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Abstract INTRODUCTION Commercially available plasma p‐tau217 biomarker tests are not well studied in ethnically diverse samples. METHODS We evaluated associations between ALZPath plasma p‐tau217 and amyloid‐beta positron emission tomography (Aβ‐PET) in Hispanic/Latino (88% of Cuban or South American ancestry) and non‐Hispanic/Latino older adults. One‐ and two‐cutoff ranges were derived and evaluated to assess agreement with Aβ‐PET. RESULTS A total of 239 participants underwent blood draw and Aβ‐PET (age 70.8 ± 7.8, 55.2% female, education 15.6 ± 3.4 years, 48.9% Hispanic/Latino, 94.9% white). Plasma p‐tau217 showed excellent discrimination of Aβ‐PET positive and negative participants (visual read: AUC = 0.91 [0.87–0.95], p

Abstract Background Restricted repetitive behavior (RRB) is one of two behavioral domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding brain alterations linked to RRB. Methods We utilized neuroimaging data from the National Institute of Mental Health Data Archive to assess basal ganglia and cerebellum structure in a cohort of children and adolescents with ASD compared to typically developing (TD) controls. We evaluated regional gray matter volumes from T1-weighted anatomical scans and assessed diffusion-weighted scans to quantify white matter microstructure with free-water imaging. We also investigated the interaction of biological sex and ASD diagnosis on these measures, and their correlation with clinical scales of RRB. Results Individuals with ASD had significantly lower free-water corrected fractional anisotropy (FAT) and higher free-water (FW) in cortico-basal ganglia white matter tracts. These microstructural differences did not interact with biological sex. Moreover, both FAT and FW in basal ganglia white matter tracts significantly correlated with measures of RRB. In contrast, we found no significant difference in basal ganglia or cerebellar gray matter volumes. Limitations The basal ganglia and cerebellar regions in this study were selected due to their hypothesized relevance to RRB. Differences between ASD and TD individuals that may occur outside the basal ganglia and cerebellum, and their potential relationship to RRB, were not evaluated. Conclusions These new findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FAT was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure. Future diffusion imaging investigations in ASD may benefit from free-water estimation and correction in order to better understand how white matter is affected in ASD, and how such measures are linked to RRB.

IntroductionPlasma Aβ42/40 ratio can help predict amyloid PET status, but its clinical utility in Alzheimer’s disease (AD) assessment is unclear.MethodsAβ42/40 ratio was measured by LC-MS/MS for 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and for 6,192 consecutive clinical specimens submitted for Aβ42/40 testing.ResultsHigh diagnostic sensitivity and negative predictive value (NPV) for Aβ-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aβ42/40 values for individuals with positive vs. negative Aβ-PET results. Assuming a moderate prevalence of Aβ-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients’ cognitive impairment and help reduce PET evaluation by about 40%.ConclusionHigh-throughput plasma Aβ42/40 LC-MS/MS assays can help identify patients with low likelihood of AD pathology, which can reduce PET evaluations, allowing for cost savings.

Abstract Objective measures of disease progression are critically needed in research on Parkinson’s disease (PD) and atypical Parkinsonism but may be hindered by both practicality and cost. The Purdue Pegboard Test (PPT) is objective, has high test-retest reliability, and has a low cost. The goals of this study were to determine: (1) longitudinal changes in PPT in a multisite cohort of patients with PD, atypical Parkinsonism, and healthy controls; (2) whether PPT performance reflects brain pathology revealed by neuroimaging; (3) quantify kinematic deficits shown by PD patients during PPT. Parkinsonian patients showed a decline in PPT performance that correlated with motor symptom progression, which was not seen in controls. Neuroimaging measures from basal ganglia were significant predictors of PPT performance in PD, whereas cortical, basal ganglia, and cerebellar regions were predictors for atypical Parkinsonism. Accelerometry in a subset of PD patients showed a diminished range of acceleration and irregular patterns of acceleration, which correlated with PPT scores.

