Cerebrospinal Fluid Flow in Patients with Huntington's Disease.

OBJECTIVE: Investigations of cerebrospinal fluid (CSF) flow aberrations in Huntington's disease (HD) are of growing interest, as impaired CSF flow may contribute to mutant Huntington retention and observed heterogeneous responsiveness to intrathecally administered therapies. METHOD: We assessed net cerebral aqueduct CSF flow and velocity in 29 HD participants (17 premanifest and 12 manifest) and 51 age- and sex matched non-HD control participants using 3-Tesla magnetic resonance imaging methods. Regression models were applied to test hypotheses regarding: (i) net CSF flow and cohort, (ii) net CSF flow and disease severity (CAP-score), and (iii) CSF volume after correcting for age and sex. RESULTS: Group-wise analyses support a decrease in net CSF flow in HD (mean 0.14 ± 0.27 mL/min) relative to control (mean 0.32 ± 0.20 mL/min) participants (p = 0.02), with lowest flow in the manifest HD cohort (mean 0.04 ± 0.25 mL/min). This finding was explained by hyperdynamic CSF movement, manifesting as higher caudal systolic CSF flow velocity and higher diastolic cranial CSF flow velocity across the cardiac cycle, in HD (caudal flow: 0.17 ± 0.07 mL/s, cranial flow: 0.14 ± 0.08 mL/s) compared to control (caudal flow: 0.13 ± 0.06 mL/s, cranial flow: 0.11 ± 0.04 mL/s) participants. A positive correlation between cranial diastolic flow and disease severity was observed (p = 0.02). INTERPRETATIONS: Findings support aqueductal CSF flow dynamics changing with disease severity in HD. These accelerated changes are consistent with changes observed over the typical adult lifespan, and may have relevance to mutant Huntington retention and intrathecally administered therapeutics responsiveness. ANN NEUROL 2023;94:885-894.

Measuring Antisocial Behaviors in Behavioral Variant Frontotemporal Dementia With a Novel Informant-Based Questionnaire.

OBJECTIVE: Antisocial behaviors are common and problematic among patients with behavioral variant frontotemporal dementia (bvFTD). In the present study, the investigators aimed to validate an informant-based questionnaire developed to measure the extent and severity of antisocial behaviors among patients with dementia. METHODS: The Social Behavior Questionnaire (SBQ) was developed to measure 26 antisocial behaviors on a scale from absent (0) to very severe (5). It was administered to 23 patients with bvFTD, 19 patients with Alzheimer's disease, and 14 patients with other frontotemporal lobar degeneration syndromes. Group-level differences in the presence and severity of antisocial behaviors were measured. Psychometric properties of the SBQ were assessed by using Cronbach's alpha, exploratory factor analysis, and comparisons with a psychopathy questionnaire. Cluster analysis was used to determine whether the SBQ identifies different subgroups of patients. RESULTS: Antisocial behaviors identified by using the SBQ were common and severe among patients with bvFTD, with at least one such behavior endorsed for 21 of 23 (91%) patients. Antisocial behaviors were more severe among patients with bvFTD, including the subsets of patients with milder cognitive impairment and milder disease severity, than among patients in the other groups. The SBQ was internally consistent (Cronbach's α=0.81). Exploratory factor analysis supported separate factors for aggressive and nonaggressive behaviors. Among the patients with bvFTD, the factor scores for aggressive behavior on the SBQ were correlated with those for antisocial behavior measured on the psychopathy scale, but the nonaggressive scores were not correlated with psychopathy scale measures. The k-means clustering analysis identified a subset of patients with severe antisocial behaviors. CONCLUSIONS: The SBQ is a useful tool to identify, characterize, and measure the severity of antisocial behaviors among patients with dementia.

Anosognosia and Memory Encoding in Huntington Disease.

