Impact of brain aging and neurodegeneration on cognition: evidence from MRI.

PURPOSE OF REVIEW: We present an overview of recent concepts in mechanisms underlying cognitive decline associated with brain aging and neurodegeneration from the perspective of MRI. RECENT FINDINGS: Recent findings challenge the established link between neuroimaging biomarkers of neurodegeneration and age-related or disease-related cognitive decline. Amyloid burden, white matter hyperintensities and local patterns of brain atrophy seem to have differential impact on cognition, particularly on episodic and working memory - the most vulnerable domains in 'normal aging' and Alzheimer's disease. Studies suggesting that imaging biomarkers of neurodegeneration are independent of amyloid-β give rise to new hypothesis regarding the pathological cascade in Alzheimer's disease. Findings in patients with autosomal-dominant Alzheimer's disease confirm the notion of differential temporal trajectory of amyloid deposition and brain atrophy to add another layer of complexity on the basic mechanisms of cognitive aging and neurodegeneration. Finally, the concept of cognitive reserve in 'supernormal aging' is questioned by evidence for the preservation of neurochemical, structural and functional brain integrity in old age rather than recruitment of 'reserves' for maintaining cognitive abilities. SUMMARY: Recent advances in clinical neuroscience, brain imaging and genetics challenge pathophysiological hypothesis of neurodegeneration and cognitive aging dominating the field in the last decade and call for reconsidering the choice of therapeutic window for early intervention.

Prenatal brain atrophy due to a giant vein of Galen malformation.

We report a full-term newborn girl with a giant vein of Galen malformation and extreme cerebral atrophy of prenatal origin. She presented on the 3rd day of life with intractable congestive heart failure. The diagnosis of the vascular malformation was confirmed by ultrasound and magnetic resonance imaging.

The management of brain metastases

Brain metastases occur in 20-50% of NSCLC and 50-80% of SCLC. In this review, we will look at evidence-based medicine data and give some perspectives on the management of BM. We will address the problems of multiple BM, single BM and prophylactic cranial irradiation. Recursive Partitioning Analysis (RPA) is a powerful prognostic tool to facilitate treatment decisions. Dealing with multiple BM, the use of corticosteroids was established more than 40 years ago by a unique randomized trial (RCT). Palliative effect is high (_80%) as well as side-effects. Whole brain radiotherapy (WBRT) was evaluated in many RCTs with a high (60-90%) response rate; several RT regimes are equivalent, but very high dose per fraction should be avoided. In multiple BM from SCLC, the effect of WBRT is comparable to that in NSCLC but chemotherapy (CXT) although advocated is probably less effective than RT. Single BM from NSCLC occurs in 30% of all BM cases; several prognostic classifications including RPA are very useful. Several options are available in single BM: WBRT, surgery (SX), radiosurgery (RS) or any combination of these. All were studied in RCTs and will be reviewed: the addition of WBRT to SX or RS gives a better neurological tumour control, has little or no impact on survival, and may be more toxic. However omitting WBRT after SX alone gives a higher risk of cerebro-spinal fluid dissemination. Prophylactic cranial irradiation (PCI) has a major role in SCLC. In limited disease, meta-analyses have shown a positive impact of PCI in the decrease of brain relapse and in survival improvement, especially for patients in complete remission. Surprisingly, this has been recently confirmed also in extensive disease. Experience with PCI for NSCLC is still limited, but RCT suggest a reduction of BM with no impact on survival. Toxicity of PCI is a matter of debate, as neurological or neuro-cognitive impairment is already present prior to PCI in almost half of patients. However RT toxicity is probably related to total dose and dose per fraction. Perspectives : Future research should concentrate on : 1) combined modalities in multiple BM. 2) Exploration of treatments in oligo-metastases. 3) Further exploration of PCI in NSCLC. 4) Exploration of new, toxicity-sparing radiotherapy techniques (IMRT, Tomotherapy etc).

In vivo detection of brain Krebs cycle intermediate by hyperpolarized magnetic resonance.

The Krebs (or tricarboxylic acid (TCA)) cycle has a central role in the regulation of brain energy regulation and metabolism, yet brain TCA cycle intermediates have never been directly detected in vivo. This study reports the first direct in vivo observation of a TCA cycle intermediate in intact brain, namely, 2-oxoglutarate, a key biomolecule connecting metabolism to neuronal activity. Our observation reveals important information about in vivo biochemical processes hitherto considered undetectable. In particular, it provides direct evidence that transport across the inner mitochondria membrane is rate limiting in the brain. The hyperpolarized magnetic resonance protocol designed for this study opens the way to direct and real-time studies of TCA cycle kinetics.