Early detection of Alzheimer’s disease (AD) during the Mild Cognitive Impairment (MCI) stage could enable effective intervention to slow down disease progression. Computer-aided diagnosis of AD relies on a sufficient amount of biomarker data. When this requirement is not fulfilled, transfer learning can be used to transfer knowledge from a source domain with more amount of labeled data than available in the desired target domain. In this study, an instance-based transfer learning framework is presented based on the gradient boosting machine (GBM). In GBM, a sequence of base learners is built, and each learner focuses on the errors (residuals) of the previous learner. In our transfer learning version of GBM (TrGB), a weighting mechanism based on the residuals of the base learners is defined for the source instances. Consequently, instances with different distribution than the target data will have a lower impact on the target learner. The proposed weighting scheme aims to transfer as much information as possible from the source domain while avoiding negative transfer. The target data in this study was obtained from the Mount Sinai dataset which is collected and processed in a collaborative 5-year project at the Mount Sinai Medical Center. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset was used as the source domain. The experimental results showed that the proposed TrGB algorithm could improve the classification accuracy by 1.5 and 4.5% for CN vs. MCI and multiclass classification, respectively, as compared to the conventional methods. Also, using the TrGB model and transferred knowledge from the CN vs. AD classification of the source domain, the average score of early MCI vs. late MCI classification improved by 5%.

Advanced diffusion imaging which accounts for complex tissue properties, such as crossing fibers and extracellular fluid, may detect longitudinal changes in widespread pathology in atypical Parkinsonian syndromes. We implemented fixel-based analysis, Neurite Orientation and Density Imaging (NODDI), and free-water imaging in Parkinson’s disease (PD), multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and controls longitudinally over one year. Further, we used these three advanced diffusion imaging techniques to investigate longitudinal progression-related effects in key white matter tracts and gray matter regions in PD and two common atypical Parkinsonian disorders. Fixel-based analysis and free-water imaging revealed longitudinal declines in a greater number of descending sensorimotor tracts in MSAp and PSP compared to PD. In contrast, only the primary motor descending sensorimotor tract had progressive decline over one year, measured by fiber density (FD), in PD compared to that in controls. PSP was characterized by longitudinal impairment in multiple transcallosal tracts (primary motor, dorsal and ventral premotor, pre-supplementary motor, and supplementary motor area) as measured by FD, whereas there were no transcallosal tracts with longitudinal FD impairment in MSAp and PD. In addition, free-water (FW) and FW-corrected fractional anisotropy (FAt) in gray matter regions showed longitudinal changes over one year in regions that have previously shown cross-sectional impairment in MSAp (putamen) and PSP (substantia nigra, putamen, subthalamic nucleus, red nucleus, and pedunculopontine nucleus). NODDI did not detect any longitudinal white matter tract progression effects and there were few effects in gray matter regions across Parkinsonian disorders. All three imaging methods were associated with change in clinical disease severity across all three Parkinsonian syndromes. These results identify novel extra-nigral and extra-striatal longitudinal progression effects in atypical Parkinsonian disorders through the application of multiple diffusion methods that are related to clinical disease progression. Moreover, the findings suggest that fixel-based analysis and free-water imaging are both particularly sensitive to these longitudinal changes in atypical Parkinsonian disorders.

In addition to the well-established somatotopy in the pre- and post-central gyrus, there is now strong evidence that somatotopic organization is evident across other regions in the sensorimotor network. This raises several experimental questions: To what extent is activity in the sensorimotor network effector-dependent and effector-independent? How important is the sensorimotor cortex when predicting the motor effector? Is there redundancy in the distributed somatotopically organized network such that removing one region has little impact on classification accuracy? To answer these questions, we developed a novel experimental approach. fMRI data were collected while human subjects performed a precisely controlled force generation task separately with their hand, foot, and mouth. We used a simple linear iterative clustering (SLIC) algorithm to segment whole-brain beta coefficient maps to build an adaptive brain parcellation and then classified effectors using extreme gradient boosting (XGBoost) based on parcellations at various spatial resolutions. This allowed us to understand how data-driven adaptive brain parcellation granularity altered classification accuracy. Results revealed effector-dependent activity in regions of the post-central gyrus, precentral gyrus, and paracentral lobule. SMA, regions of the inferior and superior parietal lobule, and cerebellum each contained effector-dependent and effector-independent representations. Machine learning analyses showed that increasing the spatial resolution of the data-driven model increased classification accuracy, which reached 94% with 1755 supervoxels. Our SLIC-based supervoxel parcellation outperformed classification analyses using established brain templates and random simulations. Occlusion experiments further demonstrated redundancy across the sensorimotor network when classifying effectors. Our observations extend our understanding of effector-dependent and effector-independent organization within the human brain and provide new insight into the functional neuroanatomy required to predict the motor effector used in a motor control task.

