IntroductionAtypical parkinsonian syndromes (APS) are rare neurodegenerative syndromes for which parkinsonism is one significant feature. APS includes progressive supranuclear palsy (PSP), multiple ...system atrophy (MSA) and corticobasal syndrome (CBS). The diagnosis of APS remains reliant on clinical features with no available diagnostic or prognostic biomarker. Clinical scales remain the gold standard assessment measures in clinical trials and research. The lack of standardised approach for research cohorts has contributed to shortcomings in disease understanding and limits collaboration between researchers. The primary objectives of this study are to (1) establish an assessment protocol for parkinsonian syndromes and (2) to implement it at a single site to establish the viability and utility of populating a clinical and biological databank of patients with APS.MethodsThe Monash Alfred Protocol for Assessment of APS was devised by expert consensus within a broad multidisciplinary team. Eligible patients are diagnosed as possible or probable PSP, MSA or CBS by a consultant neurologist with expertise in movement disorders. Participants will be assessed at recruitment and then annually for up to 3 years; individuals within 5 years of index symptom onset will also undergo a once-off 6-month assessment.Ethics and disseminationEach participant or their legally authorised representative will provide informed written consent prior to commencement of the study. Data will be stored on a locally hosted Research Electronic Data Capture database.Trial registration numberAustralian New Zealand Clinical Trials Registry (ANZCTN 12622000923763).
IntroductionSodium selenate is a potential disease-modifying treatment for Alzheimer’s disease (AD) which reduces hyperphosphorylated tau through activation of the protein phosphatase 2A enzyme. We ...have shown sodium selenate to be safe and well tolerated in a 24-week, phase 2a double-blind placebo-controlled randomised controlled trial (RCT), also reporting sodium selenate reduced neurodegeneration on diffusion-weighted MRI. This study assessed the safety and tolerability of chronic sodium selenate treatment (up to 23 months) in patients with AD who had been enrolled in the RCT. Cognitive measures served as secondary outcomes of potential disease-modification.MethodsAn open-label extension study of sodium selenate (10 mg three times a day) in patients with AD who had completed the previous RCT. Twenty-eight patients were enrolled. Patients were regularly monitored for safety, adverse events (AEs) and protocol compliance. Cognitive tests were administered for measures of disease progression.ResultsSixteen patients were discontinued by the sponsor, and 12 discontinued for other reasons. Treatment duration ranged from 6 to 23 months. The majority of AEs were mild (83%), and 33% were treatment-related. Common treatment-related AEs were alopecia (21%) and nail disorder (32%), which both resolved either prior to or following cessation of treatment. Two serious AEs occurred, which were not treatment-related. Alzheimer’s Disease Assessment Scale—Cognitive Subscale 11 score increased 1.8 points over 12 months.DiscussionChronic sodium selenate treatment is safe and well tolerated in patients with AD. Cognitive measures suggest a slowing of disease progression though this could not be confirmed as the study was not controlled. Further research into sodium selenate as a treatment for AD is warranted.
Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether (18)F-flumazenil ...((18)F-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE.
Dynamic (18)F-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5-25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an (18)F-FMZ PET scan (3.6-4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the (18)F-FMZ PET data.
The PSM was found to adequately model (18)F-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with (18)F-FMZ binding.
Alterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with (18)F-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. (18)F-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE.
Introduction
Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open‐label Phase 1b study of sodium selenate as a disease‐modifying treatment ...for behavioral variant frontotemporal dementia (bvFTD).
Methods
Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t‐tau), phosphorylated tau (p‐tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52.
Results
Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t‐tau, p‐tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study—one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12‐month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction).
Conclusion
Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized‐controlled trials are warranted to investigate potential efficacy.
Neuroinflammation is implicated in the pathogenesis of a wide range of neurologic and neuropsychiatric diseases. For over 20 years, (11)C-PK11195 PET, which aims to image expression of the ...translocator protein (TSPO) on activated microglia in the brain, has been used in preclinical and clinical research to investigate neuroinflammation in vivo in patients with brain diseases. However, (11)C-PK11195 suffers from two major limitations: its low brain permeability and high nonspecific and plasma binding results in a low signal-to-noise ratio, and the use of (11)C restricts its use to PET research centers and hospitals with an on-site cyclotron. In recent years, there has been a great deal of work into the development of new TSPO-specific PET radiotracers. This work has focused on fluorinated radiotracers, which would enable wider use and improved signal-to-noise ratios. These radiotracers have been utilized in preclinical and clinical studies of several neurologic diseases with varying degrees of success. Unfortunately, the application of these second-generation TSPO radiotracers has revealed additional problems, including a polymorphism that affects TSPO binding. In this review, the developments in TSPO imaging are discussed, and current limitations and suggestions for future directions are explored.
