ORCID Profile
0000-0002-5374-2839
Current Organisations
University of Melbourne
,
Florey Institute of Neuroscience and Mental Health
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-09-2022
DOI: 10.1212/WNL.0000000000200857
Abstract: Traumatic brain injury (TBI) has been promoted as a risk factor for Alzheimer disease (AD). There is evidence of elevated β-amyloid (Aβ) and tau, the pathologic hallmarks of AD, immediately following TBI. It is not clear whether Aβ and tau remain elevated in the chronic period. To address this issue, we assessed Aβ and tau burden in long-term TBI survivors and healthy controls using PET imaging. Using a cross-sectional design, we recruited in iduals following a single moderate to severe TBI at least 10 years previously from an inpatient rehabilitation program. A demographically similar healthy control group was recruited from the community. PET data were acquired using 18 F-NAV4694 (Aβ) and 18 F-MK6240 (tau) tracers. Aβ deposition was quantified using the Centiloid scale. Tau deposition was quantified using the standardized uptake value ratio (SUVR) in 4 regions of interest (ROIs). As a secondary measure, PET scans were also visually read as positive or negative. We examined PET data in relation to time since injury and age at injury. PET data were analyzed in a series of regression analyses. The s le comprised 87 in iduals with TBI (71.3% male 28.7% female mean 57.53 years, SD 11.53) and 59 controls (59.3% male 40.7% female mean 60.34 years, SD 11.97). In iduals with TBI did not have significantly higher 18 F-NAV4694 Centiloid values ( p = 0.067) or 18 F-MK6240 tau SUVRs in any ROI ( p ≤ 0.001 SUVR greater for controls). Visual assessment was consistent with the quantification in iduals with TBI were not more likely than controls to have a positive Aβ ( p = 0.505) or tau scan ( p = 0.221). No associations were identified for Aβ or tau burden with time since injury ( p = 0.057 to 0.332) or age at injury. A single moderate to severe TBI was not associated with higher burden of Aβ or tau pathologies in the chronic period relative to healthy controls. Aβ and tau burden did not show a significant increase with years since injury, and burden did not appear to be greater for those who were older at the time of injury.
Publisher: BMJ
Date: 06-2021
DOI: 10.1136/BMJNO-2021-000145
Abstract: Anecdotally, the incidence of idiopathic intracranial hypertension (IIH) is increasing, linked to an increase in the obesity rate in Australian society. However, formal incidence and prevalence studies are rare. We therefore sought to determine the incidence and clinical features of IIH in Southern Tasmania, Australia. Neurology discharge summaries and lumbar puncture referrals from the single tertiary referral centre in this region were screened for an IIH diagnosis. All regional neurologists were surveyed to capture patients diagnosed through private neurology clinics. A retrospective review of medical records was conducted to confirm the diagnosis and determine whether patients met the Modified Dandy Criteria (MDC). Patients were included if they were above the age of 18 years and received a new diagnosis of IIH between June 2016 and June 2018. Population statistics were obtained from the Australian Bureau of Statistics. IIH incidence was 5.4/100 000. All patients were females, aged between 18 and 45 years. Headache was the most commonly reported symptom, with high rates of pre-existing or concurrent migraine diagnoses. Weight loss and commencement of oral acetazolamide were the most common treatment approaches. Four patients were medically refractory and required surgical intervention. The incidence of IIH in Southern Tasmania is comparable with the incidence reported in subgroups of females of childbearing age in recent prior studies. The demographic, diagnostic and therapeutic data presented can inform future local health service provision and serve as a baseline for ongoing assessment of change in incidence and treatment of IIH at a community level.
