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1.  Selective neuronal loss in ischemic stroke and cerebrovascular disease 
As a sequel of brain ischemia, selective neuronal loss (SNL)—as opposed to pannecrosis (i.e. infarction)—is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and 11C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary ‘exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences—including the impact on neurological recovery and contribution to vascular cognitive impairment—association with possible causal processes such as microglial activation, and preventability of SNL.
doi:10.1038/jcbfm.2013.188
PMCID: PMC3887360  PMID: 24192635
carotid disease; cerebral ischemia; 11C-flumazenil; neuronal death; PET; vascular cognitive impairment
2.  Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy 
Neurology  2013;81(19):1666-1673.
Objective:
To investigate whether cortical superficial siderosis (cSS) on MRI, especially if disseminated (involving more than 3 sulci), increases the risk of future symptomatic lobar intracerebral hemorrhage (ICH) in cerebral amyloid angiopathy (CAA).
Methods:
European multicenter cohort study of 118 patients with CAA (104 with baseline symptomatic lobar ICH) diagnosed according to the Boston criteria. We obtained baseline clinical, MRI, and follow-up data on symptomatic lobar ICH. Using Kaplan-Meier and Cox regression analyses, we investigated cSS and ICH risk, adjusting for known confounders.
Results:
During a median follow-up time of 24 months (interquartile range 9–44 months), 23 of 118 patients (19.5%, 95% confidence interval [CI]: 12.8%–27.8%) experienced symptomatic lobar ICH. Any cSS and disseminated cSS were predictors of time until first or recurrent ICH (log-rank test: p = 0.0045 and p = 0.0009, respectively). ICH risk at 4 years was 25% (95% CI: 7.6%–28.3%) for patients without siderosis; 28.9% (95% CI: 7.7%–76.7%) for patients with focal siderosis; and 74% (95% CI: 44.1%–95.7%) for patients with disseminated cSS (log-rank test: p = 0.0031). In Cox regression models, any cSS and disseminated cSS were both independently associated with increased lobar ICH risk, after adjusting for ≥2 microbleeds and age (hazard ratio: 2.53; 95% CI: 1.05–6.15; p = 0.040 and hazard ratio: 3.16; 95% CI: 1.35–7.43; p = 0.008, respectively). These results remained consistent in sensitivity analyses including only patients with symptomatic lobar ICH at baseline.
Conclusions:
Our findings indicate that cSS, particularly if disseminated, is associated with an increased risk of symptomatic lobar ICH in CAA. cSS may help stratify future bleeding risk in CAA, with implications for prognosis and treatment.
doi:10.1212/01.wnl.0000435298.80023.7a
PMCID: PMC3812101  PMID: 24107862
3.  Acute Stroke Imaging Research Roadmap II 
doi:10.1161/STROKEAHA.113.002015
PMCID: PMC4040226  PMID: 23860298
4.  White matter perivascular spaces 
Neurology  2014;82(1):57-62.
Objective:
We investigated whether severe, MRI-visible perivascular spaces (PVS) in the cerebral hemisphere white matter (centrum semiovale) are more common in patients with pathology-proven cerebral amyloid angiopathy (CAA) than in those with pathology-proven non–CAA-related intracerebral hemorrhage (ICH).
Methods:
Using a validated 4-point scale on axial T2-weighted MRI, we compared PVS in patients with pathology-proven CAA to PVS in those with spontaneous ICH but no histopathologic evidence of CAA. In a preliminary analysis restricted to patients with T2*-weighted gradient-recalled echo MRI, we also investigated whether including severe centrum semiovale PVS increases the sensitivity of existing diagnostic criteria for probable CAA.
Results:
Fourteen patients with CAA and 10 patients with non–CAA-related ICH were included. Eight of the patients with CAA were admitted for symptomatic, spontaneous lobar ICH, 1 because of ischemic stroke, 1 with transient focal neurologic episodes, and 4 due to cognitive decline. Severe (>20) centrum semiovale PVS were more frequent in patients with CAA compared to controls (12/14 [85.7%; 95% confidence interval (CI): 57.2%–98.2%] vs 0/10 [1-sided 95% CI: 0%–30.8%], p < 0.0005); this was robust to adjustment for age. The original Boston criteria for probable CAA showed a sensitivity of 76.9% (95% CI: 46.2%–95%), which increased to 92.3% (95% CI: 64%–99.8%), without loss of specificity, after including severe centrum semiovale PVS.
Conclusions:
Severe centrum semiovale PVS on MRI may be a promising new neuroimaging marker for the in vivo diagnosis of CAA. However, our findings are preliminary and require confirmation and external validation in larger cohorts of pathology-proven CAA.
doi:10.1212/01.wnl.0000438225.02729.04
PMCID: PMC3873625  PMID: 24285616
5.  Amyloid Imaging With Carbon 11–Labeled Pittsburgh Compound B for Traumatic Brain Injury 
JAMA neurology  2014;71(1):23-31.
