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Antiamyloid antibodies have been used to reduce cerebral amyloid-beta (Aß) load in patients with Alzheimer's disease. We applied focused ultrasound with each of six monthly aducanumab infusions to temporarily open the blood-brain barrier with the goal of enhancing amyloid removal in selected brain regions in three participants over a period of 6 months. The reduction in the level of Aß was numerically greater in regions treated with focused ultrasound than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound, as measured by fluorine-18 florbetaben positron-emission tomography. Cognitive tests and safety evaluations were conducted over a period of 30 to 180 days after treatment. (Funded by the Harry T. Mangurian, Jr. Foundation and the West Virginia University Rockefeller Neuroscience Institute.).
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Doença de Alzheimer , Barreira Hematoencefálica , Terapia por Ultrassom , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/análise , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
Variability in brain structure is associated with the capacity for behavioral change. However, a causal link between specific brain areas and behavioral change (such as motor learning) has not been demonstrated. We hypothesized that greater gray matter volume of a primary motor cortex (M1) area active during a hand motor learning task is positively correlated with subsequent learning of the task, and that the disruption of this area blocks learning of the task. Healthy participants underwent structural MRI before learning a skilled hand motor task. Next, participants performed this learning task during fMRI to determine M1 areas functionally active during this task. This functional ROI was anatomically constrained with M1 boundaries to create a group-level "Active-M1" ROI used to measure gray matter volume in each participant. Greater gray matter volume in the left hemisphere Active-M1 ROI was related to greater motor learning in the corresponding right hand. When M1 hand area was disrupted with repetitive transcranial stimulation (rTMS), learning of the motor task was blocked, confirming its causal link to motor learning. Our combined imaging and rTMS approach revealed greater cortical volume in a task-relevant M1 area is causally related to learning of a hand motor task in healthy humans.
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Substância Cinzenta , Mãos , Aprendizagem , Imageamento por Ressonância Magnética , Córtex Motor , Estimulação Magnética Transcraniana , Humanos , Córtex Motor/fisiologia , Córtex Motor/diagnóstico por imagem , Masculino , Feminino , Mãos/fisiologia , Aprendizagem/fisiologia , Adulto , Adulto Jovem , Substância Cinzenta/fisiologia , Substância Cinzenta/diagnóstico por imagem , Destreza Motora/fisiologia , Mapeamento Encefálico , Lateralidade Funcional/fisiologiaRESUMO
BACKGROUND: While the cognitive hallmark of typical Alzheimer disease (AD) is impaired memory consolidation, increasing evidence suggests that the frontal lobes and associated executive functions are also impacted. OBJECTIVE: We examined two neurobehavioral executive function tasks and associations with cortical thickness in patients diagnosed with mild cognitive impairment (MCI), suspected AD dementia, and a healthy control group. METHODS: First, we compared group performances on a go/no-go (GNG) task and on Luria's Fist-Edge-Palm (FEP) motor sequencing task. We then examined correlations between neurobehavioral task performance and the thickness of frontal cortical regions, AD signature regions, broader unbiased brain regions, and white matter hyperintensities (WMH). RESULTS: Participants with MCI performed worse than healthy controls, but better than participants with suspected AD dementia on both tasks. Both GNG and FEP (to a slightly greater extent) tasks showed diffuse associations with most AD signature regions and multiple additional regions within the temporal, parietal, and occipital cortices. Similarly, both tasks showed significant associations with all other cognitive tasks examined. Of the frontal regions examined, only the middle frontal gyrus and pars opercularis were associated with performance on these tasks. Interactions between the precuneus and transtemporal gyri were most predictive of GNG task performance, while the interaction between superior temporal and lingual gyri was most predictive of FEP task performance. CONCLUSION: This study replicates difficulties with both GNG and FEP tasks in participants with MCI and AD dementia. Both tasks showed widespread associations with the cortical thickness of various brain structures rather than localizing to frontal regions, consistent with the diffuse nature of AD.
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Doença de Alzheimer , Disfunção Cognitiva , Função Executiva , Imageamento por Ressonância Magnética , Humanos , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Masculino , Feminino , Idoso , Função Executiva/fisiologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Testes Neuropsicológicos/estatística & dados numéricos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Desempenho Psicomotor/fisiologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.