Publisher: Wiley
Date: 07-2023
DOI: 10.1002/DAD2.12454
Abstract: Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale. One thousand forty‐five participants underwent tau scans with either 18 F‐flortaucipir, 18 F‐MK6240, 18 F‐PI2620, 18 F‐PM‐PBB3, 18 F‐GTP1, or 18 F‐RO948. The universal mask was generated from cognitively unimpaired amyloid beta (Aβ)− subjects and Alzheimer's disease (AD) patients with Aβ+. Four additional regional cortical masks were defined within the constraints of the universal mask. A universal scale, the CenTauR z , was constructed. None of the regions known to display off‐target signal were included in the masks. The CenTauR z allows robust discrimination between low and high levels of tau deposits. We constructed several tau‐specific cortical masks for the AD continuum and a universal standard scale designed to capture the location and degree of abnormality that can be applied across tracers and across centers. The masks are freely available at entaur‐project .
Publisher: Cold Spring Harbor Laboratory
Date: 15-02-2022
DOI: 10.1101/2022.02.13.22270894
Abstract: Tau deposition plays a critical role over cognition and neurodegeneration in Alzheimer’s disease (AD). Recent generation tracers have high target to background ratios giving a wide dynamic range that may improve sensitivity for detection of low levels of tau (Pascoal, Shin et al. 2018). Building on previous evidence, this study aims to characterize the effects of tau deposition as assessed by 18 F-MK6240, in a large cohort of patients across the AD disease spectrum. A total of 464 participants, enrolled in the AIBL-ADNeT study, underwent 18 F-MK6240 tau PET, 18 F-NAV4964 Aβ PET, 3D structural MRI (hippoc al and whole-brain cortical volumes) and extensive neuropsychological evaluation. Participants included 266 cognitively unimpaired controls (CU), 112 patients with mild cognitive impairment (MCI), and 86 patients with probable AD dementia. Evaluation included the characterization of the pattern and degree of 18 F-MK6240 tracer retention in each clinical group as well as assessment of the relationship between 18 F-MK6240 and age, Aβ imaging, brain volumetrics and cognition in each of the clinical groups. Standard uptake value ratios (SUVR) were estimated in four predefined composite regions of interest (ROIs), reflecting the stereotypical progression of tau pathology in the brain: 1. Mesial-temporal (Me), 2. Temporoparietal (Te), 3. Remainder of neocortex (R), 4. A temporal meta-region termed metaT+. 18 F-MK6240 retention was higher in AD patients compared with all other diagnostic groups, with 18 F-MK6240 distinguishing patients with AD from CU in iduals, with the highest effect size obtained in the amygdala (Cohen’s d : 2.07), and Me (Cohen’s d : 1.99). When considering Aβ status, 18 F-MK6240 not only was able to distinguish between Aβ+ AD patients and Aβ- CU (Cohen’s d : 2.23), but also between Aβ+ and Aβ- CU (Cohen’s d : 1.32). In Aβ- CU, 18 F-MK6240 retention in Me showed a slow age-related increase, while 18 F-MK6240 retention was higher in younger elderly Aβ+ AD patients compared to their older counterparts. There was a sigmoidal relationship between subthreshold tau and Aβ, providing evidence for a very slow but steady increase in subthreshold tau prior to a fast increase in cortical Aβ. Moreover, a non-linear relationship between Aβ and tau suggest that detectable cortical Aβ precedes detectable cortical tau. While age was the main predictor of cognitive decline in CU, and Aβ and hippoc al volume in MCI, the main predictor of cognitive decline in the AD group was tau. High tau was associated with faster cognitive decline and clinical progression in the CU and MCI groups. This large study provides further evidence that 18 F-MK6240 discriminates CU from AD and, most importantly, Aβ+ from Aβ- CU in iduals with high effect sizes, suggesting that 18 F- MK6240 can detect lower tau levels than earlier tau tracers, crucial for early detection of tau deposition as well as tracking small tau changes over time. In conclusion, identification of regional cortical tau deposition has critical diagnostic and prognostic implications and should become a standard tool to identify in iduals at risk, as well as outcome measure, in both anti- Aβ and anti-tau trials.
