Effects of a physical activity intervention on brain atrophy in older adults at risk of dementia: a randomized controlled trial.

Lack of physical activity is a risk factor for dementia, however, the utility of interventional physical activity programs as a protective measure against brain atrophy and cognitive decline is uncertain. Here we present the effect of a randomized controlled trial of a 24-month physical activity intervention on global and regional brain atrophy as characterized by longitudinal voxel-based morphometry with T1-weighted MRI images. The study sample consisted of 98 participants at risk of dementia, with mild cognitive impairment or subjective memory complaints, and having at least one vascular risk factor for dementia, randomized into an exercise group and a control group. Between 0 and 24 months, there was no significant difference detected between groups in the rate of change in global, or regional brain volumes.

Baseline White Matter Is Associated With Physical Fitness Change in Preclinical Alzheimer's Disease.

White matter (WM) microstructure is a sensitive marker to distinguish individuals at risk of Alzheimer's disease. The association of objective physical fitness (PF) measures and WM microstructure has not been explored and mixed results reported with physical activity (PA). Longitudinal studies of WM with PA and PF measures have had limited investigation. This study explored the relationship between objective PF measures over 24-months with "normal-appearing" WM microstructure. Data acquired on magnetic resonance imaging was used to measure "normal-appearing" WM microstructure at baseline and 24-months. Clinical variables such as cognitive and blood-based measures were collected longitudinally. Also, as part of the randomized controlled trial of a PA, extensive measures of PA and fitness were obtained over the 24 months. Bilateral corticospinal tracts (CST) and the corpus callosum showed a significant association between PF performance over 24-months and baseline WM microstructural measures. There was no significant longitudinal effect of the intervention or PF performance over 24-months. Baseline WM microstructural measures were significantly associated with PF performance over 24-months in this cohort of participants with vascular risk factors and at risk of Alzheimer's disease with distinctive patterns for each PF test.

Effect of a 24-month physical activity program on brain changes in older adults at risk of Alzheimer's disease: the AIBL active trial.

White matter hyperintensities (WMHs) are a risk factor for cognitive decline. Physical activity (PA) is associated with lower WMH. Whether long-term exposure to PA programs has beneficial effects on WMH progression in older adults with memory complaints and comorbid conditions has had limited exploration. This study explored whether a 24-month moderate-intensity PA intervention can delay the progression of WMH and hippocampus loss in older adults at risk for cognitive decline. Data acquired on magnetic resonance imaging were used to measure the progression of WMH and hippocampus loss. The results of this study showed no effect of intervention on either the primary outcome measure "WMH" or the secondary outcome measure "hippocampal volume." In addition, neither beta amyloid status nor the adherence to the intervention had any effect on the outcome. In this cohort of subjective memory complaints and mild cognitive impairment participants with vascular risk factors, there was no effect of long-term moderate-intensity PA on WMH or hippocampal loss.

Dynamic CT for Parathyroid Adenoma Detection: How Does Radiation Dose Compare With Nuclear Medicine?

OBJECTIVE: Dynamic CT is increasingly used for preoperative localization of parathyroid adenomas, but concerns remain about the radiation effective dose of CT compared with that of 99mTc-sestamibi scintigraphy. The purpose of this study was to compare the radiation dose delivered by three-phase dynamic CT with that delivered by 99mTc-sestamibi SPECT/CT performed in accordance with our current protocols and to assess the possible reduction in effective dose achieved by decreasing the scan length (i.e., z-axis) of two phases of the dynamic CT protocol. MATERIALS AND METHODS: The effective dose of a 99mTc-sestamibi nuclear medicine parathyroid study performed with and without coregistration CT was calculated and compared with the effective dose of our current three-phase dynamic CT protocol as well as a proposed protocol involving CT with reduced scan length. RESULTS: The median effective dose for a 99mTc-sestamibi nuclear medicine study was 5.6 mSv. This increased to 12.4 mSv with the addition of coregistration CT, which is higher than the median effective dose of 9.3 mSv associated with the dynamic CT protocol. Reducing the scan length of two phases in the dynamic CT protocol could reduce the median effective dose to 6.1 mSv, which would be similar to that of the dose from the 99mTc-sestamibi study alone. CONCLUSION: Dynamic CT used for the detection of parathyroid adenoma can deliver a lower radiation dose than 99mTc-sestamibi SPECT/CT. It may be possible to reduce the dose further by decreasing the scan length of two of the phases, although whether this has an impact on accuracy of the localization needs further investigation.