BACKGROUND: Anosognosia can manifest as an unawareness of neurobehavioral symptoms in individuals with Huntington disease (HD). Measurement of anosognosia is challenging, but the Anosognosia Scale (AS) represents a brief option with promising findings in small samples. OBJECTIVE: To replicate application of the AS in a larger HD sample than previous studies in order to assess psychometrics and demographic correlates and to investigate the genetic, motor, and neuropsychological correlates of the AS in individuals with HD. METHOD: We retrospectively reviewed the AS ratings of 74 genetically confirmed Huntington gene carriers, nearly all early motor manifest, who had been referred for clinical neuropsychological assessment. Concurrent clinical neurologic examination and neuropsychometric assessment data were compiled, where available (ns = 35-74). The severity of the anosognosia per AS ratings was characterized for the HD sample. RESULTS: The AS ratings did not correlate with demographic variables, genetic markers, or motor dysfunction severity. Correlation analyses revealed that higher AS ratings correlated with worse recognition-discrimination memory performance (r = 0.38, P < 0.05) but not cognitive control on executive functioning performance or on collateral-reported frontal-behavioral symptoms. Higher AS ratings also correlated with fewer patient-reported depressive symptoms (r = -0.38, P < 0.01) and diurnal hypersomnia symptoms (r = -0.44, P < 0.01). CONCLUSION: Anosognosia (per AS) is associated with recognition-discrimination deficits and fewer self-reported neuropsychiatric symptoms in individuals with pre-to-early manifest HD, though not with HD severity per genetic or motor markers, nor to executive dysfunction or collateral-reported frontal-behavioral symptoms.

Automated synthesis of (R)-[18 F]MH.MZ on the iPhase Flexlab reaction platform.

(R)-[18 F]MH.MZ ([18 F]MH.MZ) is a promising positron emission tomography (PET) radiotracer for in vivo study of the 5-HT2A receptor. To facilitate clinical trials, a fully automated radiosynthesis procedure for [18 F]MH.MZ was developed using commercially available materials on the iPhase Flexlab module. The overall synthesis time was 100 min with a radiochemical yield of 7 ± 0.9% (n = 3). The radiochemical purity was greater than 99% for [18 F]MH.MZ with a molar activity of 361 ± 57 GBq/µmol (n = 3). The protocol described herein reliably provides [18 F]MH.MZ that meets all relevant release criteria for a GMP radiopharmaceutical.

Introducing the ImPACT-5: An Empirically Derived Multivariate Validity Composite.

OBJECTIVE: To create novel Immediate Post-Concussion and Cognitive Testing (ImPACT)-based embedded validity indicators (EVIs) and to compare the classification accuracy to 4 existing EVIImPACT. METHOD: The ImPACT was administered to 82 male varsity football players during preseason baseline cognitive testing. The classification accuracy of existing EVIImPACT was compared with a newly developed index (ImPACT-5A and B). The ImPACT-5A represents the number of cutoffs failed on the 5 ImPACT composite scores at a liberal cutoff (0.85 specificity); ImPACT-5B is the sum of failures on conservative cutoffs (≥0.90 specificity). RESULTS: ImPACT-5A ≥1 was sensitive (0.81), but not specific (0.49) to invalid performance, consistent with EVIImPACT developed by independent researchers (0.68 sensitivity at 0.73-0.75 specificity). Conversely, ImPACT-5B ≥3 was highly specific (0.98), but insensitive (0.22), similar to Default EVIImPACT (0.04 sensitivity at 1.00 specificity). ImPACT-5A ≥3 or ImPACT-5B ≥2 met forensic standards of specificity (0.91-0.93) at 0.33 to 0.37 sensitivity. Also, the ImPACT-5s had the strongest linear relationship with clinically meaningful levels of invalid performance of existing EVIImPACT. CONCLUSIONS: The ImPACT-5s were superior to the standard EVIImPACT and comparable to existing aftermarket EVIImPACT, with the flexibility to optimize the detection model for either sensitivity or specificity. The wide range of ImPACT-5 cutoffs allows for a more nuanced clinical interpretation.

Atypical Clinical Manifestations of Cerebral Amyloid Angiopathy.

