Purpose of review

New research on the mechanisms of neurodegeneration highlights parallels between prion disease pathogenesis and other, more common disorders not typically thought to be infectious. This involves propagation of protein misfolding from cell to cell by templated conformational change. This review focuses on the cell biology that underlies propagation of protein aggregation between cells, including a discussion of protein biochemistry and relevant mouse models.

Recent findings

Like the prion protein, several other proteins exhibit self-propagating fibrillar conformations in vitro. Multiple cellular studies have now implicated endocytic mechanisms in the uptake of aggregates into cells. Aggregates that enter cells somehow escape endocytic vesicles to contact cytosolic protein. The mechanism of release of protein monomers and aggregates from cells is not well understood. Animal models have confirmed that brain lysates and purified protein can accelerate brain disorder in a manner similar to prions.

Summary

Aggregate flux in and out of cells likely contributes to the progression of neuropathology in neurodegenerative diseases. A better understanding of these mechanisms is emerging and can help explain local spread of protein aggregation and the role of neural networks in disease. This will also inform new therapeutic strategies aimed at blocking this process.

Purpose of review

Intracranial atherosclerotic disease (IAD) is likely the most common cause of stroke world-wide, and is associated with a very high risk of recurrence. It results in cerebral ischemia due to a variety of mechanisms, including artery-to-artery embolism, hemodynamic failure and occlusion of penetrating arteries. New imaging modalities focused on physiological consequences of IAD have become available and recent treatment trials have been completed.

Recent findings

We review the traditional imaging modalities, emphasizing the advantages and limitations of each method, and discuss novel physiological approaches that interrogate physiological process to indicate specific mechanisms of ischemia. These allow deeper understanding of the pathophysiological processes that underlie IAD-related ischemia. The key findings of recent therapeutic trails are reviewed, including the landmark randomized studies showing advantage of antiplatelet agents and risk factor modification, and a significant risk of complications with endovascular approaches.

Summary

Current evidence argues for aggressive medical management and suggests caution with interventional treatments. We propose that mechanistic information will further refine the risk assessment of patients with IAD to offer targeted therapy.

Purpose of review

To summarize the current status of retinal prostheses, recent accomplishments, and major remaining research, engineering, and rehabilitation challenges.

Recent findings

Retinal research, materials and biocompatibility studies, and clinical trials in patients blind from RP are representative of an emerging field with considerable promise and sobering challenges. A summary of progress in dozens of labs, companies, and clinics around the world is presented through a synopsis of relevant papers, not only to summarize the progress, but also to convey the remarkable increase in interest, effort, and outside funding this field has enjoyed.

Summary

At the present time, clinical applications of retinal implant technology are dominated by one or two groups/companies, but the field is wide open for others to take the lead through novel approaches in technology, tissue interfacing, information transfer paradigms, and rehabilitation. Where the field will go in the next few years is almost anybody’s guess, but that it will move forward is a certainty.

Purpose of review

This review describes the evolution of the clinical criteria for Alzheimer’s disease over the past 25 years, with special emphasis on those recently published that have incorporated the use of biomarkers.

Recent findings

One of the most important advances in the knowledge of Alzheimer’s disease was the development of cerebrospinal fluid, PET and MRI biomarkers. These have shown that the Alzheimer’s disease is present in cognitively normal individuals, suggesting that there is a long incubation process that precedes the onset of the symptoms. Although there are diagnostic criteria for Alzheimer’s disease, the National Institute on Aging and the Alzheimer’s Association has proposed a set of diagnostic criteria oriented to provide a unified vision of the pathological process from preclinical, to mild cognitive impairment, and to full-blown dementia. These new criteria take advantage of different biomarkers to support the clinical diagnosis of the different stages of the disease.

Summary

The new guidelines provide a definition of the dementia syndrome and core diagnostic features to be used in research and clinical practice, although they caution about the use of biomarkers, since they still require validation, and the longitudinal interaction and dynamics of these biomarkers in relationship to the manifestation of the symptoms are not fully understood.

Purpose of review

To review the recent advances in the epidemiology and pathophysiology of impulse control disorders (ICD) in Parkinson’s disease (PD).