Four-Dimensional Computed Tomography: Clinical Impact for Patients with Primary Hyperparathyroidism.

BACKGROUND: In recent years, four-dimensional computed tomography (4DCT) has emerged as a new localization study for primary hyperparathyroidism (pHPT). OBJECTIVE: We aimed to assess the added value of 4DCT in our institution in the first 4 years of use. METHODS: A retrospective cohort study was conducted from February 2004 to June 2015. Since 2011, patients over 50 years of age without concordant sestamibi-SPECT (SeS) and ultrasound (US) findings underwent 4DCT. Imaging results, surgical findings, histopathology, and postoperative biochemistry were collected. RESULTS: A total of 536 parathyroid operations in 510 patients were performed during the study period. The overall cure rate was 99.2% after reoperation in some patients, and the overall sensitivity for SeS was 76.0%, and 74.8% for US. Since 2011, 100 patients without concordant SeS/US findings have undergone 4DCT, with a sensitivity of 72.9%. This is in comparison to the sensitivities for SeS (48.3%) and US (52.3%). 4DCT was more sensitive in patients with persistent/recurrent disease (60.0% compared with SeS 43.8% and US 36.4%) and patients with multigland disease (67.4% compared with SeS 40.9% and US 42.1%). Comparison between outcomes in the pre- versus post-CT era demonstrated no difference in the initial cure rate (95.4 vs. 95.9%, p = 0.85) or the rate of minimally invasive parathyroidectomies (74.5 vs. 79.9%, p = 0.22). CONCLUSION: Parathyroid 4DCT can aid surgical planning in cases without concordant SeS/US findings; however, the introduction of 4DCT as a second-line test did not change our overall cure rate or rate of minimally invasive parathyroidectomy. The role of 4DCT as the primary localization study for pHPT merits further investigation.

Emotional reactivity following surgery to the prefrontal cortex.

We aimed to elicit emotion in patients with surgically circumscribed lesions of the prefrontal cortex (PFC) in order to elucidate the precise functional roles in emotion processing of the discrete subregions comprising the ventromedial PFC, including the medial PFC and orbitofrontal cortex (OFC). Three components of emotional reactivity were measured: subjective experience, behaviour, and physiological response. These included measures of self-reported emotion, observer-rated facial expression of emotion and measurements of heart rate and heart rate variability (HRV) during film viewing, and a measure of subjective emotional change since surgery. Patients with lesions to the ventromedial PFC demonstrated significant differences compared with controls in HRV during the film clips, suggesting a shift to greater dominance of sympathetic input. In contrast, patients with lesions restricted to the OFC showed significant differences in HRV suggesting reduced sympathetic input. They also showed less facial expression of emotion during positive film clips, and reported more subjective emotional change since surgery compared with controls. This human lesion study is important for refining theoretical models of emotion processing by the ventromedial PFC, which until now have primarily been based on anatomical connectivity, animal lesion, and human functional neuroimaging research. Such theories have implications for the treatment of a wide variety of emotional disorders.

Comparison between site and central radiological assessments for patients with recurrent glioblastoma on a clinical trial.

AIM: Assessment of magnetic resonance imaging (MRI) in glioblastoma can be challenging. For patients with recurrent glioblastoma managed on the CABARET trial, we compared disease status assessed at hospitals and subsequent blinded central expert radiological review. METHODS: MRI results and clinical status at specified time points were used for site and central assessment of disease status. Clinical status was determined by the site. Response Assessment in Neuro-Oncology (RANO) criteria were used for both assessments. Site and central assessments of progression-free survival (PFS) and response rates were compared. Inter-rater variability for central review progression dates was assessed. RESULTS: Central review resulted in shorter PFS in 45% of 89 evaluable patients (n = 40). Median PFS was 3.6 (central) versus 3.9 months (site) (hazard ratio 1.5, 95% confidence interval 1.3-1.8, P < 0.001). Responses were documented more frequently by sites (n = 16, 18%) than centrally (n = 11, 12%). Seven of 120 patients continued on trial without site-determined progression for more than 6 months beyond the central review determination of progression. Of scans reviewed by all three central reviewers, 33% were fully concordant for progression date. CONCLUSION: While the difference between site and central PFS dates was statistically significant, the 0.3-month median difference is small. The variability within central review is consistent with previous studies, highlighting the challenges in MRI interpretation in this context. A small proportion of patients benefited from treatment well beyond the centrally determined progression date, reinforcing that clinical status together with radiology results are important determinants of whether a therapy is effective for an individual.