PURPOSE: Cerebral amyloid angiopathy is a vasculopathy caused by ß-amyloid deposition in cerebral arterioles and capillaries. It is closely linked to Alzheimer's disease and predisposes elderly patients to intracerebral hemorrhage, transient focal neurological episodes, and cognitive impairment. Because of a predilection for symptomatic hemorrhage, particularly in the frontal lobes, cerebral amyloid angiopathy may also cause a dysexecutive syndrome. RECENT FINDINGS: In this case series, we describe presentations of classic clinical dementia syndromes which are not are widely thought to be associated with cerebral amyloid angiopathy, namely logopenic variant primary progressive aphasia (n = 3), normal pressure hydrocephalus (n = 3), and Lewy body dementia (n = 2). In every case, after a clinical diagnosis was established, neuroimaging, brain biopsy, and/or autopsy confirmed the presence of cerebral amyloid angiopathy. Cerebral amyloid angiopathy has significant clinical implications, and its ability to mimic and/or contribute to other clinical dementia syndromes can complicate its diagnosis. This series of cases broadens the range of clinical scenarios associated with cerebral amyloid angiopathy.

Sleep Biomarkers, Health Comorbidities, and Neurocognition in Obstructive Sleep Apnea.

OBJECTIVES: Obstructive sleep apnea (OSA) is associated with cognitive impairment but the relationships between specific biomarkers and neurocognitive domains remain unclear. The present study examined the influence of common health comorbidities on these relationships. Adults with suspected OSA (N=60; 53% male; M age=52 years; SD=14) underwent neuropsychological evaluation before baseline polysomnography (PSG). Apneic syndrome severity, hypoxic strain, and sleep architecture disturbance were assessed through PSG. METHODS: Depression (Center for Epidemiological Studies Depression Scale, CESD), pain, and medical comorbidity (Charlson Comorbidity Index) were measured via questionnaires. Processing speed, attention, vigilance, memory, executive functioning, and motor dexterity were evaluated with cognitive testing. A winnowing approach identified 9 potential moderation models comprised of a correlated PSG variable, comorbid health factor, and cognitive performance. RESULTS: Regression analyses identified one significant moderation model: average blood oxygen saturation (AVO2) and depression predicting recall memory, accounting for 31% of the performance variance, p<.001. Depression was a significant predictor of recall memory, p<.001, but AVO2 was not a significant predictor. The interaction between depression and AVO2 was significant, accounting for an additional 10% of the variance, p<.001. The relationship between low AVO2 and low recall memory performance emerged when depression severity ratings approached a previously established clinical cutoff score (CESD=16). CONCLUSIONS: This study examined sleep biomarkers with specific neurocognitive functions among individuals with suspected OSA. Findings revealed that depression burden uniquely influence this pathophysiological relationship, which may aid clinical management. (JINS, 2018, 28, 864-875).

Decreased Fronto-Limbic Activation and Disrupted Semantic-Cued List Learning in Major Depressive Disorder.

OBJECTIVES: Individuals with major depressive disorder (MDD) demonstrate poorer learning and memory skills relative to never-depressed comparisons (NDC). Previous studies report decreased volume and disrupted function of frontal lobes and hippocampi in MDD during memory challenge. However, it has been difficult to dissociate contributions of short-term memory and executive functioning to memory difficulties from those that might be attributable to long-term memory deficits. METHODS: Adult males (MDD, n=19; NDC, n=22) and females (MDD, n=23; NDC, n=19) performed the Semantic List Learning Task (SLLT) during functional magnetic resonance imaging. The SLLT Encoding condition consists of 15 lists, each containing 14 words. After each list, a Distractor condition occurs, followed by cued Silent Rehearsal instructions. Post-scan recall and recognition were collected. Groups were compared using block (Encoding-Silent Rehearsal) and event-related (Words Recalled) models. RESULTS: MDD displayed lower recall relative to NDC. NDC displayed greater activation in several temporal, frontal, and parietal regions, for both Encoding-Silent Rehearsal and the Words Recalled analyses. Groups also differed in activation patterns in regions of the Papez circuit in planned analyses. The majority of activation differences were not related to performance, presence of medications, presence of comorbid anxiety disorder, or decreased gray matter volume in MDD. CONCLUSIONS: Adults with MDD exhibit memory difficulties during a task designed to reduce the contribution of individual variability from short-term memory and executive functioning processes, parallel with decreased activation in memory and executive functioning circuits. Ecologically valid long-term memory tasks are imperative for uncovering neural correlates of memory performance deficits in adults with MDD.