The brain's glymphatic system is a network of intracerebral vessels that function to remove “waste products” such as degraded proteins from the brain. It comprises of the vasculature, perivascular ...spaces (PVS), and astrocytes. Poor glymphatic function has been implicated in numerous diseases; however, its contribution is still unknown. Efforts have been made to image the glymphatic system to further assess its role in the pathogenesis of different diseases. Numerous imaging modalities have been utilized including two‐photon microscopy and contrast‐enhanced magnetic resonance imaging (MRI). However, these are associated with limitations for clinical use. PVS form a part of the glymphatic system and can be visualized on standard MRI sequences when enlarged. It is thought that PVS become enlarged secondary to poor glymphatic drainage of metabolites. Thus, quantitating PVS could be a good surrogate marker for glymphatic function. Numerous manual rating scales have been developed to measure the PVS number and size on MRI scans; however, these are associated with many limitations. Instead, automated methods have been created to measure PVS more accurately in different diseases. In this review, we discuss the imaging techniques currently available to visualize the glymphatic system as well as the automated methods currently available to measure PVS, and the strengths and limitations associated with each technique.
Evidence Level
1
Technical Efficacy
Stage 1
Abstract
Background
Tau positron emission tomography (PET) can detect abnormal tau in neurodegenerative diseases. Conventional reference regions show high PET signal variability and are susceptible ...to contamination from partial‐volume effects of tracer uptake. The parametric estimation of reference signal intensity (PERSI) has been introduced as a new method to overcome those issues in patients with Alzheimer’s disease. The current study investigates its applicability on patients with underlying 4R‐tauopathy with the radiotracer
18
F‐PI‐2620.
Method
In this preliminary, cross‐sectional analysis, 9 patients with clinically suspected 4R‐tauopathy underwent T1‐weighted MRI and 0‐60 min dynamic
18
F‐PI‐2620 PET scanning. PERSI identified voxels within the white matter without specific binding for use as a reference region, which was compared with conventional anatomically defined reference regions. Time‐activity curves (TAC) and standardized uptake value ratios in the time window of 20‐40 min (SUVr
20‐40
) were generated for regions of interest (frontal lobe and globus pallidum). Data was analysed with FSL, PETSurfer, and R.
Result
SUVr
20‐40
in the globus pallidum were generally higher than in the frontal lobe for all reference regions (
p
< 0.001). Frontal lobe, but not globus pallidum SUVr
20‐40
were lower when derived from PERSI than when using the cerebellum (
p
< 0.001) or pons (
p
< 0.001). When comparing TACs, the PERSI ROI did not show the rapid peak (perfusion) as seen in all other regions (both target and reference), resulting in an overestimation of SUVR in the early phases of the scan. However, activity was the same for all reference regions at later timepoints resulting in similar SUVr
20‐40
measures in the globus pallidum.
Conclusion
PERSI derived reference regions do not provide an accurate estimate of early phase perfusion and as such are not appropriate for use as reference regions for reference tissue modelling of PET data. Nonetheless, PERSI provides a suitable reference region for late phase SUVR calculations which is particularly relevant for diseases and tracers were an anatomically defined reference region cannot be easily determined. Future analyses on a larger cohort will determine effect sizes and ROCs to see whether PERSI is a suitable semi‐quantitative investigation to compare between different methodologies and diagnostic groups.
Background
Tau positron emission tomography (PET) can detect abnormal tau in neurodegenerative diseases. Conventional reference regions show high PET signal variability and are susceptible to ...contamination from partial‐volume effects of tracer uptake. The parametric estimation of reference signal intensity (PERSI) has been introduced as a new method to overcome those issues in patients with Alzheimer’s disease. The current study investigates its applicability on patients with underlying 4R‐tauopathy with the radiotracer 18F‐PI‐2620.
Method
In this preliminary, cross‐sectional analysis, 9 patients with clinically suspected 4R‐tauopathy underwent T1‐weighted MRI and 0‐60 min dynamic 18F‐PI‐2620 PET scanning. PERSI identified voxels within the white matter without specific binding for use as a reference region, which was compared with conventional anatomically defined reference regions. Time‐activity curves (TAC) and standardized uptake value ratios in the time window of 20‐40 min (SUVr20‐40) were generated for regions of interest (frontal lobe and globus pallidum). Data was analysed with FSL, PETSurfer, and R.