OBJECTIVES
To image amyloid deposition in patients with traumatic brain injury (TBI) using carbon 11–labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) and to validate these findings using tritium-labeled PiB ([3H]PiB) autoradiography and immunocytochemistry in autopsy-acquired tissue.
DESIGN, SETTING, AND PARTICIPANTS
In vivo PET at tertiary neuroscience referral center and ex vivo immunocytochemistry of autopsy-acquired brain tissue from a neuropathology archive. [11C]PiB PET was used to image amyloid deposition in 11 controls (median [range] age, 35 [24–60] years) and in 15 patients (median [range] age, 33 [21–50] years) between 1 and 361 days after a TBI. [3H]PiB autoradiography and immunocytochemistry for β-amyloid (Aβ) and β-amyloid precursor protein in brain tissue were obtained from separate cohorts of 16 patients (median [range] age, 46 [21–70] years) who died between 3 hours and 56 days after a TBI and 7 controls (median [range] age, 61 [29–71] years) who died of other causes.
MAIN OUTCOMES AND MEASURES
We quantified the [11C]PiB distribution volume ratio and standardized uptake value ratio in PET images. The distribution volume ratio and the standardized uptake value ratio were measured in cortical gray matter, white matter, and multiple cortical and white matter regions of interest, as well as in striatal and thalamic regions of interest. We examined [3H]PiB binding and Aβ and β-amyloid precursor protein immunocytochemistry in autopsy-acquired brain tissue.
RESULTS
Compared with the controls, the patients with TBI showed significantly increased [11C]PiB distribution volume ratios in cortical gray matter and the striatum (corrected P < .05 for both), but not in the thalamus or white matter. Increases in [11C]PiB distribution volume ratios in patients with TBI were seen across most cortical subregions, were replicated using comparisons of standardized uptake value ratios, and could not be accounted for by methodological confounders. Autoradiography revealed [3H]PiB binding in neocortical gray matter, in regions where amyloid deposition was demonstrated by immunocytochemistry; white matter showed Aβ and β-amyloid precursor protein by immunocytochemistry, but no [3H]PiB binding. No plaque-associated amyloid immunoreactivity or [3H]PiB binding was seen in cerebellar gray matter in autopsy-acquired tissue from either controls or patients with TBI, although 1 sample of cerebellar tissue from a patient with TBI showed amyloid angiopathy in meningeal vessels.
CONCLUSIONS AND RELEVANCE
[11C]PiB shows increased binding following TBI. The specificity of this binding is supported by neocortical [3H]PiB binding in regions of amyloid deposition in the postmortem tissue of patients with TBI. [11C]PiB PET could be valuable in imaging amyloid deposition following TBI.
doi:10.1001/jamaneurol.2013.4847
PMCID: PMC4084932  PMID: 24217171
6.  Effects of Healthy Ageing on Activation Pattern within the Primary Motor Cortex during Movement and Motor Imagery: An fMRI Study 
PLoS ONE  2014;9(6):e88443.
The increase in older adults over the coming decades will be accompanied by a greater burden of chronic neurological diseases affecting the motor system. The motor system adapts to maintain motor performance with the primary motor cortex (BA4) emerging as a pivotal node within this neuroplastic process. Studies of ageing often consider BA4 a homogenous area but cytoarchitectonic studies have revealed two subdivisions, an anterior (BA4a) and posterior subdivision (BA4p). Here we focus upon the effects of ageing on the involvement of BA4a and BA4p during movement and motor imagery (MI). Thirty-one right-handed healthy volunteers were recruited and screened for their ability to perform imagery (5 subjects excluded). The sample was split into an older group (n = 13, mean age 56.4 SD 9.4) and a younger group (n = 13, mean age 27.4 SD 5.3). We used an fMRI block-design (auditory-paced [1 Hz] right hand finger-thumb opposition sequence [2,3,4,5, 2…]) with MI & rest and actual movement & rest. We explored the distribution-based clustering and weighted laterality index within BA4a and BA4p. The involvement of BA4p during MI (measured with distribution-based clustering) was significantly greater in the older group (p<0.05) than in the younger group. Hemispheric balance of BA4p decreased with age during MI (Spearman rho −0.371; p<0.05), whereas that of BA4a decreased with age during actual movement (Spearman rho = −0.458 p<0.01). Irrespective of age, we found BA4 is involved during motor imagery, strengthening the rationale for its potential use in older subjects. These findings suggest that the functions of the subdivisions of BA4 are differentially affected by ageing and have implications regarding how ageing affects the cognitive processes underlying motor functions.
