PRS. Mild TBI and PTSD were not associated with cortical thickness change.

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Source: Hayes, J. P., Pierce, M. E., Brown, E., et al. (2023). Genetic Risk for Alzheimer Disease and Plasma Tau Are Associated With Accelerated Parietal Cortex Thickness Change in Middle-Aged Adults. Neuro Genetics. 2023; 9(1): e200053. Published: February, 2023. DOI: 10.1212/NXG.0000000000200053.



GPi-DBS-Induced Brain Metabolic Activation in Cervical Dystonia

GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.

source: J Neurol Neurosurg Psychiatry

Summary

[Posted 1/Apr/2024]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a highly efficacious treatment for cervical dystonia, but its mechanism of action is not fully understood. Here, we investigate the brain metabolic effects of GPi-DBS in cervical dystonia.

DETAILS: Eleven patients with GPi-DBS underwent brain 18F-fluorodeoxyglucose positron emission tomography imaging during stimulation on and off. Changes in regional brain glucose metabolism were investigated at the active contact location and across the whole brain. Changes in motor symptom severity were quantified using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), executive function using trail making test (TMT) and parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS). The mean (SD) best therapeutic response to DBS during the treatment was 81 (22)%. The TWSTRS score was 3.2 (3.9) points lower DBS on compared with off (p=0.02). At the stimulation site, stimulation was associated with increased metabolism, which correlated with DBS stimulation amplitude (r=0.70, p=0.03) but not with changes in motor symptom severity (p>0.9). In the whole brain analysis, stimulation increased metabolism in the GPi, subthalamic nucleus, putamen, primary sensorimotor cortex (PFDR0.05). Acute improvement in TWSTRS correlated with metabolic activation in the sensorimotor cortex and overall treatment response in the supplementary motor area. Worsening of TMT-B score was associated with activation of the anterior cingulate cortex and parkinsonism with activation in the putamen.

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Source: Honkanen E. A., Rönkä J., Pekkonen E., et al. (2024). GPi-DBS-Induced Brain Metabolic Activation in Cervical Dystonia. Journal of Neurology, Neurosurgery & Psychiatry. 2024; 95(4): 300-308. Published: April, 2024. DOI: 10.1136/jnnp-2023-331668.



Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies

HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy.

source: Neuro Genetics

Summary

[Posted 26/Mar/2024]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy.

BACKGROUND: Pathogenic variants in PI3K-AKT-mTOR pathway and GATOR1 complex genes resulting in hyperactivation of mechanistic target of rapamycin (mTOR) complex 1 are a major cause of drug-resistant epilepsy and focal cortical malformations (FCM). Resective neurosurgery is often required to achieve seizure control in patients with mTORopathies due to lack of effectiveness of nonsurgical therapies, including antiseizure medication and mTOR inhibitors. Elevated hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4) has been proposed as a key marker in some mTOR-related brain malformations. This study aimed to investigate HCN4 as a biomarker in the brain across the genetic spectrum of mTORopathies in humans.

DETAILS: The study investigated the relative steady-state levels and cellular localization of HCN4 in resected human brain tissue from 18 individuals with mTORopathies (3 individuals with tuberous sclerosis complex (TSC) due to TSC2 variants, 5 individuals with focal cortical dysplasia type IIA (FCD IIA) due to genetic variants in MTOR, AKT3, and PIK3CA, and 10 individuals with FCD IIB due to variants in TSC1, MTOR, RHEB, DEPDC5, or NPRL3). Elevated HCN4 was observed to be highly restricted to abnormal cell types (dysmorphic neurons and balloon cells) in brain tissue from all mTORopathy tissues (p < 0.0001) compared with those in controls, regardless of genetic cause or variant allele frequency. Elevated HCN4 was not observed in controls or individuals with non-mTOR-related focal epilepsy due to pathogenic variants in ATP1A3, SLC35A2, or FGFR1.

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Source: Coleman, M., Pinaes-Garcia, P., Stephenson, S. E., et al. (2024). Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies. Neuro Genetics. 2024; 10(2). Published: March, 2024. DOI: 10.1212/NXG.0000000000200135.



Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant

This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.

source: Neuro Genetics

Summary

[Posted 8/Mar/2024]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.

BACKGROUND: Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy.

DETAILS: This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records. All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene.

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Source: Baskar, D., Polavarapu, K., Preethish-kumar, V., et al. (2024). Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant. Neuro Genetics. 2024; 10(1): Published: February, 2024. DOI: 10.1212/NXG.000000000020012.



Enhancing Functional Recovery Following Postpartum Femoral Neuropathy

The case report describes how an early multimodal rehabilitation program within a multidisciplinary framework allows for sooner neuromotor function improvement and activities of daily living independence.

source: Intl J Gynecol Obstet.

Summary

Early Neurorehabilitation and Multidisciplinary Obstetric Care

[Posted 5/Mar/2024]

AUDIENCE: Ob/Gyn, Neurology

KEY FINDINGS: The case report describes how an early multimodal rehabilitation program within a multidisciplinary framework allows for sooner neuromotor function improvement and activities of daily living independence.

BACKGROUND: Postpartum femoral neuropathy has a reported incidence of less than 1% and its total recovery time extends up to 6 months to a year. A multidisciplinary approach is vital to rule out permanent disability and to assure a correct diagnosis and earlier rehabilitation.

DETAILS: Authors report a case of a 37-year-old puerperal woman with a history of intrapartum epidural analgesia, who presented post-labor unilateral lower-limb motor weakness and sensory loss, with functional compromise on independent gait. A multidisciplinary team consisting of an anesthesiologist, a physiatrist, a neurologist, and an obstetrician was then established. In the initial physiatry and neurology assessment, the patient reported pain (numerical rating scale 7/10) over the inguinal ligament, lower limb hypoesthesia, and muscle weakness. Femoral neuropathy was suspected. Magnetic resonance imaging ruled out potential complications related to the anesthetic procedure. The patient was then enrolled in a supervised rehabilitation program and, 3 weeks later, electrodiagnostic studies confirmed the initial suspicion. Two months later, the patient had regained lower-limb active range of motion and no pain nor paresthesia was reported.

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Copyright © John Wiley & Sons, Inc. All rights reserved

Source: Goncalves, E. M., Lanzaro, C., Silva, L. C., et al. (2024). Enhancing Functional Recovery Following Postpartum Femoral Neuropathy: Early Neurorehabilitation and Multidisciplinary Obstetric Care. Intl J Gynecol Obstet.. 2024; 164(3): 830-834. Published: March, 2024. DOI: 10.1002/ijgo.15025.



Converging Evidence for Frontopolar Cortex as a Target for Neuromodulation in Addiction Treatment

The review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials.

source: Am J Psychiatry

Summary

[Posted 22/Feb/2024]

AUDIENCE: Psychiatry, Neurology

KEY FINDINGS: This review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials.

BACKGROUND: Noninvasive brain stimulation technologies such as transcranial electrical and magnetic stimulation (tES and TMS) are emerging neuromodulation therapies that are being used to target the neural substrates of substance use disorders.

DETAILS: By the end of 2022, 205 trials of tES or TMS in the treatment of substance use disorders had been published, with heterogeneous results, and there is still no consensus on the optimal target brain region. Recent work may help clarify where and how to apply stimulation, owing to expanding databases of neuroimaging studies, new systematic reviews, and improved methods for causal brain mapping. Whereas most previous clinical trials targeted the dorsolateral prefrontal cortex, accumulating data highlight the frontopolar cortex as a promising therapeutic target for transcranial brain stimulation in substance use disorders. This approach is supported by converging multimodal evidence, including lesion-based maps, functional MRI-based maps, tES studies, TMS studies, and dose-response relationships.

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Copyright © American Psychiatric Association. All rights reserved.

Source: Soleimani, G., Joutsa, J., Moussawi, K., et al. (2024). Converging Evidence for Frontopolar Cortex as a Target for Neuromodulation in Addiction Treatment. American Journal of Psychiatry. 2024; 181(2): 100-114. Published: February, 2024. DOI: 10.1176/appi.ajp.20221022.



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