RAX and anophthalmia in humans: Evidence of brain anomalies.

PURPOSE: To report the clinical and genetic study of two families of Egyptian origin with clinical anophthalmia. To further determine the role of the retina and anterior neural fold homeobox gene (RAX) in anophthalmia and associated cerebral malformations. METHODS: Three patients with clinical anophthalmia and first-degree relatives from two consanguineous families of Egyptian origin underwent full ophthalmologic, general and neurologic examination, and blood tests. Cerebral magnetic resonance imaging (MRI) was performed in the index cases of both families. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of RAX was performed after PCR amplification. RESULTS: Clinical bilateral anophthalmia was observed in all three patients. General and neurologic examinations were normal; obesity and delay in psychomotor development were observed in the isolated case. Orbital MRI showed a hypoplastic orbit with present but rudimentary extraocular muscles and normal lacrimal glands. Cerebral MRI showed agenesis of the optic nerves, optic tracts, and optic chiasma. In the index case of family A, the absence of the frontal and sphenoidal sinuses was also noted. In the index case of family B, only the sphenoidal sinus was absent, and there was significant cortical atrophy. The three patients carried a novel homozygous c.543+3A>G mutation (IVS2+3A>G) in RAX. Parents were healthy heterozygous carriers. No mutations were detected in orthodenticle homeobox 2 (OTX2), ventral anterior homeobox 1 (VAX1), or sex determining region Y-box 2 (SOX2). CONCLUSIONS: This is the first report of a homozygous splicing RAX mutation associated with autosomal recessive bilateral anophthalmia. To our knowledge, only two isolated cases of anophthalmia, three null and one missense case affecting nuclear localization or the DNA-binding homeodomain, have been found to be caused by compound heterozygote RAX mutations. A novel missense RAX mutation was identified in three patients with bilateral anophthalmia and a distinct systemic and neurologic phenotype. The mutation potentially affects splicing of the last exon and is thought to result in a protein that has an aberrant homeodomain and no paired-tail domain. Functional consequences of this change still need to be characterized.

Improved statistical evaluation of group differences in connectomes by screening-filtering strategy with application to study maturation of brain connections between childhood and adolescence.

Detecting local differences between groups of connectomes is a great challenge in neuroimaging, because the large number of tests that have to be performed and the impact on multiplicity correction. Any available information should be exploited to increase the power of detecting true between-group effects. We present an adaptive strategy that exploits the data structure and the prior information concerning positive dependence between nodes and connections, without relying on strong assumptions. As a first step, we decompose the brain network, i.e., the connectome, into subnetworks and we apply a screening at the subnetwork level. The subnetworks are defined either according to prior knowledge or by applying a data driven algorithm. Given the results of the screening step, a filtering is performed to seek real differences at the node/connection level. The proposed strategy could be used to strongly control either the family-wise error rate or the false discovery rate. We show by means of different simulations the benefit of the proposed strategy, and we present a real application of comparing connectomes of preschool children and adolescents.

Quantification of brain glycogen concentration and turnover through localized 13C NMR of both the C1 and C6 resonances.

We have recently shown that at isotopic steady state (13)C NMR can provide a direct measurement of glycogen concentration changes, but that the turnover of glycogen was not accessible with this protocol. The aim of the present study was to design, implement and apply a novel dual-tracer infusion protocol to simultaneously measure glycogen concentration and turnover. After reaching isotopic steady state for glycogen C1 using [1-(13)C] glucose administration, [1,6-(13)C(2)] glucose was infused such that isotopic steady state was maintained at the C1 position, but the C6 position reflected (13)C label incorporation. To overcome the large chemical shift displacement error between the C1 and C6 resonances of glycogen, we implemented 2D gradient based localization using the Fourier series window approach, in conjunction with time-domain analysis of the resulting FIDs using jMRUI. The glycogen concentration of 5.1 +/- 1.6 mM measured from the C1 position was in excellent agreement with concomitant biochemical determinations. Glycogen turnover measured from the rate of label incorporation into the C6 position of glycogen in the alpha-chloralose anesthetized rat was 0.7 micromol/g/h.

Phase I trial combining temozolomide plus lapatinib for the treatment of brain metastases in patients with HER2-positive metastatic breast cancer: the LAPTEM trial.