Dystonia is a neurological movement disorder characterized by sustained or intermittent muscle contractions, repetitive movement, and sometimes abnormal postures. DYT1 dystonia is one of the most common genetic dystonias, and most patients carry heterozygous DYT1 ∆GAG mutations causing a loss of a glutamic acid of the protein torsinA. Patients can be treated with anticholinergics, such as trihexyphenidyl, suggesting an abnormal cholinergic state. Early work on the cell-autonomous effects of Dyt1 deletion with ChI-specific Dyt1 conditional knockout mice (Dyt1 Ch1KO) revealed abnormal electrophysiological responses of striatal ChIs to muscarine and quinpirole, motor deficits, and no changes in the number or size of the ChIs. However, the Chat-cre line that was used to derive Dyt1 Ch1KO mice contained a neomycin cassette and was reported to have ectopic cre-mediated recombination. In this study, we generated a Dyt1 Ch2KO mouse line by removing the neomycin cassette in Dyt1 Ch1KO mice. The Dyt1 Ch2KO mice showed abnormal paw clenching behavior, motor coordination and balance deficits, impaired motor learning, reduced striatal choline acetyltransferase protein level, and a reduced number of striatal ChIs. Furthermore, the mutant striatal ChIs had a normal muscarinic inhibitory function, impaired quinpirole-mediated inhibition, and altered current density. Our findings demonstrate a cell-autonomous effect of Dyt1 deletion on the striatal ChIs and a critical role for the striatal ChIs and corticostriatal pathway in the pathogenesis of DYT1 dystonia.

Integrating visual information for motor output is an essential process of visually-guided motor control. The brainstem is known to be a major center involved in the integration of sensory information for motor output, however, limitations of functional imaging in humans have impaired our knowledge about the individual roles of sub-nuclei within the brainstem. Thus, the bulk of our knowledge surrounding the function of the brainstem is based on anatomical and behavioral studies in non-human primates, cats, and rodents, despite studies demonstrating differences in the organization of visuomotor processing between mammals. fMRI studies in humans have examined activity related to visually-guided motor tasks, however, few have done so while controlling for both force without visual feedback activity and visual stimuli without force activity. Of the studies that have controlled for both conditions, none have reported brainstem activity. Here, we employed a novel fMRI paradigm focused on the brainstem and cerebellum to systematically investigate the hypothesis that the pons and midbrain are critical for the integration of visual information for motor control. Visuomotor activity during visually-guided pinch-grip force was measured while controlling for force without visual feedback activity and visual stimuli without force activity in healthy adults. Using physiological noise correction and multiple task repetitions, we demonstrated that visuomotor activity occurs in the inferior portion of the basilar pons and the midbrain. These findings provide direct evidence in humans that the pons and midbrain support the integration of visual information for motor control. We also determined the effect of physiological noise and task repetitions on the visuomotor signal that will be useful in future studies of neurodegenerative diseases affecting the brainstem.

DYT1 early-onset generalized torsion dystonia is a hereditary movement disorder characterized by abnormal postures and repeated movements. It is caused mainly by a heterozygous trinucleotide deletion in DYT1/TOR1A, coding for torsinA. The mutation may lead to a partial loss of torsinA function. Functional alterations of the basal ganglia circuits have been implicated in this disease. Striatal dopamine receptor 2 (D2R) levels are significantly decreased in DYT1 dystonia patients and in the animal models of DYT1 dystonia. D2R-expressing cells, such as the medium spiny neurons in the indirect pathway, striatal cholinergic interneurons, and dopaminergic neurons in the basal ganglia circuits, contribute to motor performance. However, the function of torsinA in these neurons and its contribution to the motor symptoms is not clear. Here, D2R-expressing-cell-specific Dyt1 conditional knockout (d2KO) mice were generated and in vivo effects of torsinA loss in the corresponding cells were examined. The Dyt1 d2KO mice showed significant reductions of striatal torsinA, acetylcholine metabolic enzymes, Tropomyosin receptor kinase A (TrkA), and cholinergic interneurons. The Dyt1 d2KO mice also showed significant reductions of striatal D2R dimers and tyrosine hydroxylase without significant alteration in striatal monoamine contents or the number of dopaminergic neurons in the substantia nigra. The Dyt1 d2KO male mice showed motor deficits in the accelerated rotarod and beam-walking tests without overt dystonic symptoms. Moreover, the Dyt1 d2KO male mice showed significant correlations between striatal monoamines and locomotion. The results suggest that torsinA in the D2R-expressing cells play a critical role in the development or survival of the striatal cholinergic interneurons, expression of striatal D2R mature form, and motor performance. Medical interventions to compensate for the loss of torsinA function in these neurons may affect the onset and symptoms of this disease.