Forensic Neurology and the Role of Neurologists in Forensic Evaluations.

Forensic psychiatrists may be asked to opine on neurological evidence or neurological diseases outside the scope of their expertise. This article discusses the value of involving experts trained in behavioral neurology in such cases. First, we describe the field of behavioral neurology and neuropsychiatry, the subspecialty available to both neurologists and psychiatrists focused on the behavioral, cognitive, and neuropsychiatric manifestations of neurological diseases. Next, we discuss the added value of behavioral neurologists in forensic cases, including assisting in the diagnostic evaluation for complex neuropsychiatric diseases, using expertise in localization to provide a strong scientific basis for linking neurodiagnostic testing to relevant neuropsychiatric symptoms, and assisting in relating these symptoms to the relevant legal question in cases where such symptoms may be less familiar to forensic psychiatrists, such as frontal lobe syndromes. We discuss approaches to integrating behavioral neurology with forensic psychiatry, highlighting the need for collaboration and mentorship between disciplines. Finally, we discuss several forensic cases highlighting the additional value of experts trained in behavioral neurology. We conclude that forensic psychiatrists should involve behavioral neurology experts when encountering neurological evidence that falls outside their scope of expertise, and the need for further cross-disciplinary collaboration and training.

Forensic neurology: a distinct subspecialty at the intersection of neurology, neuroscience and law.

Neurological evidence is increasingly used in criminal cases to argue that a defendant is less responsible for their behaviour, is not competent to stand trial or should receive a reduced punishment for the crime. Unfortunately, neurologists are rarely involved in such cases despite having the expertise to help to inform these decisions in court. In this Perspective, we advocate for the development of 'forensic neurology', a subspecialty of neurology focused on using neurological clinical and scientific expertise to address legal questions for the criminal justice system. We review literature suggesting that the incidence of criminal behaviour is higher in people with certain neurological disorders than the general public and that undiagnosed neurological abnormalities are common in people who commit crimes. We discuss the need for forensic neurologists in criminal cases to provide an opinion on what neurological diagnoses are present, the resulting symptoms and ultimately whether the symptoms affect legal determinations such as criminal responsibility or competency.

Forensic Neurology: Practice Considerations and Training Opportunities.

Neurologic evidence, including MRI, PET, and EEG, has been introduced in more than 2,800 criminal cases in the past decade, including 12% of all murder trials and 25% of death penalty trials, to argue whether neurologic diseases are present, contribute to criminal behavior, and ultimately whether the defendant is less criminally responsible, competent to stand trial, or should receive a reduced punishment for his or her crime. Unfortunately, neurologists are often not involved in these criminal cases despite being the medical specialty with the most relevant training and expertise to address these issues for the court. Reasons for the absence of neurologists in criminal cases include a lack of awareness from lawyers, judges, and other expert witnesses on the value of including neurologists in forensic evaluations, and the lack of experience, training, and willingness of neurologists to work as expert witnesses in criminal cases. Here, we discuss forensic neurology, a field bridging the gap between neurology, neuroscience, and the law. We discuss the process of performing forensic evaluations, including answering 3 fundamental questions: the neurologic diagnostic question, the behavioral neurology/neuropsychiatry question, and the forensic neurology question. We discuss practical aspects of performing forensic expert witness work and important ethical differences between the neurologist's role in treatment vs forensic settings. Finally, we discuss the currently available pathways for interested neurologists to receive additional training in forensic assessments.

Cognitive, Sleep-Arousal, Physical, and Affective Domain Scores on the Post-Concussion Symptom Scale: Added Utility in Detecting Symptom Elevations among Student-Athletes with a Remote History of Concussion.