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Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Terapia por Ultrassom/métodos , Idoso , Doença de Alzheimer/metabolismo , Transporte Biológico , Barreira Hematoencefálica/fisiologia , Encéfalo/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Microbolhas , Pessoa de Meia-Idade , Ondas Ultrassônicas , UltrassonografiaRESUMO
Background Opening of the blood-brain barrier (BBB) induced with MRI-guided focused ultrasound has been shown in experimental animal models to reduce amyloid-ß plaque burden, improve memory performance, and facilitate delivery of therapeutic agents to the brain. However, physiologic effects of this procedure in humans with Alzheimer disease (AD) require further investigation. Purpose To assess imaging effects of focused ultrasound-induced BBB opening in the hippocampus of human participants with early AD and to evaluate fluid flow patterns after BBB opening by using serial contrast-enhanced MRI. Materials and Methods Study participants with early AD recruited to a Health Insurance Portability and Accountability Act-compliant, prospective, ongoing phase II clinical trial (ClinicalTrials.gov identifier, NCT03671889) underwent three separate focused ultrasound-induced BBB opening procedures that used a 220-kHz transducer with a concomitant intravenous microbubble contrast agent administered at 2-week intervals targeting the hippocampus and entorhinal cortex between October 2018 and May 2019. Posttreatment effects and gadolinium-based contrast agent enhancement patterns were evaluated by using 3.0-T MRI. Results Three women (aged 61, 72, and 73 years) consecutively enrolled in the trial successfully completed repeated focused ultrasound-induced BBB opening of the hippocampus and entorhinal cortex. Postprocedure contrast enhancement was clearly identified within the targeted brain volumes, indicating immediate spatially precise BBB opening. Parenchymal enhancement resolved within 24 hours after all treatments, confirming BBB closure. Transient perivenous enhancement was consistently observed during the acute phase after BBB opening. Notably, contrast enhancement reappeared in the perivenular regions after BBB closure. This imaging marker is consistent with blood-meningeal barrier permeability and persisted for 24-48 hours before spontaneous resolution. No evidence of intracranial hemorrhage or other adverse effect was identified. Conclusion MRI-guided focused ultrasound-induced blood-brain barrier opening was safely performed in the hippocampi of three participants with Alzheimer disease without any adverse effects. Posttreatment MRI reveals a unique spatiotemporal contrast enhancement pattern that suggests a perivenular immunologic healing response downstream from targeted sites. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Klibanov in this issue.
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Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/diagnóstico por imagem , Sistemas de Liberação de Medicamentos/métodos , Imagem por Ressonância Magnética Intervencionista/métodos , Terapia por Ultrassom/métodos , Idoso , Meios de Contraste , Córtex Entorrinal , Feminino , Hipocampo , Humanos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
The role of primary motor cortex (M1) in the control of hand movements is still unclear. Functional magnetic resonance imaging (fMRI) studies of unimanual performance reported a relationship between level of precision of a motor task and additional ipsilateral M1 (iM1) activation. In the present study, we determined whether the demand on accuracy of a movement influences the magnitude of the inhibitory effect between primary motor cortices (IHI). We used transcranial magnetic stimulation (TMS) to measure active IHI (aIHI) of the iM1 on the contralateral M1 (cM1) in the premovement period of a left-hand motor task. Ten healthy participants manipulated a joystick to point to targets of two different sizes. For aIHI, the conditioning stimulus (CS) was applied to iM1, and the test stimulus (TS) to cM1, with an interstimulus interval of 10 ms. The amount of the inhibitory effect of the CS on the motor-evoked potential (MEP) of the subsequent TS was expressed as percentage of the mean MEP amplitude evoked by the single TS. Across different time points of aIHI measurements in the premovement period, there was a significant effect for target size on aIHI. Preparing to point to small targets was associated with weaker aIHI compared with pointing to large targets. The present findings suggest that, during the premovement period, aIHI from iM1 on cM1 is modulated by the demand on accuracy of the motor task. This is consistent with task fMRI findings showing bilateral M1 activation during high-precision movements but only unilateral M1 activity during low-precision movements.