doi:10.1371/journal.pone.0088443
PMCID: PMC4041563  PMID: 24887402
7.  Clinical and Magnetic Resonance Imaging Predictors of Very Early Neurological Response to Intravenous Thrombolysis in Patients With Middle Cerebral Artery Occlusion 
Background
The early identification of patients who are unlikely to respond to intravenous recombinant tissue plasminogen activator (IV‐tPA) could help select candidates for additional intra‐arterial therapy or add‐on antithrombotic drugs during the acute stage of stroke. Given that very early neurological improvement (VENI) is a reliable surrogate of early recanalization, we assessed the clinical and magnetic resonance imaging predictors of lack of VENI.
Methods and Results
We reviewed consecutive ischemic stroke patients with middle cerebral artery occlusion and treated within 4.5 hours by IV‐tPA between 2003 and 2012 in our center, where magnetic resonance imaging is systematically implemented as first‐line diagnostic workup. Lack of VENI was defined as a <40% decrease in baseline National Institutes of Health Stroke Scale (NIHSS) score 1 hour after start of IV‐tPA. Poor outcome was defined as a 3‐month modified Rankin scale ≥2. Associations between lack of VENI and potential determinants were assessed in logistic regression models. In all, 186 patients were included (median baseline NIHSS score, 16; median onset to treatment time, 155 minutes). One hundred forty‐three patients (77%) had no VENI. The variables significantly associated with lack of VENI in multivariable analysis were baseline NIHSS (OR, 1.08; 95% CI, 1.01 to 1.16 per 1‐point increase; P=0.03), onset to treatment time >120 minutes (OR, 2.94; 95% CI, 1.31 to 6.63; P=0.009) and diffusion weighted imaging—Alberta Stroke Programme Early CT Score ≤5 (OR, 3.60; 95% CI, 1.14 to 11.35; P=0.03). Patients without VENI were more likely to have a modified Rankin Scale ≥2 than those without VENI (68% versus 24%; OR, 5.01; 95% CI, 2.12 to 11.82) and less likely to have recanalization after 24 hours (OR, 0.41; 95% CI, 0.19 to 0.88).
Conclusions
Lack of VENI provides an early estimate of 3‐month outcome and recanalization after IV‐tPA. Baseline NIHSS, onset to treatment time, and diffusion weighted imaging—Alberta Stroke Programme Early CT Score could help to predict lack of VENI and, in turn, might help early selection of candidates for complementary reperfusion strategies.
doi:10.1161/JAHA.113.000511
PMCID: PMC3886747  PMID: 24308937
acute stroke; outcome; thrombolysis
8.  A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment 
Brain  2013;136(11):3252-3270.
Through the combined use of 18F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case–control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.
doi:10.1093/brain/awt263
PMCID: PMC4125626  PMID: 24163364
attention deficit/hyperactivity disorder; 18F-fallypride PET; dopamine; methylphenidate; sustained attention
9.  Motor Imagery After Stroke 
Annals of neurology  2009;66(5):604-616.
Objective
Neuroplasticity is essential for recovery after stroke and is the target for new stroke therapies. During recovery from subcortical motor stroke, brain activations associated with movement may appear normal despite residual functional impairment. This raises an important question: how far does recovery of motor performance depend on the processes that precede movement execution involving the premotor and prefrontal cortex, rather than recovery of the corticospinal system alone?
Methods
We examined stroke patients with functional magnetic resonance imaging while they either imagined or executed a finger-thumb opposition sequence. In addition to classical analyses of regional activations, we studied neuroplasticity in terms of differential network connectivity using structural equation modeling. The study included 8 right-handed patients who had suffered a left-hemisphere subcortical ischemic stroke with paresis, and 13 age-matched healthy controls.
Results
With good functional recovery, the regional activations had returned to normal in patients. However, connectivity within the extended motor network remained abnormal. These abnormalities were seen predominantly during motor imagery and correlated with motor performance.
Interpretation
Our results indicate that neuroplasticity can manifest itself as differences in connectivity among cortical areas remote from the infarct, rather than in the degree of regional activation. Connection strengths between nodes of the cortical motor network correlate with motor outcome. The altered organization of connectivity of the prefrontal areas may reflect the role of the prefrontal cortex in higher order planning of movement. Our results are relevant to the assessment and understanding of emerging physical and neurophysiological therapies for stroke rehabilitation.
doi:10.1002/ana.21810
PMCID: PMC3791355  PMID: 19938103
11.  Mental Rotation: Effects of Gender, Training and Sleep Consolidation 
PLoS ONE  2013;8(3):e60296.