OBJECTIVE: The evaluation of self-reported symptoms is a standard component of concussion assessment and management. Clinicians typically evaluate a total symptom severity score rather than scores corresponding to specific symptom domains (i.e., cognitive, sleep-arousal, physical, and affective symptoms). This study examined (i) whether elevations in specific symptom domains would be missed when interpreting only the total symptom severity score and (ii) if a single symptom domain elevation was more common than having elevated symptoms across multiple domains. METHOD: Adolescent student-athletes (N = 1,008) with concussion history (i.e., ≥6 months since last concussion) completed the Post-Concussion Symptom Scale (PCSS). The PCSS total score and cognitive, sleep-arousal, physical, and affective domain scores were calculated. To determine if symptoms were elevated, scores were compared to normative data matched on gender and pre-existing conditions, with scores considered elevated if they were ≥84th percentile. The frequency of total and domain score elevations were calculated and stratified by gender and number of prior concussions (i.e., 1 or ≥2 prior concussions). RESULTS: Overall, 26% of student-athletes had an elevated symptom domain score without being elevated on the total score. The most common symptom presentation was to have a single elevated symptom domain (21%), followed by two (11%), three (8%), or four elevated domains (6%). CONCLUSIONS: Interpreting PCSS symptom domains may be beneficial in detecting student-athletes with elevated symptoms following a remote concussion. Roughly a quarter of student-athletes have domain-specific symptom elevations that would be missed by interpreting the total score alone.

Deciphering Cognitive Impairments in Huntington's Disease: A Comparative Study of Stroop Test Variations.

Background: Huntington's disease (HD) is a neurodegenerative disorder marked by cognitive impairment, movement abnormalities, and behavioral disturbances. The Stroop Color Word Test (SCWT) is a widely used tool to detect cognitive decline in HD. Variations in SCWT formats-horizontal (original) and vertical (Golden)-may influence performance, given HD's impact on cognitive and oculomotor abilities. Objective: This study aimed to compare the effectiveness of the horizontal and Golden vertical SCWT formats in detecting cognitive decline in HD, and to determine how performance may have been influenced by eye movement abnormalities. Methods: Forty-five participants with genetically confirmed HD were recruited. Both SCWT formats were administered to each participant in a counterbalanced fashion. Individual performance of all three sections on each format was standardized across 2 different norms. Raw and normed scores on each variation were compared and correlated with eye movement ratings on the Unified Huntington's Disease Rating Scale. Results: The Golden variation elicited significantly slower responses, particularly in the Word Reading section, across two benchmark norms. Statistical analysis revealed significant performance differences between the two formats. Correlations between vertical eye movement ratings and performance on the Golden SCWT were highly significant, highlighting the impact of oculomotor coordination on cognitive assessments in HD. Conclusion: This study underscores the importance of considering test format in cognitive assessments for HD. The Golden vertical SCWT demonstrates increased sensitivity in detecting deficits in HD, possibly linked to vertical saccade abnormalities. These insights are important for improving the sensitivity of cognitive assessments and monitoring disease progression in HD research and clinical practice.

Deep learning segmentation of the choroid plexus from structural magnetic resonance imaging (MRI): validation and normative ranges across the adult lifespan.