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Lateralidade Funcional/fisiologia , Córtex Motor/fisiologia , Destreza Motora/fisiologia , Inibição Neural/fisiologia , Idoso , Eletromiografia , Potencial Evocado Motor/fisiologia , Feminino , Mãos/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/diagnóstico por imagem , Músculo Esquelético/fisiologia , Testes Neuropsicológicos , Tempo de Reação , Estimulação Magnética TranscranianaAssuntos
Amnésia/induzido quimicamente , Transtornos Relacionados ao Uso de Cocaína/complicações , Fentanila/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/complicações , Adulto , Amnésia/diagnóstico por imagem , Amnésia/patologia , Globo Pálido/diagnóstico por imagem , Globo Pálido/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Masculino , SíndromeRESUMO
INTRODUCTION: Older adults living alone in rural areas frequently experience health declines, social isolation, and limited access to services. To address these challenges, our medical academic university supported a quality improvement project for developing and evaluating the Visiting Neighbors program in two rural Appalachian counties. Our Visiting Neighbors program trained local volunteers to visit and guide rural older adults in healthy activities. These age-appropriate activities (Mingle, Manage, and Move- 3M's) were designed to improve the functional health of older adults. The program includes four in-home visits and four follow-up telephone calls across three months. PURPOSE: The purpose of this paper was to describe the 3M's Visiting Neighbors protocol steps guiding the quality improvement procedures relating to program development, implementation, and evaluation. METHODS AND MATERIALS: This Visiting Neighbors study used a single-group exploratory quality improvement design. This program was tested using quality improvement standards, including collecting participant questionnaires and visit observations. RESULTS: Older adults (> 65 years) living alone (N = 30) participants were female (79%) with a mean age of 82.96 (SD = 7.87) years. Volunteer visitor participants (N = 10) were older adult females. Two volunteer visitors implemented each visit, guided by the 3M's activities manual. All visits were verified as being consistently delivered (fidelity). Enrollment and retention data found the program was feasible to conduct. The older adult participants' total program helpfulness ratings (1 to 5) were high (M = 51.27, SD = 3.77). All volunteer visitor's program helpfulness ratings were also high (M = 51.78, SD = 3.73). DISCUSSION: The Visiting Neighbors program consistently engaged older Appalachian adults living alone in the 3M's activities. The feasibility and fidelity of the 3M's home visits were verified. The quality improvement processes included engaging the expert advisory committee and rural county stakeholders to ensure the quality of the program development, implementation, and evaluation.
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Melhoria de Qualidade , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Avaliação de Programas e Projetos de Saúde/métodos , Desenvolvimento de Programas , Região dos Apalaches , Inquéritos e QuestionáriosRESUMO
Background: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are typically associated with very different clinical and neuroanatomical presentations; however, there is increasing recognition of similarities. Objective: To examine memory and executive functions, as well as cortical thickness, and glucose metabolism in AD and bvFTD signature brain regions. Methods: We compared differences in a group of biomarker-defined participants with Alzheimer's disease and a group of clinically diagnosed participants with bvFTD. These groups were also contrasted with healthy controls (HC). Results: As expected, memory functions were generally more impaired in AD, followed by bvFTD, and both clinical groups performed more poorly than the HC group. Executive function measures were similar in AD compared to bvFTD for motor sequencing and go/no-go, but bvFTD had more difficulty with a set shifting task. Participants with AD showed thinner cortex and lower glucose metabolism in the angular gyrus compared to bvFTD. Participants with bvFTD had thinner cortex in the insula and temporal pole relative to AD and healthy controls, but otherwise the two clinical groups were similar for other frontal and temporal signature regions. Conclusions: Overall, the results of this study highlight more similarities than differences between AD and bvFTD in terms of cognitive functions, cortical thickness, and glucose metabolism. Further research is needed to better understand the mechanisms mediating this overlap and how these relationships evolve longitudinally.