A wide range of experimental studies have provided evidence that a night of sleep contributes to memory consolidation. Mental rotation (MR) skill is characterized by fundamental aspect of both cognitive and motor abilities which can be improved within practice sessions, but little is known about the effect of consolidation after MR practice. In the present study, we investigated the effect of MR training and the following corresponding day- and sleep-related time consolidations in taking into account the well-established gender difference in MR. Forty participants (20 women) practiced a computerized version of the Vandenberg and Kuse MR task. Performance was evaluated before MR training, as well as prior to, and after a night of sleep or a similar daytime interval. Data showed that while men outperformed women during the pre-training test, brief MR practice was sufficient for women to achieve equivalent performance. Only participants subjected to a night of sleep were found to enhance MR performance during the retest, independently of gender. These results provide first evidence that a night of sleep facilitates MR performance compared with spending a similar daytime interval, regardless gender of the participants. Since MR is known to involve motor processes, the present data might contribute to schedule relevant mental practice interventions for fruitful applications in rehabilitation and motor learning processes.
doi:10.1371/journal.pone.0060296
PMCID: PMC3609807  PMID: 23544134
12.  Does motor imagery share neural networks with executed movement: a multivariate fMRI analysis 
Introduction: Motor imagery (MI) is the mental rehearsal of a motor first person action-representation. There is interest in using MI to access the motor network after stroke. Conventional fMRI modeling has shown that MI and executed movement (EM) activate similar cortical areas but it remains unknown whether they share cortical networks. Proving this is central to using MI to access the motor network and as a form of motor training. Here we use multivariate analysis (tensor independent component analysis-TICA) to map the array of neural networks involved during MI and EM.
Methods: Fifteen right-handed healthy volunteers (mean-age 28.4 years) were recruited and screened for their ability to carry out MI (Chaotic MI Assessment). fMRI consisted of an auditory-paced (1 Hz) right hand finger-thumb opposition sequence (2,3,4,5; 2…) with two separate runs acquired (MI & rest and EM & rest: block design). No distinction was made between MI and EM until the final stage of processing. This allowed TICA to identify independent-components (IC) that are common or distinct to both tasks with no prior assumptions.
Results: TICA defined 52 ICs. Non-significant ICs and those representing artifact were excluded. Components in which the subject scores were significantly different to zero (for either EM or MI) were included. Seven IC remained. There were IC's shared between EM and MI involving the contralateral BA4, PMd, parietal areas and SMA. IC's exclusive to EM involved the contralateral BA4, S1 and ipsilateral cerebellum whereas the IC related exclusively to MI involved ipsilateral BA4 and PMd.
Conclusion: In addition to networks specific to each task indicating a degree of independence, we formally demonstrate here for the first time that MI and EM share cortical networks. This significantly strengthens the rationale for using MI to access the motor networks, but the results also highlight important differences.
doi:10.3389/fnhum.2013.00564
PMCID: PMC3771114  PMID: 24062666
motor imagery; functional imaging; fMRI; mental imagery; brain mapping
13.  Validation and quantification of [18F]altanserin binding in the rat brain using blood input and reference tissue modeling 
The 5-hydroxytryptamine type 2a (5-HT2A) selective radiotracer [18F]altanserin has been subjected to a quantitative micro-positron emission tomography study in Lister Hooded rats. Metabolite-corrected plasma input modeling was compared with reference tissue modeling using the cerebellum as reference tissue. [18F]altanserin showed sufficient brain uptake in a distribution pattern consistent with the known distribution of 5-HT2A receptors. Full binding saturation and displacement was documented, and no significant uptake of radioactive metabolites was detected in the brain. Blood input as well as reference tissue models were equally appropriate to describe the radiotracer kinetics. [18F]altanserin is suitable for quantification of 5-HT2A receptor availability in rats.
doi:10.1038/jcbfm.2011.94
PMCID: PMC3323196  PMID: 21750562
[18F]altanserin; animal; brain; 5-HT2A; modeling; PET
14.  The Effect of Aging on the Neural Correlates of Phonological Word Retrieval 
Journal of cognitive neuroscience  2012;24(11):2135-2146.
Age has a differential effect on cognition, with word retrieval being one of the cognitive domains most affected by aging. This study examined the functional and structural neural correlates of phonological word retrieval in younger and older adults using word and picture rhyme judgment tasks. Although the behavioral performance in the fMRI task was similar for the two age groups, the older adults had increased activation in the right pars triangularis across tasks and in the right pars orbitalis for the word task only. Increased activation together with preserved performance in the older participants would suggest that increased activation was related to compensatory processing. We validated this hypothesis by showing that right pars triangularis activation during correct rhyme judgments was highest in participants who made overall more errors, therefore being most error-prone. Our findings demonstrate that the effect of aging differ in adjacent but distinct right inferior frontal regions. The differential effect of age on word and picture tasks also provides new clues to the level of processing that is most affected by age in speech production tasks. Specifically, we suggest that right inferior frontal activation in older participants is needed to inhibit errors.
doi:10.1162/jocn_a_00278
PMCID: PMC3477855  PMID: 22849403
15.  A comparison of VLSM and VBM in a cohort of patients with post-stroke aphasia☆ 
NeuroImage : Clinical  2012;1(1):37-47.