BACKGROUND: The choroid plexus functions as the blood-cerebrospinal fluid (CSF) barrier, plays an important role in CSF production and circulation, and has gained increased attention in light of the recent elucidation of CSF circulation dysfunction in neurodegenerative conditions. However, methods for routinely quantifying choroid plexus volume are suboptimal and require technical improvements and validation. Here, we propose three deep learning models that can segment the choroid plexus from commonly-acquired anatomical MRI data and report performance metrics and changes across the adult lifespan. METHODS: Fully convolutional neural networks were trained from 3D T1-weighted, 3D T2-weighted, and 2D T2-weighted FLAIR MRI using gold-standard manual segmentations in control and neurodegenerative participants across the lifespan (n = 50; age = 21-85 years). Dice coefficients, 95% Hausdorff distances, and area-under-curve (AUCs) were calculated for each model and compared to segmentations from FreeSurfer using two-tailed Wilcoxon tests (significance criteria: p < 0.05 after false discovery rate multiple comparisons correction). Metrics were regressed against lateral ventricular volume using generalized linear models to assess model performance for varying levels of atrophy. Finally, models were applied to an expanded cohort of adult controls (n = 98; age = 21-89 years) to provide an exemplar of choroid plexus volumetry values across the lifespan. RESULTS: Deep learning results yielded Dice coefficient = 0.72, Hausdorff distance = 1.97 mm, AUC = 0.87 for T1-weighted MRI, Dice coefficient = 0.72, Hausdorff distance = 2.22 mm, AUC = 0.87 for T2-weighted MRI, and Dice coefficient = 0.74, Hausdorff distance = 1.69 mm, AUC = 0.87 for T2-weighted FLAIR MRI; values did not differ significantly between MRI sequences and were statistically improved compared to current commercially-available algorithms (p < 0.001). The intraclass coefficients were 0.95, 0.95, and 0.96 between T1-weighted and T2-weighted FLAIR, T1-weighted and T2-weighted, and T2-weighted and T2-weighted FLAIR models, respectively. Mean lateral ventricle choroid plexus volume across all participants was 3.20 ± 1.4 cm3; a significant, positive relationship (R2 = 0.54-0.60) was observed between participant age and choroid plexus volume for all MRI sequences (p < 0.001). CONCLUSIONS: Findings support comparable performance in choroid plexus delineation between standard, clinically available, non-contrasted anatomical MRI sequences. The software embedding the evaluated models is freely available online and should provide a useful tool for the growing number of studies that desire to quantitatively evaluate choroid plexus structure and function ( https://github.com/hettk/chp_seg ).

An Exploratory Pilot Study of Neuropsychological Performance in Two Huntington Disease Centers of Excellence Clinics.

OBJECTIVES: To describe the characteristics of patients receiving a clinical referral for neuropsychological evaluation in two Huntington's Disease Society of America Centers of Excellence (HDSA COE). In this exploratory pilot study, we used an empirically supported clinical neuropsychological battery to assess differences in cognitive performance between premanifest and manifest HD patient groups (compared with each other and normative expectations). METHOD: Clinical data from 76 adult genetically confirmed patients referred for neuropsychological evaluations was retrospectively collected from two HDSA COEs. ANOVA and Chi-square tests were used to compare variables between pre-manifest (n = 14) and manifest (n = 62) groups for demographic, cognitive, neuropsychiatric, and disease severity variables. RESULTS: Our clinics serviced a disproportionate number of motor manifest patients. Six measures were excluded from analyses due to infrequent administration. The full WAIS-IV Digit Span was disproportionately administered to the manifest group. The premanifest group showed stronger cognitive performance with effect sizes in the large range on subtests of the WAIS-IV Digit Span, HVLT-R, SDMT, and verbal fluency. CONCLUSIONS: This is the first study to assess an empirically supported neuropsychological research battery in a clinical setting with a relatively large sample size given the rarity of HD. The battery adequately captured areas of impairment across the disease spectrum. Application of the current battery with larger premanifest samples is warranted.

Deep learning segmentation of peri-sinus structures from structural magnetic resonance imaging: validation and normative ranges across the adult lifespan.