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INTRODUCTION: Memory deficits are the primary symptom in amnestic Mild Cognitive Impairment (aMCI); however, executive function (EF) deficits are common. The current study examined EF in aMCI based upon amyloid status (A+/A-) and regional atrophy in signature areas of Alzheimer's disease (AD). METHOD: Participants included 110 individuals with aMCI (A+ = 66; A- = 44) and 33 cognitively healthy participants (HP). EF was assessed using four neuropsychological assessment measures. The cortical thickness of the AD signature areas was calculated using structural MRI data. RESULTS: A + had greater EF deficits and cortical atrophy relative to A - in the supramarginal gyrus and superior parietal lobule. A - had greater EF deficits relative to HP, but no difference in signature area cortical thickness. DISCUSSION: The current study found that the degree of EF deficits in aMCI are a function of amyloid status and cortical thinning in the parietal cortex.
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OBJECTIVE: There were more than 107,000 drug overdose deaths in the US in 2021, the most ever recorded. Despite advances in behavioral and pharmacological treatments, over 50% of those receiving treatment for opioid use disorder (OUD) experience drug use recurrence (relapse). Given the prevalence of OUD and other substance use disorders (SUDs), the high rate of drug use recurrence, and the number of drug overdose deaths, novel treatment strategies are desperately needed. The objective of this study was to evaluate the safety and feasibility of deep brain stimulation (DBS) targeting the nucleus accumbens (NAc)/ventral capsule (VC) and potential impact on outcomes in individuals with treatment-refractory OUD. METHODS: A prospective, open-label, single-arm study was conducted among participants with longstanding treatment-refractory OUD (along with other co-occurring SUDs) who underwent DBS in the NAc/VC. The primary study endpoint was safety; secondary/exploratory outcomes included opioid and other substance use, substance craving, and emotional symptoms throughout follow-up and 18FDG-PET neuroimaging. RESULTS: Four male participants were enrolled and all tolerated DBS surgery well with no serious adverse events (AEs) and no device- or stimulation-related AEs. Two participants sustained complete substance abstinence for > 1150 and > 520 days, respectively, with significant post-DBS reductions in substance craving, anxiety, and depression. One participant experienced post-DBS drug use recurrences with reduced frequency and severity. The DBS system was explanted in one participant due to noncompliance with treatment requirements and the study protocol. 18FDG-PET neuroimaging revealed increased glucose metabolism in the frontal regions for the participants with sustained abstinence only. CONCLUSIONS: DBS of the NAc/VC was safe, feasible, and can potentially reduce substance use, craving, and emotional symptoms in those with treatment-refractory OUD. A randomized, sham-controlled trial in a larger cohort of patients is being initiated.
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Estimulação Encefálica Profunda , Overdose de Drogas , Transtornos Relacionados ao Uso de Opioides , Humanos , Masculino , Núcleo Accumbens/diagnóstico por imagem , Estimulação Encefálica Profunda/métodos , Fluordesoxiglucose F18 , Estudos Prospectivos , Estudos de Viabilidade , Recidiva Local de Neoplasia , Transtornos Relacionados ao Uso de Opioides/terapiaRESUMO
Amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) dementia are characterized by pathological changes to the medial temporal lobes, resulting in explicit learning and retention reductions. Studies demonstrate that implicit/procedural memory processes are relatively intact in these populations, supporting different anatomical substrates for differing memory systems. This study examined differences between explicit and procedural learning and retention in individuals with aMCI and AD dementia relative to matched healthy controls. We also examined anatomical substrates using volumetric MRI. Results revealed expected difficulties with explicit learning and retention in individuals with aMCI and AD with relatively preserved procedural memory. Explicit verbal retention was associated with medial temporal cortex volumes. However, procedural retention was not related to medial temporal or basal ganglia volumes. Overall, this study confirms the dissociation between explicit relative to procedural learning and retention in aMCI and AD dementia and supports differing anatomical substrates.
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BACKGROUND: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer's disease (AD). METHODS: At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI. RESULTS: Post-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24-48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant. CONCLUSIONS: FUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018.