The role of early magnetic resonance imaging in predicting survival on bevacizumab for recurrent glioblastoma: Results from a prospective clinical trial (CABARET).

BACKGROUND: Bevacizumab has been associated with prolonged progression-free survival for patients with recurrent glioblastoma; however, not all derive a benefit. An early indicator of efficacy or futility may allow early discontinuation for nonresponders. This study prospectively assessed the role of early magnetic resonance imaging (eMRI) and its correlation with subsequent routine magnetic resonance imaging (MRI) results and survival. METHODS: Patients were part of a randomized phase 2 clinical trial (CABARET) comparing bevacizumab with bevacizumab plus carboplatin for recurrent glioblastoma. eMRI was conducted after 4 weeks in the trial (after 2 treatments with bevacizumab [10 mg/kg every 2 weeks]). The results were compared with the results of the subsequent 8-week MRI standard. RESULTS: For 119 of 122 patients, eMRI was available, and 111 had subsequent MRI for comparison. Thirty-six (30%) had an early radiological response, and 17 (14%) had progressive disease. The concordance between eMRI and 8-week MRI was moderate (κ = 0.56), with most providing the same result (n = 79 [71%]). There was strong evidence that progression-free survival and overall survival were predicted by the eMRI response (both P values < .001). The median survival was 8.6 months for an eMRI response, 6.6 months for stable disease, and 3.7 months for progressive disease; the hazard ratio (progressive disease vs stable disease) was 3.4 (95% confidence interval, 1.9-6.0). Landmark analyses showed that eMRI progression was a strong predictor of mortality independent of other potential baseline predictors. CONCLUSIONS: In this study, early progression on MRI appears to be a robust marker of a poor prognosis for patients on bevacizumab. Cancer 2017;123:3576-82. © 2017 American Cancer Society.

Angiocentric glioma transformed into anaplastic ependymoma: Review of the evidence for malignant potential.

Angiocentric glioma (AG) is a low grade glioma, that was first described in 2002. Since this description, 83 patients with AG have been described, including ours. AG typically presents in childhood with medically refractory seizures that are cured with gross surgical resection. Whilst the natural history is that of a benign tumour, there have been reports of recurrence, transformation, and malignant features that suggest that AG is potentially malignant. We add to the literature a case of a 16-year-old girl who presented in May 2011 with a 3-month history of complex partial seizures, with MRI showing a T2-weighted hyperintense lesion in the left insula and inferior frontal lobe. This was confirmed on biopsy as AG and was followed with surveillance imaging. In April 2012, she presented with disease progression and underwent a left temporal lobectomy, with histology showing both AG and grade II astrocytoma. Adjuvant radiotherapy of 50 Gray in 28 fractions was administered. A small area of contrast enhancement appeared in the left parietal lobe in December 2012, which progressed over subsequent months. In June 2013, she underwent a near total excision, with histology showing anaplastic ependymoma. She received six cycles of adjuvant temozolamide. Despite this, the tumour continued to progress, with her seizure control deteriorating, and the development of a right hemiparesis. The patient died in January 2014, aged 19years.

Assessment of Optic Pathway Structure and Function in Patients With Compression of the Optic Chiasm: A Correlation With Optical Coherence Tomography.

PURPOSE: The purpose of this study was to investigate correlations between retinal fiber thickness measured by optical coherence tomography (OCT) and anterograde functional and structural differences in the optic pathway of patients with compression of the optic chiasm. Our hypothesis was that loss of visual acuity caused by chronic compressive pathologies may lead to an irreversible decline in vision because of permanent neurodegeneration of the optic radiations and visual cortex. METHODS: Quantitative OCT, functional magnetic resonance imaging (MRI) and diffusion tensor MRI measurements were made in 17 patients being surgically treated for chiasmal compression. RESULTS: In our study we found that surgically irreversible visual field defects and reduced retinal nerve fiber layer thickness were significantly associated with lower fractional diffusion anisotropy and higher diffusivities in optic radiations and less functional MRI activation in the visual cortex. CONCLUSIONS: Damage to the retinal nerve fiber layer is associated with downstream structural and functional degradation of the optic pathway. This may be related to trans-synaptic degeneration and the fact that these factors are important potential imaging biomarkers for predicting visual recovery after surgical decompression.

Audit of CT reporting standards in cases of intracerebral haemorrhage at a comprehensive stroke centre in Australia.