We investigated the effect of acute levodopa administration on movement-related cortical oscillations and movement velocity in Parkinson's disease (PD). Patients with PD on and off medication and age- and sex-matched healthy controls performed a ballistic upper limb flexion movement as fast and accurately as possible while cortical oscillations were recorded with high-density electroencephalography. Patients off medication were also studied using task-based functional magnetic resonance imaging (fMRI) using a force control paradigm. Percent signal change of functional activity during the force control task was calculated for the putamen and subthalamic nucleus (STN) contralateral to the hand tested. We found that patients with PD off medication had an exaggerated movement-related beta-band (13–30 Hz) desynchronization in the supplementary motor area (SMA) compared to controls. In PD, spectral power in the beta-band was correlated with movement velocity. Following an acute dose of levodopa, we observed that the beta-band desynchronization in the SMA was reduced in PD, and was associated with increased movement velocity and increased voltage of agonist muscle activity. Further, using fMRI we found that the functional activity in the putamen and STN in the off medication state, was related to how responsive that cortical oscillations in the SMA of PD were to levodopa. Collectively, these findings provide the first direct evaluation of how movement-related cortical oscillations relate to movement velocity during the ballistic phase of movement in PD and demonstrate that functional brain activity in the basal ganglia pathways relate to the effects of dopaminergic medication on cortical neuronal oscillations during movement. Keywords: Parkinson's disease, Ballistic movements, Levodopa, EEG, Supplementary motor area, fMRI

Multiple lines of evidence implicate striatal dysfunction in the pathogenesis of dystonia, including in DYT1, a common inherited form of the disease. The impact of striatal dysfunction on connected motor circuits and their interaction with other brain regions is poorly understood. Conditional knock-out (cKO) of the DYT1 protein torsinA from forebrain cholinergic and GABAergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to antimuscarinic drugs. We performed diffusion MRI and resting-state functional MRI on cKO mice of either sex to define abnormalities of diffusivity and functional connectivity in cortical, subcortical, and cerebellar networks. The striatum was the only region to exhibit an abnormality of diffusivity, indicating a selective microstructural deficit in cKO mice. The striatum of cKO mice exhibited widespread increases in functional connectivity with somatosensory cortex, thalamus, vermis, cerebellar cortex and nuclei, and brainstem. The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1 dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network. These findings have important implications for the assignment of a causative region in CNS disease.

For adults age 65 and older, the brain shows acute functional connectivity decreases after total knee arthroplasty with the severity of change predicted by preoperative cognitive function and brain disease burden. The extent of acute structural microstructural brain changes acutely after surgery remains unknown within the literature. For the current study, we report on the severity of acute post-surgery microstructural brain changes as measured by diffusion imaging and free-water analysis. Participants who underwent total knee arthroplasty under general anesthesia and non-surgery peers were part of a federally funded prospective cohort investigation involving participants. Recruitment occurred between 2013 and 2017. Data were collected in outpatient and inpatient settings within a university-affiliated medical center. A total of 232 TKA patients were referred by the study surgeon and contacted for study inclusion. Of these, 78 met inclusion and exclusion criteria and completed assessment. Five participants were excluded due to anesthetic protocol changes (spinal instead of general) with an additional 12 excluded for imaging-related complications. The total included sample size was 61. A total of 127 non-surgery participants were screened with 66 enrolled. One non-surgery participant was excluded for an imaging-related complication. Total knee arthroplasty and general anesthetic protocols were standardized. Participants received preoperative neurocognitive assessment and brain magnetic resonance imaging, with repeat imaging 48 h after surgery or pseudo surgery. Free-water analyses were performed using diffusion weighted images and tract-based spatial statistics with baseline cognitive data used to predict free-water changes. Surgery participants had widespread increases in white matter free-water. Surgery participants with higher cognitive functions as measured by immediate memory and less evidence of brain atrophy and disease (i.e., brain integrity) had greater free-water increase. Non-surgery peers had no free-water change. We interpret the surgery group’s free-water change as indicating widespread brain white matter glial response, with greater change indicative of better brain response to the acute surgery/anesthesia experience.