BACKGROUND: Brain metastases (BMs) pose a clinical challenge in breast cancer (BC). Lapatinib or temozolomide showed activity in BM. Our study assessed the combination of both drugs as treatment for patients with HER2-positive BC and BM. METHODS: Eighteen patients were enrolled, with sixteen of them having recurrent or progressive BM. Any type of previous therapy was allowed, and disease was assessed by gadolinium (Gd)-enhanced magnetic resonance imaging (MRI). The primary end points were the evaluation of the dose-limiting toxicities (DLTs) and the determination of the maximum-tolerated dose (MTD). The secondary end points included objective response rate, clinical benefit and duration of response. RESULTS: The lapatinib-temozolomide regimen showed a favorable toxicity profile because the MTD could not be reached. The most common adverse events (AEs) were fatigue, diarrhea and constipation. Disease stabilization was achieved in 10 out of 15 assessable patients. The estimated median survival time for the 16 patients with BM reached 10.94 months (95% CI: 1.09-20.79), whereas the median progression-free survival time was 2.60 months [95% confidence interval (CI): 1.82-3.37]. CONCLUSIONS: The lapatinib-temozolomide combination is well tolerated. Preliminary evidence of clinical activity was observed in a heavily pretreated population, as indicated by the volumetric reductions occurring in brain lesions.

Treatment of brain metastases from non-small cell lung cancer with whole-brain radiotherapy (wbrt) in combination with gefitinib (gft) or temozolomide (tmz): a randomized multicenter phase ii trial of the swiss group of clinical cancer research (sakk #70/03)

BACKGROUND: Patients with BM rarely survive .6 months and are commonly excluded from clinical trials. We aimed at improving outcome by exploring 2 combined modality regimens with at the time novel agents for which single-agent activity had been shown. METHODS: NSCLC patients with multiple BM were randomized to WBRT (10 × 3 Gy) and either GFT 250 mg p.o. daily or TMZ 75 mg/m2 p.o. daily ×21/28 days, starting on Day 1 of RT and to be continued until PD. Primary endpoint was overall survival, a Simon's optimal 2-stage design was based on assumptions for the 3-month survival rate. Cognitive functioning and quality of life were also evaluated. RESULTS: Fifty-nine patients (36 M, 23 F; 9 after prior chemo) were included. Median age was 61 years (range 46-82), WHO PS was 0 in 18 patients, 1 in 31 patients, and 2 in 10 patients. All but 1 patients had extracranial disease; 33 of 43 (TMZ) and 15 of 16 (GFT) had adenocarcinoma histology. GFT arm was closed early after stage 1 analysis when the prespecified 3-mo survival rate threshold (66%) was not reached, causes of death were not GFT related. Main causes of death were PD in the CNS 24%, systemic 41%, both 8%, and toxicity 10% [intestinal perforation (2 patients), pneumonia (2), pulmonary emboli (1), pneumonitis NOS (1), seizure (1)]. We summarize here other patients' characteristics for the 2 trial arms: TMZ (n ¼ 43)/GFT (n ¼ 16); median treatment duration: 1.6 /1.8 mo; Grade 3-4 toxicity: lymphopenia 5 patients (12%)/0; fatigue 8 patients (19%)/2 patients (13%). Survival data for TMZ/GFT arms: 3-month survival rate: 58.1% (95% CI 42.1-73)/62.5% (95% CI 35- 85); median OS: 4.9 months (95% CI 2.5-5.6)/6.3 months (95% CI 2.2- 14.6); median PFS: 1.8 months (95% CI 1.5-1.8)/1.8 (95% CI 1.1-3.9); median time to neurol. progr.: 8.0 months (95% CI 2.2-X)/4.8 (95% CI 3.9-10.5). In a model to predict survival time including the variables' age, PS, number of BM, global QL, total MMSE score, and subjective cognitive function, none of the variables accounted for a significant improvement in survival time. CONCLUSIONS: The combinations of WBRT with GFT or TMZ were feasible. However, in this unselected patient population, survival remains poor and a high rate of complication was observed. Four patients died as a result of high-dose corticosteroids. Preliminary evaluation of cognitive function andQL failed to show significant improvement. Indications and patient selection for palliative treatment should be revisited and careful monitoring and supportive care is required. Research and progress for this frequent clinical situation is urgently needed. Trial partly supported by AstraZeneca (Switzerland), Essex Chemie (Switzerland) and Swiss Federal Government.

Role of surgery in the management of brain arteriovenous malformations: prospective cohort study.