Recent findings

Large cross-sectional and case-control multicentre studies show that ICDs in PD are common with a frequency of 13.6%. These behaviours are associated with impaired functioning and with depressive, anxiety and obsessive symptoms, novelty seeking and impulsivity. Behavioural subtypes demonstrate differences in novelty seeking and impulsivity suggesting pathophysiological differences. Observational and neurophysiological studies point towards a potential mechanistic overlap between the behavioural (ICDs) and motor (dyskinesias) dopaminergic sequelae. Converging data suggest dopamine agonists in ICDs appear to enhance learning from rewarding outcomes and impulsive choice. ICD patients also have enhanced risk preference and impaired working memory. Neuroimaging data points towards enhanced bottom-up ventral striatal dopamine release to incentive cues, gambling tasks and reward prediction, and possibly inhibition of top-down orbitofrontal influences. Dopamine agonist-related ventral striatal hypoactivity to risk is consistent with impaired risk evaluation.

Summary

Recent large scale studies and converging findings are beginning to provide an understanding of mechanisms underlying ICDs in PD which can guide prevention of these behaviours and optimize therapeutic approaches.

Purpose of review

Analysis of the auditory environment, source identification and vocal communication all require efficient brain mechanisms for disambiguating, representing and understanding complex natural sounds as ‘auditory objects’. Failure of these mechanisms leads to a diverse spectrum of clinical deficits. Here we review current evidence concerning the phenomenology, mechanisms and brain substrates of auditory agnosias and related disorders of auditory object processing.

Recent findings

Analysis of lesions causing auditory object deficits has revealed certain broad anatomical correlations: deficient parsing of the auditory scene is associated with lesions involving the parieto-temporal junction, while selective disorders of sound recognition occur with more anterior temporal lobe or extra-temporal damage. Distributed neural networks have been increasingly implicated in the pathogenesis of such disorders as developmental dyslexia, congenital amusia and tinnitus. Auditory category deficits may arise from defective interaction of spectrotemporal encoding and executive and mnestic processes. Dedicated brain mechanisms are likely to process specialised sound objects such as voices and melodies.

Summary

Emerging empirical evidence suggests a clinically relevant, hierarchical and fractionated neuropsychological model of auditory object processing that provides a framework for understanding auditory agnosias and makes specific predictions to direct future work.

Purpose of review

Neurological comorbidities in autism spectrum disorders (ASD) are not only common, but they are also associated with more clinical severity. This review highlights the most recent literature on three of autism’s most prevalent neurological comorbidities: motor impairment, sleep disorders, and epilepsy.

Recent findings

Motor impairment in ASD manifests as both delays and deficits, with delays found in gross and fine motor domains and deficits found in praxis, coordination, and gait, all of which affect other cognitive and behavioral domains. Sleep disorders, especially insomnia, occur in up to 83% of children with ASD and recent studies have begun to explore the underlying biochemical and behavioral basis of the impairment, which has bolstered treatment studies. Epilepsy is reported in up to one-third of children with ASD, and new studies have focused on identifying the genetic causes of this association.

Summary

Better characterization of the phenotype, developmental trajectory, and underlying pathophysiology of these neurological comorbidities will enable us to define neurological endophenotypes within the autism spectrum. Future studies must investigate the emergence of these comorbidities prospectively in order to determine whether they lie on the causal pathway to ASD or whether they reflect epiphenomena of the disorder. Since epilepsy and sleep disorders can be treated and may contribute significantly to behavioral and cognitive abnormalities in ASD, their identification is of high clinical relevance.

Purpose of review

Mendelian disorders that affect cognition provide a unique opportunity to study the mechanisms of neurodevelopmental disorders through the examination of genetic defects in animals and development of hypotheses that can be tested in human subjects. Tuberous sclerosis complex (TSC) is a genetic disease that presents with epilepsy, autism and intellectual disability. Here we review recent advances in our understanding of TSC pathogenesis and signaling pathways that may be modulated to treat the neurological symptoms.

Recent findings

Accumulating evidence suggests that TSC patients have non-tuber abnormalities that contribute to the development of the neurological phenotype – in particular, disorganization of axon tracts and deficient myelination. TSC mouse models have failed to replicate the human neuropathology entirely, but have shed light on the cellular abnormalities and the neurobehavioral phenotypes. Most importantly, cell culture and animal models have identified the mTORC1 pathway as a therapeutic target in this disease.

Summary

Preclinical data strongly suggest that TSC is a disease of abnormal neuronal connectivity. The high incidence of neurodevelopmental deficits, early detection of the disease in very young ages, and availability of mTORC1 inhibitors make TSC a model for other Mendelian disorders of neurocognition and an avenue for the mechanism-based treatment trials of neurodevelopmental disorders.