BACKGROUND: Peri-sinus structures such as arachnoid granulations (AG) and the parasagittal dural (PSD) space have gained much recent attention as sites of cerebral spinal fluid (CSF) egress and neuroimmune surveillance. Neurofluid circulation dysfunction may manifest as morphological changes in these structures, however, automated quantification of these structures is not possible and rather characterization often requires exogenous contrast agents and manual delineation. METHODS: We propose a deep learning architecture to automatically delineate the peri-sinus space (e.g., PSD and intravenous AG structures) using two cascaded 3D fully convolutional neural networks applied to submillimeter 3D T2-weighted non-contrasted MRI images, which can be routinely acquired on all major MRI scanner vendors. The method was evaluated through comparison with gold-standard manual tracing from a neuroradiologist (n = 80; age range = 11-83 years) and subsequently applied in healthy participants (n = 1,872; age range = 5-100 years), using data from the Human Connectome Project, to provide exemplar metrics across the lifespan. Dice-Sørensen and a generalized linear model was used to assess PSD and AG changes across the human lifespan using quadratic restricted splines, incorporating age and sex as covariates. RESULTS: Findings demonstrate that the PSD and AG volumes can be segmented using T2-weighted MRI with a Dice-Sørensen coefficient and accuracy of 80.7 and 74.6, respectively. Across the lifespan, we observed that total PSD volume increases with age with a linear interaction of gender and age equal to 0.9 cm3 per year (p < 0.001). Similar trends were observed in the frontal and parietal, but not occipital, PSD. An increase in AG volume was observed in the third to sixth decades of life, with a linear effect of age equal to 0.64 mm3 per year (p < 0.001) for total AG volume and 0.54 mm3 (p < 0.001) for maximum AG volume. CONCLUSIONS: A tool that can be applied to quantify PSD and AG volumes from commonly acquired T2-weighted MRI scans is reported and exemplar volumetric ranges of these structures are provided, which should provide an exemplar for studies of neurofluid circulation dysfunction. Software and training data are made freely available online ( https://github.com/hettk/spesis ).

Reduced cerebrospinal fluid motion in patients with Parkinson's disease revealed by magnetic resonance imaging with low b-value diffusion weighted imaging.

BACKGROUND: Parkinson's disease is characterized by dopamine-responsive symptoms as well as aggregation of α-synuclein protofibrils. New diagnostic methods assess α-synuclein aggregation characteristics from cerebrospinal fluid (CSF) and recent pathophysiologic mechanisms suggest that CSF circulation disruptions may precipitate α-synuclein retention. Here, diffusion-weighted MRI with low-to-intermediate diffusion-weightings was applied to test the hypothesis that CSF motion is reduced in Parkinson's disease relative to healthy participants. METHODS: Multi-shell diffusion weighted MRI (spatial resolution = 1.8 × 1.8 × 4.0 mm) with low-to-intermediate diffusion weightings (b-values = 0, 50, 100, 200, 300, 700, and 1000 s/mm2) was applied over the approximate kinetic range of suprasellar cistern fluid motion at 3 Tesla in Parkinson's disease (n = 27; age = 66 ± 6.7 years) and non-Parkinson's control (n = 32; age = 68 ± 8.9 years) participants. Wilcoxon rank-sum tests were applied to test the primary hypothesis that the noise floor-corrected decay rate of CSF signal as a function of b-value, which reflects increasing fluid motion, is reduced within the suprasellar cistern of persons with versus without Parkinson's disease and inversely relates to choroid plexus activity assessed from perfusion-weighted MRI (significance-criteria: p < 0.05). RESULTS: Consistent with the primary hypothesis, CSF decay rates were higher in healthy (D = 0.00673 ± 0.00213 mm2/s) relative to Parkinson's disease (D = 0.00517 ± 0.00110 mm2/s) participants. This finding was preserved after controlling for age and sex and was observed in the posterior region of the suprasellar cistern (p < 0.001). An inverse correlation between choroid plexus perfusion and decay rate in the voxels within the suprasellar cistern (Spearman's-r=-0.312; p = 0.019) was observed. CONCLUSIONS: Multi-shell diffusion MRI was applied to identify reduced CSF motion at the level of the suprasellar cistern in adults with versus without Parkinson's disease; the strengths and limitations of this methodology are discussed in the context of the growing literature on CSF flow.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN, MAPT) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

Hyperactivity in patients with narcolepsy and idiopathic hypersomnia: an exploratory study.