BACKGROUND AND PURPOSE: Management of brain arteriovenous malformation (bAVM) is controversial. We have analyzed the largest surgical bAVM cohort for outcome. METHODS: Both operated and nonoperated cases were included for analysis. A total of 779 patients with bAVMs were consecutively enrolled between 1989 and 2014. Initial management recommendations were recorded before commencement of treatment. Surgical outcome was prospectively recorded and outcomes assigned at the last follow-up visit using modified Rankin Scale. First, a sensitivity analyses was performed to select a subset of the entire cohort for which the results of surgery could be generalized. Second, from this subset, variables were analyzed for risk of deficit or near miss (intraoperative hemorrhage requiring blood transfusion of ≥2.5 L, hemorrhage in resection bed requiring reoperation, and hemorrhage associated with either digital subtraction angiography or embolization). RESULTS: A total of 7.7% of patients with Spetzler-Ponce classes A and B bAVM had an adverse outcome from surgery leading to a modified Rankin Scale >1. Sensitivity analyses that demonstrated outcome results were not subject to selection bias for Spetzler-Ponce classes A and B bAVMs. Risk factors for adverse outcomes from surgery for these bAVMs include size, presence of deep venous drainage, and eloquent location. Preoperative embolization did not affect the risk of perioperative hemorrhage. CONCLUSIONS: Most of the ruptured and unruptured low and middle-grade bAVMs (Spetzler-Ponce A and B) can be surgically treated with a low risk of permanent morbidity and a high likelihood of preventing future hemorrhage. Our results do not apply to Spetzler-Ponce C bAVMs.

Accuracy of Brain Multimodal Monitoring to Detect Cerebral Hypoperfusion After Traumatic Brain Injury.

OBJECTIVE:: To examine the accuracy of brain multimodal monitoring-consisting of intracranial pressure, brain tissue PO2, and cerebral microdialysis-in detecting cerebral hypoperfusion in patients with severe traumatic brain injury. DESIGN:: Prospective single-center study. PATIENTS:: Patients with severe traumatic brain injury. SETTING:: Medico-surgical ICU, university hospital. INTERVENTION:: Intracranial pressure, brain tissue PO2, and cerebral microdialysis monitoring (right frontal lobe, apparently normal tissue) combined with cerebral blood flow measurements using perfusion CT. MEASUREMENTS AND MAIN RESULTS:: Cerebral blood flow was measured using perfusion CT in tissue area around intracranial monitoring (regional cerebral blood flow) and in bilateral supra-ventricular brain areas (global cerebral blood flow) and was matched to cerebral physiologic variables. The accuracy of intracranial monitoring to predict cerebral hypoperfusion (defined as an oligemic regional cerebral blood flow < 35 mL/100 g/min) was examined using area under the receiver-operating characteristic curves. Thirty perfusion CT scans (median, 27 hr [interquartile range, 20-45] after traumatic brain injury) were performed on 27 patients (age, 39 yr [24-54 yr]; Glasgow Coma Scale, 7 [6-8]; 24/27 [89%] with diffuse injury). Regional cerebral blood flow correlated significantly with global cerebral blood flow (Pearson r = 0.70, p < 0.01). Compared with normal regional cerebral blood flow (n = 16), low regional cerebral blood flow (n = 14) measurements had a higher proportion of samples with intracranial pressure more than 20 mm Hg (13% vs 30%), brain tissue PO2 less than 20 mm Hg (9% vs 20%), cerebral microdialysis glucose less than 1 mmol/L (22% vs 57%), and lactate/pyruvate ratio more than 40 (4% vs 14%; all p < 0.05). Compared with intracranial pressure monitoring alone (area under the receiver-operating characteristic curve, 0.74 [95% CI, 0.61-0.87]), monitoring intracranial pressure + brain tissue PO2 (area under the receiver-operating characteristic curve, 0.84 [0.74-0.93]) or intracranial pressure + brain tissue PO2+ cerebral microdialysis (area under the receiver-operating characteristic curve, 0.88 [0.79-0.96]) was significantly more accurate in predicting low regional cerebral blood flow (both p < 0.05). CONCLUSION:: Brain multimodal monitoring-including intracranial pressure, brain tissue PO2, and cerebral microdialysis-is more accurate than intracranial pressure monitoring alone in detecting cerebral hypoperfusion at the bedside in patients with severe traumatic brain injury and predominantly diffuse injury.

Segmentation of brain structures in presence of a space-occupying lesion.