Result
SUVr20‐40 in the globus pallidum were generally higher than in the frontal lobe for all reference regions (p < 0.001). Frontal lobe, but not globus pallidum SUVr20‐40 were lower when derived from PERSI than when using the cerebellum (p < 0.001) or pons (p < 0.001). When comparing TACs, the PERSI ROI did not show the rapid peak (perfusion) as seen in all other regions (both target and reference), resulting in an overestimation of SUVR in the early phases of the scan. However, activity was the same for all reference regions at later timepoints resulting in similar SUVr20‐40 measures in the globus pallidum.
Conclusion
PERSI derived reference regions do not provide an accurate estimate of early phase perfusion and as such are not appropriate for use as reference regions for reference tissue modelling of PET data. Nonetheless, PERSI provides a suitable reference region for late phase SUVR calculations which is particularly relevant for diseases and tracers were an anatomically defined reference region cannot be easily determined. Future analyses on a larger cohort will determine effect sizes and ROCs to see whether PERSI is a suitable semi‐quantitative investigation to compare between different methodologies and diagnostic groups.
Structural MRI abnormalities are inconsistently reported in epilepsy. In the largest neuroimaging study to date, Whelan et al. report robust structural alterations across and within epilepsy ...syndromes, including shared volume loss in the thalamus, and widespread cortical thickness differences. The resulting neuroanatomical map will guide prospective studies of disease progression.
Abstract
Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = −0.24 to −0.73; P < 1.49 × 10−4), and lower thickness in the precentral gyri bilaterally (d = −0.34 to −0.52; P < 4.31 × 10−6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = −1.73 to −1.91, P < 1.4 × 10−19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = −0.36 to −0.52; P < 1.49 × 10−4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = −0.29 to −0.54; P < 1.49 × 10−4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = −0.27 to −0.51; P < 1.49 × 10−4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < −0.0018; P < 1.49 × 10−4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.
Background
There are currently no approved disease‐modifying treatments of behavioural variant frontotemporal dementia (bvFTD), with the only treatments available providing symptomatic relief to ...secondary behavioural symptoms. Approximately 45% of bvFTD cases are tauopathies, with the main pathological hallmark and proposed pathogenic mechanism being the accumulation and aggregation of hyperphosphorylated tau. For this reason, hyperphosphorylated tau represents a promising target for a disease modifying treatment in this population. Sodium selenate stimulates the PP2A enzyme, which directly dephosphorylates hyperphosphorylated tau. This study investigated the use of sodium selenate as a disease‐modifying treatment for patients with bvFTD.
Method
Fifteen patients with possible bvFTD were treated with sodium selenate (15mg tds) for twelve months. Participants underwent a battery of cognitive and behavioural tests, MRI, lumbar puncture and safety assessments at screening, baseline, and at regular intervals following the commencement of treatment. Adverse events were monitored via diary cards between clinic visits.
Result
Fourteen patients are either on treatment or have completed the study. Interim safety analysis (9 completed patients, 5 on treatment) has shown that sodium selenate is safe and well tolerated, with no study withdrawals. Commonly reported adverse events are nail changes (n=5), fatigue (n=4) and nausea (n=4). No treatment related serious adverse events have occurred. An interim mixed‐effects analysis on all available neurocognitive data showed no statistically significant change in NUCOG total score (b=‐0.02, 95% CI = ‐0.18, 0.14) or Carer Burden Scale (CBS) score (b =0.04, 95% CI = ‐0.05, 0.13), CVLT total learning score (M diff = 5.80, 95% CI = ‐6.97, 18.57), or NIH composite score (M diff = 4.72, 95%CI = ‐11.50, 14.70). Percentage change in whole‐brain volume from baseline to 12 months ranged from ‐0.68% to ‐6.26% (n=5 <‐2%, n=2 ‐5‐6%).
Conclusion
The interim results have shown that sodium selenate is safe and well tolerated in patients with bvFTD. Early indications show sodium selenate may be effective in reducing atrophy and halting cognitive decline in a subset of bvFTD patients. A larger phase 2 placebo controlled study is necessary to evaluate whether sodium selenate is efficacious as a disease modifying treatment of bvFTD.
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