Studies attempting to map post-stroke cognitive or motor symptoms to lesion location have been available in the literature for over 150 years. In the last two decades, two computational techniques have been developed to identify the lesion sites associated with behavioural impairments. Voxel Based Morphometry (VBM) has now been used extensively for this purpose in many different patient populations. More recently, Voxel-based Lesion Symptom Mapping (VLSM) was developed specifically for the purpose of identifying lesion–symptom relationships in stroke patients, and has been used extensively to study, among others functions, language, motor abilities and attention. However, no studies have compared the results of these two techniques so far. In this study we compared VLSM and VBM in a cohort of 20 patients with chronic post-stroke aphasia. Comparison of the two techniques showed overlap in regions previously found to be relevant for the tasks used, suggesting that using both techniques and looking for overlaps between them can increase the reliability of the results obtained. However, overall VBM and VLSM provided only partially concordant results and the differences between the two techniques are discussed.
Highlights
► VBM and VLSM are both used for lesion–symptom mapping in stroke. ► No studies have compared the results of these two methods so far. ► Here, VLSM and VBM were compared in a cohort of patients with post-stroke aphasia. ► VBM and VLSM provide only partially concordant results.
doi:10.1016/j.nicl.2012.08.003
PMCID: PMC3757730  PMID: 24179735
VBM; VLSM; Stroke; Lesion
16.  The vascular mean transit time: a surrogate for the penumbra flow threshold? 
Depicting the salvageable tissue is increasingly used in the clinical setting following stroke. As absolute cerebral blood flow (CBF) is difficult to measure using perfusion magnetic resonance or computed tomography and has limitations as a penumbral marker, time-based variables, particularly the mean transit time (MTT), are routinely used as surrogates. However, a direct validation of MTT as a predictor of the penumbra threshold using gold-standard positron emission tomography (PET) is lacking. Using 15O-PET data sets obtained from two independent acute stroke samples (N=7 and N=30, respectively), we derived areas under the curve (AUCs), optimal thresholds (OTs), and 90%-specificity thresholds (90%-Ts) from receiver operating characteristic curves for absolute MTT, MTT delay, and MTT ratio to predict three penumbra thresholds (‘classic': CBF <20 mL/100 g per min; ‘normalized': CBF ratio <0.5; and ‘stringent': both CBF <20 mL/100 g per min and oxygen extraction fraction >0.55). In sample 1, AUCs ranged from 0.79 to 0.92, indicating good validity; OTs ranged from 7.8 to 8.3 seconds, 2.8 to 4.7 seconds, and 151% to 267% for absolute MTT, MTT delay, and MTT ratio, respectively, while as expected, 90%-Ts were longer. There was no significant difference between sample 1 and sample 2 for any of the above measurements, save for a single MTT parameter with a single penumbra threshold. These consistent findings from gold-standard PET obtained in two independent cohorts document that MTT is a very good surrogate to CBF for depicting the penumbra threshold.
doi:10.1038/jcbfm.2010.197
PMCID: PMC3070969  PMID: 21045862
acute stroke; brain ischemia; cerebral blood flow; neurophysiology; positron emission tomography
17.  Sequential relationships between grey matter and white matter atrophy and brain metabolic abnormalities in early Alzheimer's disease 
Brain  2010;133(11):3301-3314.
Hippocampal atrophy, posterior cingulate and frontal glucose hypometabolism, and white-matter tract disruption are well-described early macroscopic events in Alzheimer’s disease. The relationships between these three types of alterations have been documented in previous studies, but their chronology still remains to be established. The present study used multi-modal Fluorodeoxyglucose - Positron Emission Tomography and Magnetic Resonance Imaging longitudinal data to address this question in patients with amnestic Mild Cognitive Impairment. We found unidirectional, specific sequential relationships between: i) baseline hippocampal atrophy and both cingulum bundle (r=0.70; p=3.10−3) and uncinate fasciculus (r=0.75; p=7.10−4) rate of atrophy; ii) baseline cingulum bundle atrophy and rate of decline of posterior (r=0.72; p=2.10−3) and anterior (r=0.74; p=1.10−3) cingulate metabolism; and iii) baseline uncinate white matter atrophy and subgenual metabolism rate of change (r=0.65; p=6.10−3). Baseline local grey matter atrophy was not found to contribute to hypometabolism progression within the posterior and anterior cingulate as well as subgenual cortices. These findings suggest that hippocampal atrophy progressively leads to disruption of the cingulum bundle and uncinate fasciculus, which in turn leads to glucose hypometabolism of the cingulate and subgenual cortices, respectively. This study reinforces the relevance of remote mechanisms above local interactions to account for the patterns of brain alteration observed in amnestic Mild Cognitive Impairment, and provides new avenues to assess the sequence of events in complex diseases characterized by multiple manifestations.