Publisher: SERDI
Date: 2023
Publisher: Frontiers Media SA
Date: 22-12-2020
DOI: 10.3389/FNEUR.2020.598980
Abstract: Introduction: It remains unclear if tau imaging may assist diagnosis of chronic traumatic encephalopathy (CTE). Flortaucipir PET has shown superior frontal with medial temporal tau binding consistent with the provisional neuropathological criteria for mid-stage CTE in group-level analyses of retired symptomatic NFL players and in one in idual with pathologically confirmed CTE. 18 F-MK6240 is a new PET ligand that has high affinity for tau. We present the case of a 63-year-old cognitively impaired, former Australian rules football player with distinct superior frontal and medial temporal 18 F-MK6240 binding and show it to be significantly different to the pattern seen in prodromal Alzheimer's disease (AD). Findings: The participant was recruited for a study of amyloid-β and tau several decades after traumatic brain injury. He had multiple concussions during his football career but no cognitive complaints at retirement. A thalamic stroke in his mid 50s left stable mild cognitive deficits but family members reported further short-term memory, behavioral, and personality decline preceding the study. Imaging showed extensive small vessel disease on MRI, a moderate burden of amyloid-β plaques, and 18 F-MK6240 binding in bilateral superior frontal and medial temporal cortices. Voxel-wise analysis demonstrated that the frontally predominant pattern of the participant was significantly different to the posterior temporo-parietal predominant pattern of prodromal AD. Conclusion: Although lacking neuropathological examination to distinguish CTE from a variant of AD, the clear demonstration of a CTE-like tau pattern in a single at-risk in idual suggests further research on the potential of 18 F-MK6240 PET for identifying CTE is warranted.
Publisher: Cold Spring Harbor Laboratory
Date: 13-03-2022
DOI: 10.1101/2022.03.11.22272240
Abstract: Background Tau PET imaging enables prospective longitudinal observation of the rate and location of tau accumulation in Alzheimer's disease (AD). 18 F-MK6240 is a newer, high affinity tracer for the paired helical filaments of tau in AD. It is widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the impact of disease stage, and two reference regions on the magnitude and effect size of regional change. Methods One hundred and fifty-eight participants: 83 cognitively unimpaired (CU) Aβ-, 37 CU Aβ+, 19 mild cognitively impaired (MCI) Aβ+ and 19 AD Aβ+ had annual 18 F-MK6240 PET for one or two years (mean 1.6 years). Standardized uptake value ratios (SUVR) were generated for three in-house composite ROI: mesial temporal (Me), temporoparietal (Te), and rest of neocortex (R), and a Free-Surfer derived meta-temporal (MT) ROI. Two reference regions were examined: cerebellar cortex (SUVR Cb ) and eroded subcortical white matter (SUVR WM ). Results Low rates of accumulation were seen in CU Aβ-, predominantly in the mesial temporal lobe (MTL). In CU Aβ+, increase was greatest in the MTL, particularly the amygdala. In MCI Aβ+, a similar increase was seen in MTL, but also globally in the cortex. In AD Aβ+, greatest increase was in temporoparietal and frontal regions, with a decrease in the MTL. In CU and MCI increases were greater using SUVR WM . In AD, the SUVR Cb showed marginally greater increase. Interpolation of the data suggests it takes approximately two decades to accumulate tau to the typical levels found in AD, similar to the rates of accumulation of Aβ plaques. Conclusions The rate of tau accumulation varies according to brain region and baseline disease stage, confirming previous reports. The PET measured change is greater, with fewer outliers, using an eroded white matter reference region, except in AD. While the eroded subcortical white matter reference may be preferred for trials in preclinical AD, the cerebellar cortex would be preferred for trials in symptomatic AD.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2022
DOI: 10.1186/S13195-022-00993-X
Abstract: Tau deposition in the mesial temporal lobe (MTL) in the absence of amyloid-β (Aβ−) occurs with aging. The tau PET tracer 18 F-MK6240 has low non-specific background binding so is well suited to exploration of early-stage tau deposition. The aim of this study was to investigate the associations between MTL tau, age, hippoc al volume (HV), cognition, and neocortical tau in Aβ− cognitively unimpaired (CU) in iduals. One hundred and ninety-nine Aβ− participants (Centiloid 25) who were CU underwent 18 F-MK6240 PET at age 75 ± 5.2 years. Tau standardized uptake value ratio (SUVR) was estimated in mesial temporal (Me), temporoparietal (Te), and rest of the neocortex (R) regions and four Me sub-regions. Tau SUVR were analyzed as continuous variables and compared between high and low MTL SUVR groups. In this cohort with a stable clinical classification of CU for a mean of 5.3 years prior to and at the time of tau PET, MTL tau was visually observed in 9% of the participants and was limited to Braak stages I–II. MTL tau was correlated with age ( r = 0.24, p 0.001). Age contributed to the variance in cognitive scores but MTL tau did not. MTL tau was not greater with subjective memory complaint, nor was there a correlation between MTL tau and Aβ Centiloid value, but high tau was associated with smaller HV. Participants with MTL tau had higher tau SUVR in the neocortex but this was driven by the cerebellar reference region and was not present when using white matter normalization. In an Aβ− CU cohort, tau tracer binding in the mesial temporal lobe was age-related and associated with smaller hippoc i, but not with subjective or objective cognitive impairment.