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Doença de Alzheimer , Barreira Hematoencefálica , Idoso , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Ultrassonografia , Masculino , FemininoRESUMO
Alzheimer's disease is primarily known for deficits in learning and retaining new information. This has long been associated with pathological changes in the mesial temporal lobes. The role of the frontal lobes in memory in Alzheimer's disease is less well understood. In this study, we examined the role of the frontal lobes in learning, recognition, and retention of new verbal information, as well as the presence of specific errors (i.e., intrusions and false-positive errors). Participants included one hundred sixty-seven patients clinically diagnosed with amnestic mild cognitive impairment or suspected Alzheimer's disease dementia who were administered the California Verbal Learning Test and completed high-resolution MRI. We confirmed the role of the mesial temporal lobes in learning and retention, including the volumes of the hippocampus, entorhinal cortex, and parahippocampal gyrus. In addition, false-positive errors were associated with all volumes of the mesial temporal lobes and widespread areas within the frontal lobes. Errors of intrusion were related to the supplementary motor cortex and hippocampus. Most importantly, the mesial temporal lobes interacted with the frontal lobes for learning, recognition, and memory errors. Lower volumes in both regions explained more performance variance than any single structure. This study supports the interaction of the frontal lobes with the temporal lobes in many aspects of memory in Alzheimer's disease.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia , Reconhecimento Psicológico , Hipocampo , Imageamento por Ressonância Magnética , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Aprendizagem Verbal , Testes NeuropsicológicosRESUMO
BACKGROUND: After stroke, increases in contralesional primary motor cortex (M1CL) activity and excitability have been reported. In pre-clinical studies, M1CL reorganization is related to the extent of ipsilesional M1 (M1IL) injury, but this has yet to be tested clinically. OBJECTIVES: We tested the hypothesis that the extent of damage to the ipsilesional M1 and/or its corticospinal tract (CST) determines the magnitude of M1CL reorganization and its relationship to affected hand function in humans recovering from stroke. METHODS: Thirty-five participants with a single subacute ischemic stroke affecting M1 or CST and hand paresis underwent MRI scans of the brain to measure lesion volume and CST lesion load. Transcranial magnetic stimulation (TMS) of M1IL was used to determine the presence of an electromyographic response (motor evoked potential (MEP+ and MEP-)). M1CL reorganization was determined by TMS applied to M1CL at increasing intensities. Hand function was quantified with the Jebsen Taylor Hand Function Test. RESULTS: The extent of M1CL reorganization was related to greater lesion volume in the MEP- group, but not in the MEP+ group. Greater M1CL reorganization was associated with more impaired hand function in MEP- but not MEP+ participants. Absence of an MEP (MEP-), larger lesion volumes and higher lesion loads in CST, particularly in CST fibers originating in M1 were associated with greater impairment of hand function. CONCLUSIONS: In the subacute post-stroke period, stroke volume and M1IL output determine the extent of M1CL reorganization and its relationship to affected hand function, consistent with pre-clinical evidence.ClinicalTrials.gov Identifier: NCT02544503.
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Córtex Motor , Acidente Vascular Cerebral , Humanos , Volume Sistólico , Encéfalo , Estimulação Magnética Transcraniana , Potencial Evocado Motor/fisiologiaRESUMO
Composite cognitive measures in large-scale studies with biomarker data for amyloid and tau have been widely used to characterize Alzheimer's disease (AD). However, little is known about how the findings from these studies translate to memory clinic populations without biomarker data, using single measures of cognition. Additionally, most studies have utilized voxel-based morphometry or limited surface-based morphometry such as cortical thickness, to measure the neurodegeneration associated with cognitive deficits. In this study, we aimed to replicate and extend the biomarker, composite study relationships using expanded surface-based morphometry and single measures of cognition in a memory clinic population. We examined 271 clinically diagnosed symptomatic individuals with mild cognitive impairment (N = 93) and Alzheimer's disease dementia (N = 178), as well as healthy controls (N = 29). Surface-based morphometry measures included cortical thickness, sulcal depth, and gyrification index within the "signature areas" of Alzheimer's disease. The cognitive variables pertained to hallmark features of Alzheimer's disease including verbal learning, verbal memory retention, and language, as well as executive function. The results demonstrated that verbal learning, language, and executive function correlated with the cortical thickness of the temporal, frontal, and parietal areas. Verbal memory retention was correlated to the thickness of temporal regions and gyrification of the inferior temporal gyrus. Language was related to the temporal regions and the supramarginal gyrus' sulcal depth and gyrification index. Executive function was correlated with the medial temporal gyrus and supramarginal gyrus sulcal depth, and the gyrification index of temporal regions and supramarginal gyrus, but not with the frontal areas. Predictions of each of these cognitive measures were dependent on a combination of structures and each of the morphometry measurements, and often included medial temporal gyrus thickness and sulcal depth. Overall, the results demonstrated that the relationships between cortical thinning and cognition are widespread and can be observed using single measures of cognition in a clinically diagnosed AD population. The utility of sulcal depth and gyrification index measures may be more focal to certain brain areas and cognitive measures. The relative importance of temporal, frontal, and parietal regions in verbal learning, language, and executive function, but not verbal memory retention, was replicated in this clinic cohort.
