Francesco Garaci

Optic Nerve and Optic Radiation Neurodegeneration in Patients with Glaucoma: In Vivo Analysis with 3-T Diffusion-Tensor MR Imaging

PURPOSE To evaluate, with high-field-strength diffusion-tensor (DT) magnetic resonance (MR) imaging, the axonal architecture of the optic nerves and optic radiations in patients with glaucoma and determine whether DT MR imaging-derived parameters correlate with disease severity. MATERIALS AND METHODS The study was approved by the institutional review board. All participants provided written informed consent. Sixteen patients with primary open-angle glaucoma were examined. Glaucoma severity was clinically assessed with use of a six-stage system based on static threshold visual field parameters. Ten healthy individuals served as control subjects. DT MR imaging was performed with a 3-T MR unit. Mean diffusivity (MD) and fractional anisotropy (FA) maps were automatically created. Regions of interest were positioned on the MD and FA maps, and mean MD and mean FA values were calculated for each optic nerve and each optic radiation. RESULTS The optic radiations and optic nerves of patients with glaucoma, as compared with control subjects, had significantly higher MD and significantly lower FA. The mean MD values for the optic nerves and the glaucoma stages varied consistently (r = 0.8087, P < .0001). A negative correlation between mean FA for the optic nerves and glaucoma stage (r = -0.7464, P < .0001) was observed. CONCLUSION Glaucoma is a complex neurologic disease that affects optic nerves and optic radiations. The finding that DT MR imaging-derived MD and FA in the optic nerves correlate with glaucoma severity suggests that these parameters could serve as complementary indicators of disease severity.

Proposed chronic cerebrospinal venous insufficiency criteria do not predict multiple sclerosis risk or severity.

It is still unclear whether chronic cerebrospinal venous insufficiency (CCSVI) is associated with multiple sclerosis (MS), because substantial methodological differences have been claimed by Zamboni to account for the lack of results of other groups. Furthermore, the potential role of venous malformations in influencing MS severity has not been fully explored. This information is particularly relevant, because uncontrolled surgical procedures are increasingly offered to MS patients to treat their venous stenoses.

Relevance of Magnetic Resonance Imaging for Early Detection and Diagnosis of Alzheimer Disease

Hippocampus volumetry currently is the best-established imaging biomarker for AD. However, the effect of multicenter acquisition on measurements of hippocampus volume needs to be explicitly considered when it is applied in large clinical trials, for example by using mixed-effects models to take the clustering of data within centers into account. The marker needs further validation in respect of the underlying neurobiological substrate and potential confounds such as vascular disease, inflammation, hydrocephalus, and alcoholism, and with regard to clinical outcomes such as cognition but also to demographic and socioeconomic outcomes such as mortality and institutionalization. The use of hippocampus volumetry for risk stratification of predementia study samples will further increase with the availability of automated measurement approaches. An important step in this respect will be the development of a standard hippocampus tracing protocol that harmonizes the large range of presently available manual protocols. In the near future, regionally differentiated automated methods will become available together with an appropriate statistical model, such as multivariate analysis of deformation fields, or techniques such as cortical-thickness measurements that yield a meaningful metrics for the detection of treatment effects. More advanced imaging protocols, including DTI, DSI, and functional MRI, are presently being used in monocenter and first multicenter studies. In the future these techniques will be relevant for the risk stratification in phase IIa type studies (small proof-of-concept trials). By contrast, the application of the broader established structural imaging biomarkers, such as hippocampus volume, for risk stratification and as surrogate end point is already today part of many clinical trial protocols. However, clinical care will also be affected by these new technologies. Radiologic expert centers already offer “dementia screening” for well-off middle-aged people who undergo an MRI scan with subsequent automated, typically VBM-based analysis, and determination of z-score deviation from a matched control cohort. Next-generation scanner software will likely include radiologic expert systems for automated segmentation, deformation-based morphometry, and multivariate analysis of anatomic MRI scans for the detection of a typical AD pattern. As these developments will start to change medical practice, first for selected subject groups that can afford this type of screening but later eventually also for other cohorts, clinicians must become aware of the potentials and limitations of these technologies. It is decidedly unclear to date how a middle-aged cognitively intact subject with a seemingly AD-positive MRI scan should be clinically advised. There is no evidence for individual risk prediction and even less for specific treatments. Thus, the development of preclinical diagnostic imaging poses not only technical but also ethical problems that must be critically discussed on the basis of profound knowledge. From a neurobiological point of view, the main determinants of cognitive impairment in AD are the density of synapses and neurons in distributed cortical and subcortical networks. MRI-based measures of regional gray matter volume and associated multivariate analysis techniques of regional interactions of gray matter densities provide insight into the onset and temporal dynamics of cortical atrophy as a close proxy for regional neuronal loss and a basis of functional impairment in specific neuronal networks. From the clinical point of view, clinicians must bear in mind that patients do not suffer from hippocampus atrophy or disconnection but from memory impairment, and that dementia screening in asymptomatic subjects should not be used outside of clinical studies.