Publisher: Wiley
Date: 2022
DOI: 10.1002/DAD2.12326
Abstract: Neocortical 3R4R (3‐repeat/4‐repeat) tau aggregates are rarely observed in the absence of amyloid beta (Aβ). 18 F‐MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer's disease (AD). We report four cases with negative Aβ, but positive tau positron emission tomography (PET) findings. All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with Aβ ( 18 F‐NAV4694) and tau ( 18 F‐MK6240) PET scans were included. Centiloid defined negative Aβ PET (Aβ–). The presence of neocortical tau was defined quantitatively and visually. Aβ– PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2 , and MAPT genes did not identify relevant functional mutations. Discordant cases were infrequent (1.4% of all Aβ– participants). In these cases, the Aβ PET ligand may not be detecting the Aβ that is present.
Publisher: SERDI
Date: 2023
Publisher: Springer Science and Business Media LLC
Date: 26-01-2021
DOI: 10.1007/S00259-021-05191-9
Abstract: Previous studies have shown that Aβ-amyloid (Aβ) likely promotes tau to spread beyond the medial temporal lobe. However, the Aβ levels necessary for tau to spread in the neocortex is still unclear. Four hundred sixty-six participants underwent tau imaging with [18F]MK6420 and Aβ imaging with [ 18 F]NAV4694. Aβ scans were quantified on the Centiloid (CL) scale with a cut-off of 25 CL for abnormal levels of Aβ (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me) temporoparietal neocortex (Te) and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippoc us, and parahippoc us). Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A- subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined. The plots of prevalence of T+ show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aβ level between 10 and 40 CL reaching 23% in Me, 15% in Te, and 11% in R. Between 40 and 70 CL, the prevalence of T+ subjects per CL increased fourfold faster and at 70 CL was 64% in Me, 51% in Te, and 37% in R. In cognitively unimpaired, there were no T+ in R below 50 CL. The highest prevalence of T+ were found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL. Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aβ below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aβ levels are required before abnormal neocortical tau becomes detectable.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2019
DOI: 10.1161/STROKEAHA.118.024347
Abstract: The computed tomography angiographic spot sign refers to contrast leakage within intracerebral hemorrhage (ICH). It has been proposed as a surrogate radiological marker for ICH growth. We conducted a meta-analysis to study the accuracy of the spot sign for predicting ICH growth and mortality. PubMed, Medline, conference proceedings, and article references in English up to June 2017 were searched for studies reporting “computed tomography angiography” and “spot sign” or “intracerebral hemorrhage” and “spot sign.” Each study was ranked on 27 criteria resulting in a quality rating score. Bivariate random effect meta-analysis was used to calculate positive and negative likelihood ratios and area under summary receiver operating characteristics curve for ICH growth and mortality. Hematoma growth was defined using the change in ≥6 mL or ≥33% increase in volume. There were 26 studies describing 5085 patients, including 15 studies not used in previous meta-analyses. Positive likelihood ratio and negative likelihood ratio for ICH growth were 4.85 (95% CI, 3.85–6.02 I 2 =76.1%) and 0.49 (95% CI, 0.40–0.58) and mortality were 4.65 (95% CI, 3.67–5.90) and 0.55 (95% CI, 0.40–0.69), respectively. For ICH growth, the pooled sensitivity was 0.57 (95% CI, 0.49–0.64) and pooled false positive rate was 0.12 (95% CI, 0.09–0.14). The post-test probability of ICH growth was 0.57. The area under the curve for ICH growth and mortality was 0.86 and 0.87 (CIs are not provided in bivariate method). Meta-regression showed sensitivity of the test to decline significantly with subsequent year of publication (β=−0.148 95% CI, −0.295 to −0.001 P =0.05). Higher quality assessment is associated with lower false positive rate (β=−0.074 95% CI, −0.126 to −0.022 P =0.006). The high area under the curve potentially suggests that the spot sign can predict hematoma growth and mortality. Caution is recommended in its application given the heterogeneity across studies, which is appropriate given the data.
