Bradley J. MacIntosh

Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele.

The APOE ε4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE ε4-carriers and 18 matched noncarriers (age range: 20–35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased “default mode network” (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in ε4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in ε4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE ε4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.

Recommended implementation of arterial spin-labeled Perfusion mri for clinical applications: A consensus of the ISMRM Perfusion Study group and the European consortium for ASL in dementia

This review provides a summary statement of recommended implementations of arterial spin labeling (ASL) for clinical applications. It is a consensus of the ISMRM Perfusion Study Group and the European ASL in Dementia consortium, both of whom met to reach this consensus in October 2012 in Amsterdam. Although ASL continues to undergo rapid technical development, we believe that current ASL methods are robust and ready to provide useful clinical information, and that a consensus statement on recommended implementations will help the clinical community to adopt a standardized approach. In this review, we describe the major considerations and trade‐offs in implementing an ASL protocol and provide specific recommendations for a standard approach. Our conclusion is that as an optimal default implementation, we recommend pseudo‐continuous labeling, background suppression, a segmented three‐dimensional readout without vascular crushing gradients, and calculation and presentation of both label/control difference images and cerebral blood flow in absolute units using a simplified model. Magn Reson Med 73:102–116, 2015.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

BACKGROUND Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. METHODS We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. FINDINGS Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). INTERPRETATION Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. FUNDING Centres of Excellence in Neurodegeneration.

Differential effects of the APOE genotype on brain function across the lifespan.

Increasing age and carrying an APOE ε4 allele are well established risk factors for Alzheimers disease (AD). The earlier age of onset of AD observed in ε4-carriers may reflect an accelerated aging process. We recently reported that APOE genotype modulates brain function decades before the appearance of any cognitive or clinical symptoms. Here we test the hypothesis that APOE influences brain aging by comparing healthy ε4-carriers and non-carriers, using the same imaging protocol in distinct groups of younger and older healthy volunteers. A cross-sectional factorial design was used to examine the effects of age and APOE genotype, and their interaction, on fMRI activation during an encoding memory task. The younger (N=36; age range 20-35; 18 ε4-carriers) and older (35 middle-age/elderly; age range 50-78 years; 15 ε4-carriers) healthy volunteers taking part in the study were cognitively normal. We found a significant interaction between age and ε4-status in the hippocampi, frontal pole, subcortical nuclei, middle temporal gyri and cerebellum, such that aging was associated with decreased activity in e4-carriers and increased activity in non-carriers. Reduced cerebral blood flow was found in the older ε4-carriers relative to older non-carriers despite preserved grey matter volume. Overactivity of brain function in young ε4-carriers is disproportionately reduced with advancing age even before the onset of measurable memory impairment. The APOE genotype determines age-related changes in brain function that may reflect the increased vulnerability of ε4-carriers to late-life pathology or cognitive decline.

Opioids Depress Cortical Centers Responsible for the Volitional Control of Respiration

Respiratory depression limits provision of safe opioid analgesia and is the main cause of death in drug addicts. Although opioids are known to inhibit brainstem respiratory activity, their effects on cortical areas that mediate respiration are less well understood. Here, functional magnetic resonance imaging was used to examine how brainstem and cortical activity related to a short breath hold is modulated by the opioid remifentanil. We hypothesized that remifentanil would differentially depress brain areas that mediate sensory-affective components of respiration over those that mediate volitional motor control. Quantitative measures of cerebral blood flow were used to control for hypercapnia-induced changes in blood oxygen level-dependent (BOLD) signal. Awareness of respiration, reflected by an urge-to-breathe score, was profoundly reduced with remifentanil. Urge to breathe was associated with activity in the bilateral insula, frontal operculum, and secondary somatosensory cortex. Localized remifentanil-induced decreases in breath hold-related activity were observed in the left anterior insula and operculum. We also observed remifentanil-induced decreases in the BOLD response to breath holding in the left dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, and periaqueductal gray, brain areas that mediate task performance. Activity in areas mediating motor control (putamen, motor cortex) and sensory-motor integration (supramarginal gyrus) were unaffected by remifentanil. Breath hold-related activity was observed in the medulla. These findings highlight the importance of higher cortical centers in providing contextual awareness of respiration that leads to appropriate modulation of respiratory control. Opioids have profound effects on the cortical centers that control breathing, which potentiates their actions in the brainstem.

Assessment of arterial arrival times derived from multiple inversion time pulsed arterial spin labeling MRI

The purpose of this study was to establish a normal range for the arterial arrival time (AAT) in whole‐brain pulsed arterial spin labeling (PASL) cerebral perfusion MRI. Healthy volunteers (N = 36, range: 20 to 35 years) provided informed consent to participate in this study. AAT was assessed in multiple brain regions, using three‐dimensional gradient and spin echo (GRASE) pulsed arterial spin labeling at 3.0 T, and found to be 641 ± 95, 804 ± 91, 802 ± 126, and 935 ± 108 ms in the temporal, parietal, frontal, and occipital lobes, respectively. Mean gray matter AAT was found to be 694 ± 89 ms for females (N = 15), which was significantly shorter than for men, 814 ± 192 ms (N = 21; P < 0.0003), and significant after correcting for brain volume (P < 0.001). Significant AAT sex differences were also found using voxelwise permutation testing. An atlas of AAT values across the healthy brain is presented here and may be useful for future experiments that aim to quantify cerebral blood flow from ASL data, as well as for clinical comparisons where disease pathology may lead to altered AAT. Pulsed arterial spin labeling signals were simulated using an identical sampling scheme as the empiric study and revealed AAT can be estimated robustly when simulated arrival times are well beyond the normal range. Magn Reson Med, 2010.