White matter reduced streamline coherence in young men with autism and mental retardation

Background and purpose:  It has been proposed that white matter alterations might play a role in autistic disorders; however, published data are mainly limited to high‐functioning autism. The goal of this study was to apply diffusion tensor imaging (DTI) and fiber tractography (FT) to study white matter in low‐functioning autism and the relationship between white matter and cognitive impairment.

CSF Aβ1-42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer's disease.

The development of validated, qualified, and standardized biomarkers for Alzheimers disease (AD) that allow for an early presymptomatic diagnosis and discrimination (classification) from other types of dementia and neurodegenerative diseases is warranted to accelerate the successful development of novel disease‐modifying therapies. Here, we focus on the value of the 42‐residue‐long amyloid β isoform (Aβ1‐42) peptide in the cerebrospinal fluid as the core, feasible neurobiochemical marker for the amyloidogenic mechanisms in early‐onset familial and late‐onset sporadic AD. We discuss the role and use of Aβ1‐42 in combination with evolving neuroimaging biomarkers in AD detection and diagnosis. Multimodal neuroimaging techniques, directly providing structural‐functional‐metabolic aspects of brain pathophysiology, are supportive to predict and monitor the progression of the disease. Advances in multimodal neuroimaging provide new insights into brain organization and enable the detection of specific proteins and/or protein aggregates associated with AD. The combination of biomarkers from different methodologies is believed to be of incrementally added risk‐value to accurately identify asymptomatic and prodromal individuals who will likely progress to dementia and represent rational biomarker candidates for preventive and symptomatic pharmacological intervention trials.

3-T Diffusion tensor imaging of the optic nerve in subjects with glaucoma: correlation with GDx-VCC, HRT-III and Stratus optical coherence tomography findings

Objectives To correlate diffusion-tensor imaging (DTI) of the optic nerve with morphological indices obtained by scanning laser polarimetry (GDx-VCC); confocal scanning laser ophthalmoscopy (Heidelberg III retinal tomograph; HRT-III) and optical coherence tomography (Stratus OCT). Methods Thirty-six subjects (12 with no eye disease and 24 with perimetrically diagnosed glaucoma) were examined. One eye for each participant was studied with 3-Tesla DTI (with automatic generation of mean diffusivity (MD) and fractional anisotropy (FA) values); GDx-VCC, HRT-III and OCT. Single and multiple regression analyses of all variables studied were performed. Results MD displayed the strongest correlation with linear cup/disc ratio (LCDR) from HTR-III (r=0.662), retinal nerve fibre layer (RNFL) thickness (avThickn) from OCT (r=−0.644), and nerve fibre index (NFI) from GDx (r=0.642); FA was strongly correlated with the LCDR (r=−0.499). In multiple regression analyses, MD correlated with LCDR (p=0.02) when all variables were considered; with avThickn (p<0.01) (analysis of all RNFL parameters); with NFI (p<0.01) (analysis of all GDx parameters); with avThickn (p<0.01) (analysis of OCT parameters); with LCDR (p=0.01) (analysis of HRT-III morphometric parameters) and with linear discriminant function (RB) (p=0.02) (analysis of HRT-III indices). As for FA, it correlated with avThickn (p=0.02) when we analysed the OCT parameters and with RB (p=0.01) (analysis of HRT-III indices). Conclusions DTI parameters of the axonal architecture of the optic nerve show good correlation with morphological features of the optic nerve head and RNFL documented with GDx-VCC, HRT-III and OCT.

Is mTOR inhibition a systemic treatment for tuberous sclerosis

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by the development of hamartomas in several organs. Mutations in the TSC1 and TSC2 tumor suppressor genes determin overactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for TSC patients. Everolimus has been recently approved as a pharmacotherapy option for TSC patients with subependymal giant-cell astrocytomas (SEGAs) or renal angiomyolipomas (AMLs). However, clinical evidence suggests that this treatment can benefit other TSC-associated disease manifestations, such as skin manifestations, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and epilepsy. Therefore, the positive effects that mTOR inhibition have on a wide variety of TSC disease manifestations make this a potential systemic treatment option for this genetic multifaceted disorder.