doi:10.1093/brain/awq203
PMCID: PMC3291528  PMID: 20688814
Aged; Aged, 80 and over; Alzheimer Disease; metabolism; pathology; Atrophy; Brain; metabolism; pathology; Cerebral Cortex; metabolism; pathology; Female; Follow-Up Studies; Hippocampus; metabolism; pathology; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Fibers, Myelinated; metabolism; pathology; Time Factors; Alzheimers disease; MRI/fMRI; PET imaging; white matter; hippocampus
18.  Parametric mapping of [18F]fluoromisonidazole positron emission tomography using basis functions 
In this study, we show a basis function method (BAFPIC) for voxelwise calculation of kinetic parameters (K1, k2, k3, Ki) and blood volume using an irreversible two-tissue compartment model. BAFPIC was applied to rat ischaemic stroke micro-positron emission tomography data acquired with the hypoxia tracer [18F]fluoromisonidazole because irreversible two-tissue compartmental modelling provided good fits to data from both hypoxic and normoxic tissues. Simulated data show that BAFPIC produces kinetic parameters with significantly lower variability and bias than nonlinear least squares (NLLS) modelling in hypoxic tissue. The advantage of BAFPIC over NLLS is less pronounced in normoxic tissue. Ki determined from BAFPIC has lower variability than that from the Patlak–Gjedde graphical analysis (PGA) by up to 40% and lower bias, except for normoxic tissue at mid-high noise levels. Consistent with the simulation results, BAFPIC parametric maps of real data suffer less noise-induced variability than do NLLS and PGA. Delineation of hypoxia on BAFPIC k3 maps is aided by low variability in normoxic tissue, which matches that in Ki maps. BAFPIC produces Ki values that correlate well with those from PGA (r2=0.93 to 0.97; slope 0.99 to 1.05, absolute intercept <0.00002 mL/g per min). BAFPIC is a computationally efficient method of determining parametric maps with low bias and variance.
doi:10.1038/jcbfm.2010.141
PMCID: PMC3049519  PMID: 20736963
basis function; [18F]fluoromisonidazole; FMISO; kinetic modelling; parametric mapping; positron emission tomography
19.  The neural correlates of inner speech defined by voxel-based lesion–symptom mapping 
Brain  2011;134(10):3071-3082.
The neural correlates of inner speech have been investigated previously using functional imaging. However, methodological and other limitations have so far precluded a clear description of the neural anatomy of inner speech and its relation to overt speech. Specifically, studies that examine only inner speech often fail to control for subjects’ behaviour in the scanner and therefore cannot determine the relation between inner and overt speech. Functional imaging studies comparing inner and overt speech have not produced replicable results and some have similar methodological caveats as studies looking only at inner speech. Lesion analysis can avoid the methodological pitfalls associated with using inner and overt speech in functional imaging studies, while at the same time providing important data about the neural correlates essential for the specific function. Despite its advantages, a study of the neural correlates of inner speech using lesion analysis has not been carried out before. In this study, 17 patients with chronic post-stroke aphasia performed inner speech tasks (rhyme and homophone judgements), and overt speech tasks (reading aloud). The relationship between brain structure and language ability was studied using voxel-based lesion–symptom mapping. This showed that inner speech abilities were affected by lesions to the left pars opercularis in the inferior frontal gyrus and to the white matter adjacent to the left supramarginal gyrus, over and above overt speech production and working memory. These results suggest that inner speech cannot be assumed to be simply overt speech without a motor component. It also suggests that the use of overt speech to understand inner speech and vice versa might result in misleading conclusions, both in imaging studies and clinical practice.
doi:10.1093/brain/awr232
PMCID: PMC3187541  PMID: 21975590
stroke; aphasia; inner speech; voxel-based lesion–symptom mapping
20.  Posterior cingulate hypometabolism in early Alzheimer's disease: what is the contribution of local atrophy versus disconnection? 