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Introduction: While current treatments for substance use disorder (SUD) are beneficial, success rates remain low and treatment outcomes are complicated by co-occurring SUDs, many of which are without available medication treatments. Research involving neuromodulation for SUD has recently gained momentum. This study evaluated two doses (60 and 90 W) of Low Intensity Focused Ultrasound (LIFU), targeting the bilateral nucleus accumbens (NAc), in individuals with SUD. Methods: Four participants (three male), who were receiving comprehensive outpatient treatment for opioid use disorder at the time of enrollment and who also had a history of excessive non-opioid substance use, completed this pilot study. After confirming eligibility, these participants received 10 min sham LIFU followed by 20 min active LIFU (10 min to left then right NAc). Outcomes were the safety, tolerability, and feasibility during the LIFU procedure and throughout the 90-day follow-up. Outcomes also included the impact of LIFU on cue-induced substance craving, assessed via Visual Analog Scale (VAS), both acutely (pre-, during and post-procedure) and during the 90-day follow-up. Daily craving ratings (without cues) were also obtained for one-week prior to and one-week following LIFU. Results: Both LIFU doses were safe and well-tolerated based on reported adverse events and MRI scans revealed no structural changes (0 min, 24 h, and 1-week post-procedure). For the two participants receiving "enhanced" (90 W) LIFU, VAS craving ratings revealed active LIFU attenuated craving for participants' primary substances of choice relative to sham sonication. For these participants, reductions were also noted in daily VAS craving ratings (0 = no craving; 10 = most craving ever) across the week following LIFU relative to pre-LIFU; Participant #3 pre- vs. post-LIFU: opioids (3.6 ± 0.6 vs. 1.9 ± 0.4), heroin (4.2 ± 0.8 vs. 1.9 ± 0.4), methamphetamine (3.2 ± 0.4 vs. 0.0 ± 0.0), cocaine (2.4 ± 0.6 vs. 0.0 ± 0.0), benzodiazepines (2.8 ± 0.5 vs. 0.0 ± 0.0), alcohol (6.0 ± 0.7 vs. 2.7 ± 0.8), and nicotine (5.6 ± 1.5 vs. 3.1 ± 0.7); Participant #4: alcohol (3.5 ± 1.3 vs. 0.0 ± 0.0) and nicotine (5.0 ± 1.8 vs. 1.2 ± 0.8) (all p's < 0.05). Furthermore, relative to screening, longitudinal reductions in cue-induced craving for several substances persisted during the 90-day post-LIFU follow-up evaluation for all participants. Discussion: In conclusion, LIFU targeting the NAc was safe and acutely reduced substance craving during the LIFU procedure, and potentially had longer-term impact on craving reductions. While early observations are promising, NAc LIFU requires further investigation in a controlled trial to assess the impact on substance craving and ultimately substance use and relapse.