Giant high-flow renal arteriovenous fistula treated by percutaneous embolization

We report the case of a giant renal arteriovenous fistula after renal biopsy in a 30-year-old man with hematuria and hypertension. We performed percutaneous endovascular embolization using macrocoils to exclude the fistula. The patient made an uneventful recovery with no further hematuria and progressive reduction of blood pressure. Follow-up by digital subtraction angiography (DSA) at 6 months showed complete occlusion of the fistula with no evidence of renal parenchymal infarction. Although giant renal arteriovenous fistulas are generally treated by nephrectomy, this case shows that embolization is a reasonable alternative to surgery.

Differences between Proximal versus Distal Intraorbital Optic Nerve Diffusion Tensor Magnetic Resonance Imaging Properties in Glaucoma Patients

PURPOSE To analyze in vivo the diffusion tensor magnetic resonance imaging (DT-MRI) properties of the intraorbital optic nerve at two different levels: Proximal to the optic nerve head (ONH) and distal to the ONH at the level of the orbital apex in glaucoma patients. METHODS Twenty-four patients with primary open-angle glaucoma were examined. The categorization into early and severe glaucoma was performed by Hodapps classification. Fifteen healthy individuals served as controls. DT-MRI was performed with a 3T-MR unit. RESULTS At early stage mean diffusivity (MD) values were higher at the proximal site with respect to the distal site. On the contrary, a decrease in fractional anisotropy (FA) was observed only relative to patient stage, independent of optic nerve site. Moreover, at early disease stage an increase in overall diffusivities, was evident at the proximal site, whereas at the distal site a decrease of the largest diffusivity and an increase in both the intermediate and smallest diffusivities were observed. FA and MD measured at the proximal site, had, respectively, the highest sensitivity and specificity in discriminating between healthy and glaucomatous eyes. CONCLUSIONS Our study represents the first attempt to evaluate in vivo fiber integrity changes along the optic nerve with DT-MRI. Optic nerve degeneration appears to be a process that affects differently the proximal and the distal segments of the optic nerve. The complementary high sensitivity of FA with the high specificity of MD at the proximal site may provide reliable indexes for the identification of glaucomatous patients at early stages.

Imaging Epigenetics in Alzheimer's Disease

Sporadic Alzheimers disease (AD) is a prevalent, complex and chronically progressive brain disease. Its course is non-linear, dynamic, adaptive to maladaptive, and compensatory to decompensatory, affecting large-scale neural networks through a plethora of mechanistic and signaling pathway alterations that converge into regional and cell type-specific neurodegeneration and, finally, into clinically overt cognitive and behavioral decline. This decline includes reductions in the activities of daily living, quality of life, independence, and life expectancy. Evolving lines of research suggest that epigenetic mechanisms may play a crucial role during AD development and progression. Epigenetics designates molecular mechanisms that alter gene expression without modifications of the genetic code. This topic includes modifications on DNA and histone proteins, the primary elements of chromatin structure. Accumulating evidence has revealed the relevant processes that mediate epigenetic modifications and has begun to elucidate how these processes are apparently dysregulated in AD. This evidence has led to the clarification of the roles of specific classes of therapeutic compounds that affect epigenetic pathways and characteristics of the epigenome. This insight is accompanied by the development of new methods for studying the global patterns of DNA methylation and chromatin alterations. In particular, high-throughput sequencing approaches, such as next-generation DNA sequencing techniques, are beginning to drive the field into the next stage of development. In parallel, genetic imaging is beginning to answer additional questions through its ability to uncover genetic variants, with or without genome-wide significance, that are related to brain structure, function and metabolism, which impact disease risk and fundamental network-based cognitive processes. Neuroimaging measures can further be used to define AD systems and endophenotypes. The integration of genetic neuroimaging methods with epigenetic markers in humans appears promising. This evolving development may lead to a new research discipline - imaging epigenetics - that will provide deeper insight into the causative pathogenetic and pathophysiological pathways through which genes and environment interrelate during life and impact human brain development, physiology, aging and disease. This knowledge may open doors for the development of novel biomarkers and preventive and disease-modifying treatments.