Purpose of review

The present review develops a framework from which to understand the role of the cholinergic system in healthy cognition and in cognitive dysfunction. Traditionally, the cholinergic system has been thought to have direct influence on cognitive processes such as working memory and attention. Although the influence of cholinergic function on stimulus processing has been long appreciated, the notion that cholinergic effects on stimulus processing is the mechanism by which acetylcholine influences cognitive processes has only more recently been considered.

Recent findings

Literature supporting the hypothesis that cholinergic modulation influences cognitive functions through stimulus processing mechanisms has been growing for over a decade. Recent conceptualizations of the developing literature have argued for a new interpretation to an old and developing literature.

Summary

The argument that cholinergic function modulates cognitive processes by direct effects on basic stimulus processing extends to cognitive dysfunction in neuropathological conditions including dementia and mood disorders. Memory and attention deficits observed in these and other conditions can be understood by evaluating the impact of cholinergic dysfunction on stimulus processing, rather than on the cognitive function in general.

Purpose

The aim of this review is to explore the evolution of the logopenic variant of primary progressive aphasia as a distinct clinical entity and to outline recent advances that have clarified its clinical characteristics, neural underpinnings and potential genetic and pathological bases. This is particularly relevant as researchers attempt to identify clinico-pathological relationships in subtypes of primary progressive aphasia in hopes of utilizing language phenotype as a marker of underlying disease.

Recent findings

Recent work has served to refine and expand upon the clinical phenotype of the logopenic variant. Logopenic patients show a unique pattern of spared and impaired language processes that reliably distinguish this syndrome from other variants of progressive aphasia. Specifically, they exhibit deficits in naming and repetition in the context of spared semantic, syntactic and motor speech abilities. Further, there is a growing body of evidence indicating a possible link between the logopenic variant phenotype and specific pathological and genetic correlates.

Summary

Findings indicate that the logopenic variant is a distinct subtype of progressive aphasia that may hold value as a predictor of underlying pathology. Additional research, however, is warranted in order to further clarify the cognitive-linguistic profile and to confirm its relation to certain pathological and genetic processes.

Purpose of review

The current standard care of treatment for glioblastomas (GBM) is never curative and exclusively involves the use of cytoxics upfront (e.g. radiation and chemotherapy). Current clinical protocols involve use of single agent targeted therapies which inhibit specific pathways. Given the functional redundancies present in human tumors and escape mechanisms, it is highly unlikely that such a monotherapy approach will be successful in the treatment of GBM. Future directions of therapy for GBMs will likely involve the use of therapeutic cocktails including more than one target specific inhibitors based on tumor escape mechanism, genetic, epigenetic and molecular signatures. This review addresses some of the relevant issues.

Recent findings

Correlative clinical studies from various clinical trials and pre-clinical studies have provided the meticulous use of chemotherapeutics and radiation based on molecular profiling of tumors. Alkylating agents such as temozolomide lose their efficacy if DNA repair enzyme expression is up regulated. The alternative strategies include targeting the enzyme or one can use Poly (ADP) ribose inhibitor to inhibit base excision repair (BER) pathway rather than mismatch repair (MMR) pathway. Currently, several inhibitors in this category are in clinical trials. Next, we have addressed new avenues including radiosensitizers, hypoxia, metabolism, angiogenesis, invasive and infiltrative nature of tumors and potential molecular targets which can be exploited for clinical trials. Finally we have included some aspect of genome wide association studies and correlative analysis and the lessons learned to design better clinical trials.

Summary

Advances in profiling the non-coding RNAs, genetic, epigenetic profiles, metabolomics, genomics and proteomics may uncover important resistance mechanisms in GBM. Personalized therapy using various therapeutic cocktails targeting these resistance mechanisms may prove even more effective in the future management of GBMs.

Purpose of review

Imaging genomics is an emerging field that is rapidly identifying genes that influence the brain, cognition, and risk for disease. Worldwide, thousands of individuals are being scanned with high-throughput genotyping (genome-wide scans), and new imaging techniques [high angular resolution diffusion imaging and resting state functional magnetic resonance imaging (MRI)] that provide fine-grained measures of the brain’s structural and functional connectivity. Along with clinical diagnosis and cognitive testing, brain imaging offers highly reproducible measures that can be subjected to genetic analysis.