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OBJECTIVE: MRI-guided low-intensity focused ultrasound (FUS) has been shown to reversibly open the blood-brain barrier (BBB), with the potential to deliver therapeutic agents noninvasively to target brain regions in patients with Alzheimer's disease (AD) and other neurodegenerative conditions. Previously, the authors reported the short-term safety and feasibility of FUS BBB opening of the hippocampus and entorhinal cortex (EC) in patients with AD. Given the need to treat larger brain regions beyond the hippocampus and EC, brain volumes and locations treated with FUS have now expanded. To evaluate any potential adverse consequences of BBB opening on disease progression, the authors report safety, imaging, and clinical outcomes among participants with mild AD at 6-12 months after FUS treatment targeted to the hippocampus, frontal lobe, and parietal lobe. METHODS: In this open-label trial, participants with mild AD underwent MRI-guided FUS sonication to open the BBB in ß-amyloid positive regions of the hippocampus, EC, frontal lobe, and parietal lobe. Participants underwent 3 separate FUS treatment sessions performed 2 weeks apart. Outcome assessments included safety, imaging, neurological, cognitive, and florbetaben ß-amyloid PET. RESULTS: Ten participants (range 55-76 years old) completed 30 separate FUS treatments at 2 participating institutions, with 6-12 months of follow-up. All participants had immediate BBB opening after FUS and BBB closure within 24-48 hours. All FUS treatments were well tolerated, with no serious adverse events related to the procedure. All 10 participants had a minimum of 6 months of follow-up, and 7 participants had a follow-up out to 1 year. Changes in the Alzheimer's Disease Assessment Scale-cognitive and Mini-Mental State Examination scores were comparable to those in controls from the Alzheimer's Disease Neuroimaging Initiative. PET scans demonstrated an average ß-amyloid plaque of 14% in the Centiloid scale in the FUS-treated regions. CONCLUSIONS: This study is the largest cohort of participants with mild AD who received FUS treatment, and has the longest follow-up to date. Safety was demonstrated in conjunction with reversible and repeated BBB opening in multiple cortical and deep brain locations, with a concomitant reduction of ß-amyloid. There was no apparent cognitive worsening beyond expectations up to 1 year after FUS treatment, suggesting that the BBB opening treatment in multiple brain regions did not adversely influence AD progression. Further studies are needed to determine the clinical significance of these findings. FUS offers a unique opportunity to decrease amyloid plaque burden as well as the potential to deliver targeted therapeutics to multiple brain regions in patients with neurodegenerative disorders.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Humanos , Pessoa de Meia-Idade , Idoso , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/terapia , Placa Amiloide , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismo , CogniçãoRESUMO
Abnormal contralesional M1 activity is consistently reported in patients with compromised upper limb and hand function after stroke. The underlying mechanisms and functional implications of this activity are not clear, which hampers the development of treatment strategies targeting this brain area. The goal of the present study was to determine the extent to which contralesional M1 activity can be explained by the demand of a motor task, given recent evidence for increasing ipsilateral M1 activity with increasing demand in healthy age-matched controls. We hypothesized that higher activity in contralesional M1 is related to greater demand on precision in a hand motor task. fMRI data were collected from 19 patients with ischemic stroke affecting hand function in the subacute recovery phase and 31 healthy, right-handed, age-matched controls. The hand motor task was designed to parametrically modulate the demand on movement precision. Electromyography data confirmed strictly unilateral task performance by all participants. Patients showed significant impairment relative to controls in their ability to perform the task in the fMRI scanner. However, patients and controls responded similarly to an increase in demand for precision, with better performance for larger targets and poorer performance for smaller targets. Patients did not show evidence of elevated ipsilesional or contralesional M1 blood oxygenation level-dependent (BOLD) activation relative to healthy controls and mean BOLD activation levels were not elevated for patients with poorer performance relative to patients with better task performance. While both patients and healthy controls showed demand-dependent increases in BOLD activation in both ipsilesional/contralateral and contralesional/ipsilateral hemispheres, patients with stroke were less likely to show evidence of a linear relationship between the demand on precision and BOLD activation in contralesional M1 than healthy controls. Taken together, the findings suggest that task demand affects the BOLD response in contralesional M1 in patients with stroke, though perhaps less strongly than in healthy controls. This has implications for the interpretation of reported abnormal bilateral M1 activation in patients with stroke because in addition to contralesional M1 reorganization processes it could be partially related to a response to the relatively higher demand of a motor task when completed by patients rather than by healthy controls.