Publisher: Wiley
Date: 2022
DOI: 10.1002/DAD2.12307
Abstract: We evaluated a new Simoa plasma assay for phosphorylated tau (P‐tau) at aa217 enhanced by additional p‐tau sites (p217+tau). Plasma p217+tau levels were compared to 18 F‐NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and 18 F‐MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Compared to Aβ− CU, the plasma levels of p217+tau increased 2‐fold in Aβ+ CU and 3.5‐fold in Aβ+ CI. In Aβ− the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloids P = .67 (CI, P = .64 CU, P = .45) and tau SUVR MT P = .63 (CI, P = .69 CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aβ− CU was 0.94, for AD dementia versus other dementia was 0.93, for Aβ+ versus Aβ− PET was 0.89, and for tau+ versus tau− PET was 0.89. Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Mary Ann Liebert Inc
Date: 06-2023
Publisher: Elsevier BV
Date: 02-2023
Publisher: Society of Nuclear Medicine
Date: 27-01-2022
Publisher: Elsevier BV
Date: 05-2021
DOI: 10.1053/J.SEMNUCLMED.2020.12.005
Abstract: Amyloid-β (Aβ) PET imaging has now been available for over 15 years. The ability to detect Aβ in vivo has greatly improved the clinical and research landscape of Alzheimer's disease (AD) and other neurodegenerative conditions. Aβ imaging provides very reliable, accurate, and reproducible measurements of regional and global Aβ burden in the brain. It has proved invaluable in anti-Aβ therapy trials, and is now recognized as a powerful diagnostic tool. The appropriate use of Aβ PET, when combined with comprehensive clinical evaluation by a dementia-trained specialist, can improve the accuracy of a clinical diagnosis of AD and substantially alter management. It can assist in differentiating AD from other neurodegenerative conditions, often by its ability to rule out the presence of Aβ. When combined with tau imaging, further increase in specificity for the diagnosis of AD can be achieved. The integration of Aβ PET, in conjunction with biomarkers of tau, neurodegeneration and neuroinflammation, into large, longitudinal, observational cohort studies continues to increase our understanding of the development of AD. Its incorporation into clinical trials has been pivotal in defining the most effective anti-Aβ biological therapies and optimal dosing so that effective disease modifying therapy now appears imminent. Aβ deposition is a gradual and protracted process, permitting a wide treatment window for anti-Aβ therapies and Aβ PET has made trials in this preclinical AD period feasible. Continuing improvement in Aβ tracer target to background ratio is allowing trials in earlier AD that tailor drug dosage to Aβ level. The quest to standardize quantification and define universally applicable thresholds for all Aβ tracers has produced the Centiloid method. Centiloid values that correlate well with neuropathologic findings and prognosis have been identified. Rapid cloud-based automated in idual scan analysis is now possible and does not require MRI. Challenges remain, particularly around cross camera standardized uptake value ratio variation that need to be addressed. This review will compare available Aβ radiotracers, discuss approaches to quantification, as well as the clinical and research applications of Aβ PET.
Publisher: Society of Nuclear Medicine
Date: 27-01-2022
Location: Australia
No related grants have been discovered for Natasha Krishnadas.