INTRODUCTION: Multiple CT-derived biomarkers that are predictive of intracerebral haemorrhage (ICH) growth and outcome have been described in the literature, but the extent to which these appear in imaging reports of ICH is unknown. The aim of this retrospective process audit was to determine which of the known predictors of ICH outcome was recorded in reports of the disease, with a view to providing reporting recommendations, as appropriate. METHOD: We examined the initial CT report of patients diagnosed with ICH presenting to a metropolitan comprehensive stroke centre and meeting inclusion criteria during the audit period between 1 March 2013 and 28 February 2014. Each report was assessed for the inclusion of the following ICH characteristics: the number of measurement dimensions; volume; location; hydrocephalus; shape; density; 'CTA spot sign' (where CTA was performed). RESULTS: A total of 100 patients met audit inclusion criteria. At least one ICH dimension was recorded in 90% of reports; however, 39% did not include the measurements in three dimensions and volume was reported in just 6%. No ICH dimension was recorded in 10% of reports. With the exception of density and shape, reporting of other CT features exceeded 95%. Where CTA was performed (58%), 14 (24%) of 58 reported the 'CTA spot sign' status. CONCLUSION: In this audit, volume was the most under-reported of the established ICH characteristics predictive of ICH outcome. Readily calculated from multiplanar reformats using the ABC/2 technique, the routine reporting of ICH volume is recommended. More reporting attention to ICH density heterogeneity and shape irregularity is encouraged, given their emerging importance. Where acute CTA is performed, the presence of any dynamic haemorrhage (CTA spot sign) should be reported.

Imaging characteristics of nodal metastases in paraganglioma, ameloblastoma and olfactory neuroblastoma: case reports and literature review.

Paraganglioma, ameloblastoma and olfactory neuroblastoma are uncommon primary head and neck tumours. When nodal metastases from these tumours occur, they may present later than and with different imaging characteristics compared with squamous cell carcinoma (SCC), demonstrating appearances similar to the primary tumour type rather than features typical of metastatic nodal SCC. We present three cases in which imaging characteristics of nodal metastases in paraganglioma, ameloblastoma and olfactory neuroblastoma mimicked the primary tumour and discuss their implications for clinicoradiological follow-up.

Cervical CT scan-guided epidural blood patches for spontaneous intracranial hypotension.

We describe two patients with spontaneous intracranial hypotension (SIH), presenting with postural headache due to C1-C2 cerebrospinal fluid (CSF) leak. Both patients were refractory to lumbar epidural blood patching (EBP), and subsequently underwent successful CT scan-guided cervical EBP. SIH affects approximately 1 in 50,000 patients, with females more frequently affected. Its associated features are variable, and as such, misdiagnosis is common. Therefore, imaging plays an important role in the diagnostic workup of SIH and can include MRI of the brain and spine, CT myelogram, and radionuclide cisternography. In patients with an established diagnosis and confirmed CSF leak, symptoms will usually resolve with conservative management. However, in a select subgroup of patients, the symptoms are refractory to medical management and require more invasive therapies. In patients with cervical leaks, EBP in the cervical region is an effective management approach, either in close proximity to, or directly targeting a dural defect. CT scan-guided cervical EBP is an effective treatment approach in refractory SIH, and should be considered in those patients who are refractory to conservative management.

Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma.

BACKGROUND: The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy. METHODS: This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS). RESULTS: One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately. CONCLUSIONS: Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies. CLINICAL TRIALS REGISTRATION NR: ACTRN12610000915055.

Primary angiitis of the central nervous system presenting as a mass lesion.

We report a 51-year-old Asian man with primary angiitis of the central nervous system (PACNS) with atypical presentation as a mass lesion. PACNS is an uncommon condition causing inflammation and destruction of the blood vessels of the central nervous system. The aetiology is unclear and multiple mechanisms have been proposed. Its incidence is estimated at 2.4 per million per year, affecting patients of all ages (median 50 years) and more commonly Caucasian men. In Australia, 12 patients fulfilled the diagnostic criteria for PACNS between 1998 and 2009 at The Royal Melbourne Hospital, a university-affiliated tertiary referral centre. The accurate and timely diagnosis of PACNS is very challenging due to disease mimicry and the absence of specific serological tests. This patient illustrates additional diagnostic difficulty with his atypical PACNS presentation as a mass lesion.

Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer.

Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

Probabilistic MRI tractography of the optic radiation using constrained spherical deconvolution: a feasibility study.

