Delineation of MidXq28-duplication syndrome distal to MECP2 and proximal to RAB39B genes.

Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.

CSF Aß1-42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer's disease.

The development of validated, qualified, and standardized biomarkers for Alzheimer's 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 ß isoform (Aß1-42) 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 Aß1-42 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.

Brain hemodynamic changes associated with chronic cerebrospinal venous insufficiency are not specific to multiple sclerosis and do not increase its severity.

PURPOSE: To investigate the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and cerebral hemodynamic parameters and to disclose any possible involvement in the pathophysiology of multiple sclerosis (MS). MATERIALS AND METHODS: The study was approved by the institutional review board, and written informed consent was obtained from all participants. The diagnosis of CCSVI was assigned by using specific color Doppler ultrasonographic criteria. Cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time were assessed with dynamic susceptibility contrast material-enhanced magnetic resonance imaging in normal-appearing white matter (NAWM) in 39 patients with MS. Of these, 25 had CCSVI and 14 did not. Twenty-six healthy control subjects were also evaluated, and of these, 14 had CCSVI and 12 did not. Two-way analysis of variance testing was used for statistical analysis, with Bonferroni correction for multiple comparisons. Correlation analysis was performed by calculating Spearman coefficients. RESULTS: Individuals with CCSVI showed cerebral hemodynamic anomalies, such as decreased CBF and CBV, as compared with individuals without CCSVI, without any delay in mean transit time. No significant interaction between MS and CCSVI was found for any hemodynamic parameters. Furthermore, no correlations were found between CBV and CBF values in NAWM or for severity of disability in patients with MS. The MS group showed prolonged mean transit time in the periventricular NAWM, as compared with the control group, and positive correlation was found between mean transit time values and disability scales in patients with MS. CONCLUSION: The data support a role of CCSVI in cerebral hemodynamic changes, such as a decrease of CBV and CBF, regardless of the presence of MS. CCSVI had no effect on neurologic function and disability progression in patients with MS.

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

OBJECTIVE: 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. METHODS: In the present study, CCSVI was studied in 84 MS patients and in 56 healthy subjects by applying the Zamboni method for CCSVI identification. RESULTS: We found no significant differences (p = 0.12) in CCSVI frequency between MS and control subjects. Furthermore, no differences were found between CCSVI-positive and CCSVI-negative patients in terms of relevant clinical variables such as disease duration, time between onset and first relapse, relapsing or progressive disease course, and risk of secondary progression course. Statistically significant differences were not found between CCSVI-positive and CCSVI-negative MS subjects by analyzing direct measures of disability such as mean Expanded Disability Status Scale (EDSS) (p = 0.07), mean progression index (p > 0.1), and mean MS severity score (p > 0.1). The percentage of subjects who reached EDSS 4.0 and 6.0 milestones was not different among CCSVI-negative and CCSVI-positive subjects, and no significant correlation was found between severity of disability and number of positive CCSVI criteria. INTERPRETATION: Our results indicate that CCSVI has no role in either MS risk or MS severity.

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.

Imaging epigenetics in Alzheimer's disease.

Sporadic Alzheimer's 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.

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.

Brain involvement in glaucoma: advanced neuroimaging for understanding and monitoring a new target for therapy.

On the basis of a large body of experimental data the notion that glaucoma damages retinal ganglion cells and central areas of the visual system has been put forward. The mechanisms underlying glaucomatous involvement of the central areas are not known: the most likely hypothesis is that this event is the result of an anterograde transynaptic neurodegeneration triggered by ganglion cells' death. However, it is possible that in some cases it may be the consequence of a neurodegenerative disease of the central nervous system. In any event, novel mechanisms leading to cell demise might be implicated. The development of powerful neuroimaging techniques in conjunction with sophisticated analysis has recently provided compelling support to the involvement of central stations of the visual pathway in patients suffering of glaucoma. Diffusion Tensor-MRI allows the central damage associated with glaucoma to be assessed and therapeutic efficacy of novel neuroprotective interventions to be quantified.

Long-term cognitive and behavioral therapies, combined with augmentative communication, are related to uncinate fasciculus integrity in autism.

Recent evidence points to white-matter abnormalities as a key factor in autism physiopathology. Using Diffusion Tensor Imaging, we studied white-matter structural properties in a convenience sample of twenty-two subjects with low-functioning autism exposed to long-term augmentative and alternative communication, combined with sessions of cognitive and behavioral therapy. Uncinate fasciculus structural properties correlated significantly with therapy length and early onset, as well as to clinical outcome, independently from IQ, age or symptoms severity at therapy onset. Moreover, adherence to therapy was linked with better clinical outcome and uncinate fasciculus structural integrity. The results point to the capability of a long-term rehabilitation of subjects with low-functioning autism to produce white-matter structural modifications, which could thus play a role in the rehabilitative outcome.

Increased brain apparent diffusion coefficient in tuberous sclerosis.

PURPOSE: To evaluate the water diffusivity of normal-appearing white matter (NAWM) in patients with tuberous sclerosis complex compared with that in control subjects. MATERIALS AND METHODS: Diffusion and conventional magnetic resonance (MR) imaging examinations were performed in 18 patients with clinically established tuberous sclerosis complex (10 male and eight female patients; mean age, 20.1 years; range, 12-30 years), as well as in 18 age-matched control subjects (nine male and nine female; mean age, 20.2 years; range, 11-28 years). Apparent diffusion coefficients (ADCs) were generated, and small elliptic regions of interest were manually placed both in perilesional NAWM and in six anatomic locations of NAWM remote from hamartomatous lesions. Perilesional ADCs were compared with those at the same anatomic site on the contralateral side of the brain (generalized linear regression analysis). ADCs from the predetermined sites in patients were compared with those in control subjects (generalized linear regression analysis). RESULTS: Supratentorial ADCs were higher in patients with tuberous sclerosis complex than in control subjects, and statistically significant differences were observed in the occipital white matter, frontal white matter, centrum semiovale, parietal white matter, and corona radiata (for each location, P <.001). Significant increases were also seen in the perilesional NAWM compared with NAWM at the same anatomic locations on the contralateral side (P <.001). Infratentorial ADCs were normal. CONCLUSION: Significant ADC increases were measured in the supratentorial NAWM.