Brain  2009;132(Pt 12):e133; author reply e134.
doi:10.1093/brain/awp253
PMCID: PMC3021534  PMID: 19858081
Alzheimer Disease; metabolism; physiopathology; radionuclide imaging; Atrophy; metabolism; physiopathology; radionuclide imaging; Biological Markers; analysis; metabolism; Early Diagnosis; Energy Metabolism; physiology; Fluorodeoxyglucose F18; diagnostic use; Gyrus Cinguli; metabolism; physiopathology; radionuclide imaging; Humans; Neural Pathways; metabolism; physiopathology; radionuclide imaging; Positron-Emission Tomography; methods; Predictive Value of Tests
21.  Longitudinal brain metabolic changes from amnestic mild cognitive impairment to Alzheimer's disease 
Brain  2009;132(Pt 8):2058-2067.
A sensitive marker for monitoring progression of early Alzheimer’s Disease (AD) would help to develop and test new therapeutic strategies. The present study aimed at investigating brain metabolism changes over time, as potential monitoring marker, in patients with amnestic Mild Cognitive Impairment (aMCI), according to their clinical outcome (converters or non-converters), and in relation to their cognitive decline. Seventeen aMCI patients underwent MRI and 18FDG-PET scans both at inclusion and 18 months later. Baseline and follow-up PET data were corrected for partial volume effects and spatially normalized using MRI data, scaled to the vermis and compared using SPM2. ‘PET-PAC’ maps reflecting metabolic percent annual changes were created for correlation analyses with cognitive decline. In the whole sample, the greatest metabolic decrease concerned the posterior cingulate-precuneus area. Converters had significantly greater metabolic decrease than nonconverters in two ventro-medial prefrontal areas, the subgenual (BA25) and anterior cingulate (BA24/32). PET-PAC in BA25 and BA24/32 combined allowed complete between-group discrimination. BA25 PET-PAC significantly correlated with both cognitive decline and PET-PAC in the hippocampal region and temporal pole, while BA24/32 PET-PAC correlated with posterior cingulate PET-PAC. Finally, the metabolic change in BA8/9/10 was inversely related to that in BA25 and showed relative increase with cognitive decline, suggesting that compensatory processes may occur in this dorso-medial prefrontal region. The observed ventro-medial prefrontal disruption is likely to reflect disconnection from the hippocampus, both indirectly through the cingulum bundle and posterior cingulate cortex for BA24/32, and directly through the uncinate fasciculus for BA25. Altogether, our findings emphasize the potential of 18FDG-PET for monitoring early AD progression.
doi:10.1093/brain/awp132
PMCID: PMC2936690  PMID: 19477964
Aged; Aged, 80 and over; Alzheimer Disease; complications; metabolism; psychology; radionuclide imaging; Amnesia; etiology; metabolism; radionuclide imaging; Brain; metabolism; radionuclide imaging; Brain Mapping; methods; Cognition Disorders; etiology; metabolism; radionuclide imaging; Disease Progression; Female; Fluorodeoxyglucose F18; diagnostic use; Follow-Up Studies; Humans; Image Interpretation, Computer-Assisted; methods; Magnetic Resonance Imaging; methods; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; methods; amnestic Mild Cognitive Impairment; 18FDG-PET monitoring; ventro-medial prefrontal cortex; longitudinal study
22.  Relationships between hippocampal atrophy, white matter disruption, and gray matter hypometabolism in Alzheimer's disease 
The Journal of Neuroscience  2008;28(24):6174-6181.
In early Alzheimer’s disease (AD), the hippocampal region is the area most severely affected by cellular and structural alterations, yet glucose hypometabolism predominates in the posterior association cortex and posterior cingulate gyrus. One prevalent hypothesis to account for this discrepancy is that posterior cingulate hypometabolism results from disconnection from the hippocampus through disruption of the cingulum bundle. However, only partial and indirect evidence currently supports this hypothesis. Thus, using structural MRI and 18FDG-PET in 18 patients with early AD, we assessed the relationships between hippocampal atrophy, white matter integrity and grey matter metabolism by means of a whole brain voxel-based correlative approach. We found that hippocampal atrophy is specifically related to cingulum bundle disruption, which is in turn highly correlated to hypometabolism of the posterior cingulate cortex but also of the middle cingulate gyrus, thalamus and mammillary bodies (all part of Papez’ circuit), as well as the right temporo-parietal associative cortex. These results provide the first direct evidence supporting the disconnection hypothesis as a major factor contributing to the early posterior hypometabolism in AD. Disruption of the cingulum bundle also appears to relate to hypometabolism in a large connected network over and above the posterior cingulate cortex, encompassing the whole memory circuit of Papez (consistent with the key location of this white matter tract within this loop) and also, but indirectly, the right posterior association cortex.