Brain deformations induced by space-occupying lesions may result in unpredictable position and shape of functionally important brain structures. The aim of this study is to propose a method for segmentation of brain structures by deformation of a segmented brain atlas in presence of a space-occupying lesion. Our approach is based on an a priori model of lesion growth (MLG) that assumes radial expansion from a seeding point and involves three steps: first, an affine registration bringing the atlas and the patient into global correspondence; then, the seeding of a synthetic tumor into the brain atlas providing a template for the lesion; finally, the deformation of the seeded atlas, combining a method derived from optical flow principles and a model of lesion growth. The method was applied on two meningiomas inducing a pure displacement of the underlying brain structures, and segmentation accuracy of ventricles and basal ganglia was assessed. Results show that the segmented structures were consistent with the patient's anatomy and that the deformation accuracy of surrounding brain structures was highly dependent on the accurate placement of the tumor seeding point. Further improvements of the method will optimize the segmentation accuracy. Visualization of brain structures provides useful information for therapeutic consideration of space-occupying lesions, including surgical, radiosurgical, and radiotherapeutic planning, in order to increase treatment efficiency and prevent neurological damage.

Alteration of brain glycogen turnover in the conscious rat after 5h of prolonged wakefulness.

Although glycogen (Glyc) is the main carbohydrate storage component, the role of Glyc in the brain during prolonged wakefulness is not clear. The aim of this study was to determine brain Glyc concentration ([]) and turnover time (tau) in euglycemic conscious and undisturbed rats, compared to rats maintained awake for 5h. To measure the metabolism of [1-(13)C]-labeled Glc into Glyc, 23 rats received a [1-(13)C]-labeled Glc solution as drink (10% weight per volume in tap water) ad libitum as their sole source of exogenous carbon for a "labeling period" of either 5h (n=13), 24h (n=5) or 48 h (n=5). Six of the rats labeled for 5h were continuously maintained awake by acoustic, tactile and olfactory stimuli during the labeling period, which resulted in slightly elevated corticosterone levels. Brain [Glyc] measured biochemically after focused microwave fixation in the rats maintained awake (3.9+/-0.2 micromol/g, n=6) was not significantly different from that of the control group (4.0+/-0.1 micromol/g, n=7; t-test, P>0.5). To account for potential variations in plasma Glc isotopic enrichment (IE), Glyc IE was normalized by N-acetyl-aspartate (NAA) IE. A simple mathematical model was developed to derive brain Glyc turnover time as 5.3h with a fit error of 3.2h and NAA turnover time as 15.6h with a fit error of 6.5h, in the control rats. A faster tau(Glyc) (2.9h with a fit error of 1.2h) was estimated in the rats maintained awake for 5h. In conclusion, 5h of prolonged wakefulness mainly activates glycogen metabolism, but has minimal effect on brain [Glyc].

Quantitative Measurement of Brain Perfusion with Intravoxel Incoherent Motion MR Imaging.

Purpose: To evaluate the sensitivity of the perfusion parameters derived from Intravoxel Incoherent Motion (IVIM) MR imaging to hypercapnia-induced vasodilatation and hyperoxygenation-induced vasoconstriction in the human brain. Materials and Methods: This study was approved by the local ethics committee and informed consent was obtained from all participants. Images were acquired with a standard pulsed-gradient spin-echo sequence (Stejskal-Tanner) in a clinical 3-T system by using 16 b values ranging from 0 to 900 sec/mm(2). Seven healthy volunteers were examined while they inhaled four different gas mixtures known to modify brain perfusion (pure oxygen, ambient air, 5% CO(2) in ambient air, and 8% CO(2) in ambient air). Diffusion coefficient (D), pseudodiffusion coefficient (D*), perfusion fraction (f), and blood flow-related parameter (fD*) maps were calculated on the basis of the IVIM biexponential model, and the parametric maps were compared among the four different gas mixtures. Paired, one-tailed Student t tests were performed to assess for statistically significant differences. Results: Signal decay curves were biexponential in the brain parenchyma of all volunteers. When compared with inhaled ambient air, the IVIM perfusion parameters D*, f, and fD* increased as the concentration of inhaled CO(2) was increased (for the entire brain, P = .01 for f, D*, and fD* for CO(2) 5%; P = .02 for f, and P = .01 for D* and fD* for CO(2) 8%), and a trend toward a reduction was observed when participants inhaled pure oxygen (although P > .05). D remained globally stable. Conclusion: The IVIM perfusion parameters were reactive to hyperoxygenation-induced vasoconstriction and hypercapnia-induced vasodilatation. Accordingly, IVIM imaging was found to be a valid and promising method to quantify brain perfusion in humans. © RSNA, 2012.