Measuring the effects of remifentanil on cerebral blood flow and arterial arrival time using 3D GRASE MRI with pulsed arterial spin labelling

Arterial spin labelling (ASL) has proved to be a promising magnetic resonance imaging (MRI) technique to measure brain perfusion. In this study, volumetric three-dimensional (3D) gradient and spin echo (GRASE) ASL was used to produce cerebral blood flow (CBF) and arterial arrival time (AAT) maps during rest and during an infusion of remifentanil. Gradient and spin echo ASL perfusion-weighted images were collected at multiple inflow times (500 to 2,500 ms in increments of 250 ms) to accurately fit an ASL perfusion model. Fit estimates were assessed using z-statistics, allowing voxels with a poor fit to be excluded from subsequent analyses. Nonparametric permutation testing showed voxels with a significant difference in CBF and AAT between conditions across a group of healthy participants (N = 10). Administration of remifentanil produced an increase in end-tidal CO2, an increase in CBF from 57 ± 12.0 to 77 ± 18.4 mL/100 g tissue per min and a reduction in AAT from 0.73 ± 0.073 to 0.64 ± 0.076 secs. Within grey matter, remifentanil produced a cerebrovascular response of 5.7 ± 1.60 %CBF per mm Hg. Significant differences between physiologic conditions were observed in both CBF and AAT maps, indicating that 3D GRASE-ASL has the sensitivity to study changes in physiology at a voxel level.

Cerebral Blood Flow, Blood Volume, and Oxygen Metabolism Dynamics in Human Visual and Motor Cortex as Measured by Whole-Brain Multi-Modal Magnetic Resonance Imaging

The development of neuroimaging methods to characterize flow-metabolism coupling is crucial for understanding mechanisms that subserve oxygen delivery. Functional magnetic resonance imaging (fMRI) using blood-oxygenation-level-dependent (BOLD) contrast reflects composite changes in cerebral blood volume (CBV), cerebral blood flow (CBF), and the cerebral metabolic rate of oxygen consumption (CMRO2). However, it is difficult to separate these parameters from the composite BOLD signal, thereby hampering MR-based flow-metabolism coupling studies. Here, a novel, noninvasive CBV-weighted MRI approach (VASO-FLAIR with 3D GRASE (GRadient-And-Spin-Echo)) is used in conjunction with CBF-weighted and BOLD fMRI in healthy volunteers (n=7) performing simultaneous visual (8 Hz flashing-checkerboard) and motor (1 Hz unilateral joystick) tasks. This approach allows for CBV, CBF, and CMRO2 to be estimated, yielding (mean±s.d.): ΔCBF=63%±12%, ΔCBV=17%±7%, and ΔCMRO2=13%±11% in the visual cortex, and ΔCBF=46%±11%, ΔCBV=8%±3%, and ΔCMRO2=12%±13% in the motor cortex. Following the visual and motor tasks, the BOLD signal became more negative (P=0.003) and persisted longer (P=0.006) in the visual cortex compared with the motor cortex, whereas CBV and CBF returned to baseline earlier and equivalently. The proposed whole-brain technique should be useful for assessing regional discrepancies in hemodynamic reactivity without the use of intravascular contrast agents.

Multiple inflow pulsed arterial spin-labeling reveals delays in the arterial arrival time in minor stroke and transient ischemic attack.

SUMMARY: Our purpose was to use multiple inflow pulsed ASL to investigate whether hemodynamic AAT information is sensitive to hemispheric asymmetry in acute ischemia. The cohorts included 15 patients with acute minor stroke or TIA and 15 age-matched controls. Patients were scanned by using a stroke MR imaging protocol at a median time of 74 hours. DWI lesion volumes were small and functional impairment was low; however, perfusion abnormalities were evident. Prolonged AAT values were more likely to reside in the affected hemisphere (significant when compared with controls, P < .048). An advantage of this ASL technique is the ability to use AAT information in addition to CBF to characterize ischemia.

Separation of macrovascular signal in multi-inversion time arterial spin labelling MRI.

Arterial spin labeling (ASL) provides a noninvasive method to measure brain perfusion and is becoming an increasingly viable alternative to more invasive MR methods due to improvements in acquisition, such as the use of a three‐dimensional GRASE readout. A potential source of error in ASL measurements is signal arising from intravascular blood that is destined for more distal tissue. This is typically suppressed using diffusion gradients in many ASL sequences. However, several problems exist with this approach, such as the choice of cutoff velocity and gradient direction and incompatibility with certain readout modules. An alternative approach is to explicitly model the intravascular signal. This study exploits this approach by using multi‐inversion time ASL data with a recently developed model‐fitting method. The method employed permits the intravascular contribution to be discarded in voxels where there is no support in the data for its inclusion, thereby addressing the issue of overfitting. It is shown by comparing data with and without flow suppression, and by comparing the intravascular contribution in GRASE ASL data to MR angiographic images, that the model‐fitting approach can provide a viable alternative to flow suppression in ASL where suppression is either not feasible or not desirable. Magn Reson Med 63:1357–1365, 2010.