doi:10.1523/JNEUROSCI.1392-08.2008
PMCID: PMC2902815  PMID: 18550759
Aged; Aged, 80 and over; Alzheimer Disease; complications; pathology; radionuclide imaging; Atrophy; Brain Mapping; Case-Control Studies; Female; Fluorodeoxyglucose F18; metabolism; Hippocampus; pathology; radionuclide imaging; Humans; Image Processing, Computer-Assisted; methods; Magnetic Resonance Imaging; methods; Male; Middle Aged; Neuroglia; pathology; radionuclide imaging; Neurons; pathology; radionuclide imaging; Neuropsychological Tests; Positron-Emission Tomography; methods; Statistics as Topic; Alzheimer disease; Hippocampus; white matter; Deafferentation; Morphometry; Positron Emission Tomography
23.  Morphological and Glucose Metabolism Abnormalities in Alcoholic Korsakoff's Syndrome: Group Comparisons and Individual Analyses 
PLoS ONE  2009;4(11):e7748.
Background
Gray matter volume studies have been limited to few brain regions of interest, and white matter and glucose metabolism have received limited research attention in Korsakoff's syndrome (KS). Because of the lack of brain biomarkers, KS was found to be underdiagnosed in postmortem studies.
Methodology/Principal Findings
Nine consecutively selected patients with KS and 22 matched controls underwent both structural magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography examinations. Using a whole-brain analysis, the between-group comparisons of gray matter and white matter density and relative glucose uptake between patients with KS and controls showed the involvement of both the frontocerebellar and the Papez circuits, including morphological abnormalities in their nodes and connection tracts and probably resulting hypometabolism. The direct comparison of the regional distribution and degree of gray matter hypodensity and hypometabolism within the KS group indicated very consistent gray matter distribution of both abnormalities, with a single area of significant difference in the middle cingulate cortex showing greater hypometabolism than hypodensity. Finally, the analysis of the variability in the individual patterns of brain abnormalities within our sample of KS patients revealed that the middle cingulate cortex was the only brain region showing significant GM hypodensity and hypometabolism in each of our 9 KS patients.
Conclusions/Significance
These results indicate widespread brain abnormalities in KS including both gray and white matter damage mainly involving two brain networks, namely, the fronto-cerebellar circuit and the Papez circuit. Furthermore, our findings suggest that the middle cingulate cortex may play a key role in the pathophysiology of KS and could be considered as a potential in vivo brain biomarker.
doi:10.1371/journal.pone.0007748
PMCID: PMC2777409  PMID: 19936229
24.  Acute Stroke Imaging Research Roadmap 
The recent “Advanced Neuroimaging for Acute Stroke Treatment” meeting on September 7 and 8, 2007 in Washington DC, brought together stroke neurologists, neuroradiologists, emergency physicians, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), industry representatives, and members of the US Food and Drug Administration (FDA) to discuss the role of advanced neuroimaging in acute stroke treatment. The goals of the meeting were to assess state-of-the-art practice in terms of acute stroke imaging research and to propose specific recommendations regarding: (1) the standardization of perfusion and penumbral imaging techniques, (2) the validation of the accuracy and clinical utility of imaging markers of the ischemic penumbra, (3) the validation of imaging biomarkers relevant to clinical outcomes, and (4) the creation of a central repository to achieve these goals. The present article summarizes these recommendations and examines practical steps to achieve them.
doi:10.1161/STROKEAHA.107.512319
PMCID: PMC2716734  PMID: 18477656
25.  Clinical review: Imaging in ischaemic stroke – implications for acute management 
Critical Care  2007;11(5):227.
Imaging has become a cornerstone of stroke management, translating pathophysiological knowledge to everyday decision-making. Plain computed tomography is widely available and remains the standard for initial assessment: the technique rules out haemorrhage, visualizes the occluding thrombus and identifies early tissue hypodensity and swelling, which have different implications for thrombolysis. Based on evidence from positron emission tomography (PET), however, multimodal imaging is increasingly advocated. Computed tomography perfusion and angiography provide information on the occlusion site, on recanalization and on the extent of salvageable tissue. Magnetic resonance-based diffusion-weighted imaging (DWI) has exquisite sensitivity for acute ischaemia, however, and there is increasingly robust evidence that DWI combined with perfusion-weighted magnetic resonance imaging (PWI) and angiography improves functional outcome by selecting appropriate patients for thrombolysis (small DWI lesion but large PWI defect) and by ruling out those who would receive no benefit or might be harmed (very large DWI lesion, no PWI defect), especially beyond the 3-hour time window. Combined DWI–PWI also helps predict malignant oedema formation and therefore helps guide selection for early brain decompression. Finally, DWI–PWI is increasingly used for patient selection in therapeutic trials. Although further methodological developments are awaited, implementing the individual pathophysiologic diagnosis based on multimodal imaging is already refining indications for thrombolysis and offers new opportunities for management of acute stroke patients.
doi:10.1186/cc5973
PMCID: PMC2556770  PMID: 17875224

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