Introduction: Patients with either Idiopathic Hypersomnia or Narcolepsy demonstrate excessive daytime somnolence (EDS) with resultant inattention mimicking Attention Deficit Hyperactivity Disorder (ADHD). Patients with ADHD also often express sleep problems including EDS. Thus, patients with ADHD and patients with idiopathic hypersomnia or narcolepsy may share inattention and daytime drowsiness as common features. However, it is not known whether EDS patients with idiopathic hypersomnia or narcolepsy also have increased movement (hyperactivity) like ADHD patients, the determination of which is the purpose of this study. Methods: We studied 12 patients (7 Narcolepsy type 2 and 5 Idiopathic Hypersomnia) with EDS as shown by Multiple Sleep Latency Test which served as the gold standard for entry into the study. Twelve subjects without symptoms of EDS served as the control group. None of the participants had a previous history of ADHD. Each participant underwent a one-hour session laying at 45 degrees with surveys about the need to move and actigraphy as an objective measure of movement. Results: Sleep-disordered patients with EDS reported more symptoms of inattention and hyperactivity on the ADHD Self-Report Scale. At each of the time points patients with EDS had a clear trend to express the need to move more than controls on the Suggested Immobilization Test (SIT). For the total 60 minutes, a large effect size for the need to move during the SIT test was found between patients and controls (Cohen's d = 0.61, p=0.01). Patients with EDS did not express a need to move more to combat drowsiness than controls, nor did actigraphy show any difference in objective movement between patients and controls during the SIT. Conclusion: Patients with EDS express inattention and a need to move more than controls. However, hyperactivity was not verified by objective measurement, nor did the EDS patients express a need to move to combat drowsiness more than controls. Thus, a hypothesis to be further tested, is whether narcolepsy and idiopathic hypersomnia may be more a model of the inattentive form of ADHD rather than the combined or inattentive/hyperactive form of ADHD. Further studies are needed to explore the relationship between EDS and hyperactivity.

Deep learning segmentation of the choroid plexus from structural magnetic resonance imaging (MRI): validation and normative ranges across the adult lifespan.

Background: The choroid plexus functions as the blood-cerebrospinal fluid barrier, plays an important role in neurofluid production and circulation, and has gained increased attention in light of the recent elucidation of neurofluid circulation dysfunction in neurodegenerative conditions. However, methods for routinely quantifying choroid plexus volume are suboptimal and require technical improvements and validation. Here, we propose three deep learning models that can segment the choroid plexus from commonly-acquired anatomical MRI data and report performance metrics and changes across the adult lifespan. Methods: Fully convolutional neural networks were trained from 3-D T1-weighted, 3-D T2-weighted, and 2-D T2-weighted FLAIR MRI and gold-standard manual segmentations in healthy and neurodegenerative participants across the lifespan (n=50; age=21-85 years). Dice coefficients, 95% Hausdorff distances, and area-under-curve (AUCs) were calculated for each model and compared to segmentations from FreeSurfer using two-tailed Wilcoxon tests (significance criteria: p<0.05 after false discovery rate multiple comparisons correction). Metrics were regressed against lateral ventricular volume using generalized linear models to assess model performance for varying levels of atrophy. Finally, models were applied to an expanded cohort of healthy adults (n=98; age=21-89 years) to provide an exemplar of choroid plexus volumetry values across the lifespan. Results: Deep learning results yielded Dice coefficient=0.72, Hausdorff distance=1.97 mm, AUC=0.87 for T1-weighted MRI, Dice coefficient=0.72, Hausdorff distance=2.22 mm, AUC=0.87 for T2-weighted MRI, and Dice coefficient=0.74, Hausdorff distance=1.69 mm, AUC=0.87 for T2-weighted FLAIR MRI; values did not differ significantly between2 MRI sequences and were statistically improved compared to current commercially-available algorithms (p<0.001). The intraclass coefficients were 0.95, 0.95, and 0.96 between T1-weighted and T2-FLAIR, T1-weighted and T2-weighted, and T2-weighted and T2-FLAIR models, respectively. Mean lateral ventricle choroid plexus volume across all participants was 3.20±1.4 cm3; a significant, positive relationship (R2=0.54; slope=0.047) was observed between participant age and choroid plexus volume for all MRI sequences (p<0.001). Conclusions: Findings support comparable performance in choroid plexus delineation between standard, clinically available, non-contrasted anatomical MRI sequences. The software embedding the evaluated models is freely available online and should provide a useful tool for the growing number of studies that desire to quantitatively evaluate choroid plexus structure and function (https://github.com/hettk/chp_seg).