BACKGROUND AND PURPOSE: Imaging the optic radiation (OR) is of considerable interest in studying diseases affecting the visual pathway and for pre-surgical planning of temporal lobe resections. The purpose of this study was to investigate the clinical feasibility of using probabilistic diffusion tractography based on constrained spherical deconvolution (CSD) to image the optic radiation. It was hypothesized that CSD would provide improved tracking of the OR compared with the widely used ball-and-stick model. METHODS: Diffusion weighted MRI (30 directions) was performed on twenty patients with no known visual deficits. Tractography was performed using probabilistic algorithms based on fiber orientation distribution models of local white matter trajectories. The performance of these algorithms was evaluated by comparing computational times and receiver operating characteristic results, and by correlation of anatomical landmark distances to dissection estimates. RESULTS: The results showed that it was consistently feasible to reconstruct individual optic radiations from clinically practical (4.5 minute acquisition) diffusion weighted imaging data sets using CSD. Tractography based on the CSD model resulted in significantly shorter computational times, improved receiver operating characteristic results, and shorter Meyer's loop to temporal pole distances (in closer agreement with dissection studies) when compared to the ball-and-stick based algorithm. CONCLUSIONS: Accurate tractography of the optic radiation can be accomplished using diffusion MRI data collected within a clinically practical timeframe. CSD based tractography was faster, more accurate and had better correlation with known anatomical landmarks than ball-and-stick tractography.

Progressive post traumatic tearing of an arachnoid cyst membrane resulting in intracystic and subdural haemorrhage.

We report the case of a 43-year-old man with a middle cranial fossa arachnoid cyst who presented post trauma with neurological symptoms. The initial CT scan of the brain did not detect acute changes in the arachnoid cyst but subsequent imaging revealed abnormalities which progressed over time. Arachnoid cysts are usually a benign and incidental finding. Rare complications such as intracystic haemorrhage and subdural haemorrhage can occur. It is important to be aware of these complications so that patients with arachnoid cysts are appropriately investigated when presenting with neurological symptoms.

Alterations in dorsal and ventral posterior cingulate connectivity in APOE ε4 carriers at risk of Alzheimer's disease.

BACKGROUND: Recent evidence suggests that exercise plays a role in cognition and that the posterior cingulate cortex (PCC) can be divided into dorsal and ventral subregions based on distinct connectivity patterns. AIMS: To examine the effect of physical activity and division of the PCC on brain functional connectivity measures in subjective memory complainers (SMC) carrying the epsilon 4 allele of apolipoprotein E (APOE ε4) allele. METHOD: Participants were 22 SMC carrying the APOE ε4 allele (ε4+; mean age 72.18 years) and 58 SMC non-carriers (ε4-; mean age 72.79 years). Connectivity of four dorsal and ventral seeds was examined. Relationships between PCC connectivity and physical activity measures were explored. RESULTS: ε4+ individuals showed increased connectivity between the dorsal PCC and dorsolateral prefrontal cortex, and the ventral PCC and supplementary motor area (SMA). Greater levels of physical activity correlated with the magnitude of ventral PCC-SMA connectivity. CONCLUSIONS: The results provide the first evidence that ε4+ individuals at increased risk of cognitive decline show distinct alterations in dorsal and ventral PCC functional connectivity. DECLARATION OF INTEREST: D.A. has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, Prana and Pfizer, and as Editor-in-Chief for International Psychogeriatrics; received speaker honoraria from Pfizer and Lundbeck, and research support from Eli Lilly, GlaxoSmithKline, Forest Laboratories, Novartis, and CSIRO. C.L.M. has received consulting fees from Eli Lilly and Prana Biotechnology, and has stock ownership in Prana Biotechnology. C.C.R. has received consultancy payments from Roche and Piramal, and research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Piramal and Navidea for amyloid imaging. C.S. has provided clinical consultancy and been on scientific advisory committees for the Australian CSIRO, Alzheimer's Australia, University of Melbourne and other relationships, which are subject to confidentiality clauses; she has been a named Chief Investigator on investigator-driven collaborative research projects in partnership with Pfizer, Merck, Piramal, Bayer and GE Healthcare. Her research programme has received support from the National Health and Medical Research Council Alzheimer's Association, Collier Trust, Scobie and Claire McKinnon Foundation, JO and JR Wicking Trust, Shepherd Foundation, Brain Foundation, Mason Foundation, Ramaciotti Foundation, Alzheimer's Australia and the Royal Australian College of Physicians. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.