Objective: A prior longitudinal study demonstrates that free-water diffusion magnetic resonance imaging (dMRI) tracks progression in the substantia nigra (Ofori et al., 2015b). Here, we test the acute effects of antiparkinsonian medication on this established imaging progression marker for the first time. Methods: Fifteen PD patients underwent dMRI OFF and ON-medication one day apart. ON-medication, patients were tested approximately 45 min after their usual dose of antiparkinsonian medication. OFF-medication, patients were tested after not taking antiparkinsonian medication for >12 h. OFF and ON-medication was counter-balanced across subjects. For dMRI, we computed free-water and free-water corrected fractional anisotropy (FAt) within the following regions: caudate, putamen, substantia nigra, and subthalamic nucleus. Results: ON-medication significantly reduced parkinsonian motor symptoms compared with OFF-medication (p

Developing in vivo functional and structural neuroimaging assays in Dyt1 ΔGAG heterozygous knock-in (Dyt1 KI) mice provide insight into the pathophysiology underlying DYT1 dystonia. In the current study, we examined in vivo functional connectivity of large-scale cortical and subcortical networks in Dyt1 KI mice and wild-type (WT) controls using resting-state functional magnetic resonance imaging (MRI) and an independent component analysis. In addition, using diffusion MRI we examined how structural integrity across the basal ganglia and cerebellum directly relates to impairments in functional connectivity. Compared to WT mice, Dyt1 KI mice revealed increased functional connectivity across the striatum, thalamus, and somatosensory cortex; and reduced functional connectivity in the motor and cerebellar cortices. Further, Dyt1 KI mice demonstrated elevated free-water (FW) in the striatum and cerebellum compared to WT mice, and increased FW was correlated with impairments in functional connectivity across basal ganglia, cerebellum, and sensorimotor cortex. The current study provides the first in vivo MRI-based evidence in support of the hypothesis that the deletion of a 3-base pair (ΔGAG) sequence in the Dyt1 gene encoding torsinA has network level effects on in vivo functional connectivity and microstructural integrity across the sensorimotor cortex, basal ganglia, and cerebellum.

Validating sensitive markers of hippocampal degeneration is fundamental for understanding neurodegenerative conditions such as Alzheimer's disease. In this paper, we test the hypothesis that free-water in the hippocampus will be more sensitive to early stages of cognitive decline than hippocampal volume, and that free-water in hippocampus will increase across distinct clinical stages of Alzheimer's disease. We examined two separate cohorts (N = 126; N = 112) of cognitively normal controls, early and late mild cognitive impairment (MCI), and Alzheimer's disease. Demographic, clinical, diffusion-weighted and T1-weighted imaging, and positron emission tomography (PET) imaging were assessed. Results indicated elevated hippocampal free-water in early MCI individuals compared to controls across both cohorts. In contrast, there was no difference in volume of these regions between controls and early MCI. ADNI free-water values in the hippocampus was associated with low CSF AB1–42 levels and high global amyloid PET values. Free-water imaging of the hippocampus can serve as an early stage marker for AD and provides a complementary measure of AD neurodegeneration using non-invasive imaging. Keywords: Mild cognitive impairment, Neurodegeneration, Free-water imaging, Hippocampus

This paper reviews the therapeutically beneficial effects of progressive resistance exercise (PRE) on Parkinson's disease (PD). First, this paper discusses the rationale for PRE in PD. Within the first section, the review discusses the central mechanisms that underlie bradykinesia and muscle weakness, highlights findings related to the central changes that accompany PRE in healthy individuals, and extends these findings to individuals with PD. It then illustrates the hypothesized positive effects of PRE on nigro-striatal-thalamo-cortical activation and connectivity. Second, it reviews recent findings of the use of PRE in individuals with PD. Finally, knowledge gaps of using PRE on individuals with PD are discussed along with suggestions for future research.