Recent findings

Recent studies of twin, pedigree, and population-based datasets have discovered several candidate genes that consistently show small to moderate effects on brain measures. Many studies measure single phenotypes from the images, such as hippocampal volume, but voxel-wise genomic methods can plot the profile of genetic association at each 3D point in the brain. This exploits the full arsenal of imaging statistics to discover and replicate gene effects.

Summary

Imaging genomics efforts worldwide are now working together to discover and replicate many promising leads. By studying brain phenotypes closer to causative gene action, larger gene effects are detectable with realistic sample sizes obtainable from meta-analysis of smaller studies. Imaging genomics has broad applications to dementia, mental illness, and public health.

Purpose of review

Diffusion tractography uses non-invasive brain imaging data to trace fibre bundles in the human brain in vivo. This raises immediate possibilities for clinical application but responsible use of this approach requires careful consideration of the scope and limitations of the technique.

Recent findings

To illustrate the potential for tractography to provide new information in clinical neuroscience we review recent studies in three broad areas: First, use of tractography for quantitative comparisons of specific white matter pathways in disease; second, evidence from tractography for the presence of qualitatively different pathways in congenital disorders or following recovery; third, use of tractography to gain insights into normal brain anatomy that can aid our understanding of the consequences of localised pathology, or guide interventions.

Summary

Diffusion tractography opens exciting new possibilities for exploring features of brain anatomy that previously were not visible to us in vivo.

Purpose of review

Tuberous sclerosis complex (TSC) is a multiorgan genetic disease caused by mutations in the TSC1 or TSC2 genes. TSC has been recognized for many years as an important cause of severe neurological disease with patients suffering from epilepsy, developmental delay, autism, and psychiatric problems. During the last year there has been enormous advances in basic and translational research pertaining to TSC.

Recent findings

In this review, I discuss the basic science findings that position the TSC1 and TSC2 genes as critical regulators of the mTOR kinase within mTORC1. In addition, I will discuss the development of new animal models, translational data, and recent clinical trials using mTORC1 inhibitors such as rapamycin.

Summary

The past few years have seen spectacular advances that have energized TSC related research and challenged existing symptomatic treatments. While it remains to be seen whether use of mTORC1 inhibitors will revolutionize the care of patients with TSC, the application of basic and translational research towards a specific clinical disorder emphasizes the potential and promise of molecular medicine.

PURPOSE OF REVIEW

The following is a review of the most recent research concerning the potential role of immune system dysfunction in autism. This body of literature has expanded dramatically over the past few years as researchers continue to identify immune anomalies in individuals with autism.

RECENT FINDINGS

The most exciting of these recent findings is the discovery of autoantibodies targeting brain proteins in both children with autism and their mothers. In particular, circulating maternal autoantibodies directed towards fetal brain proteins are highly specific for autism. This finding has great potential as a biomarker for disease risk, and may provide an avenue for future therapeutics and prevention. Additionally, data concerning the cellular immune system in children with autism suggest there may be a defect in signaling pathways that are shared by the immune and central nervous systems. While studies to explore this hypothesis are ongoing, there is great interest in the commonalities between the neural and immune systems and their extensive interactions.

SUMMARY

In summary, there is exciting research regarding the role of the immune system in autism spectrum disorders that may have profound implications for diagnosis and treatment of this devastating disease.

Purpose of review

The etiology of stroke remains unknown in roughly one third of patients despite extensive investigation. The prevalence of PFOs in the general population is around 25% but the prevalence in cryptogenic stroke patients is doubled. This suggests a causal relationship between PFO and CS. This has generally been attributed to paradoxical embolism. Regardless of mechanism, ~30,000 young patients each year have a cryptogenic stroke and PFO. Optimal management is uncertain.

Recent findings

Many physicians recommend PFO closure, an intuitively attractive mechanical solution for stroke prevention. Unfortunately, the benefit of PFO closure in patients with stroke has not been demonstrated. There are ongoing clinical trials comparing the safety and efficacy of PFO closure to medical therapy. Interpreting these trials will be complicated by two issues: first, it is unclear whether a patient's PFO is causally related to the event (“pathogenic”) or not (“incidental”); and second, recurrent strokes may be due to paradoxical embolism or another stroke mechanism.

Summary

Substantial heterogeneity of patients within trials along these two dimensions of risk may make overall trial results difficult to interpret. With appropriate analyses, the trials may be more informative than the overall data may suggest.

Purpose of review

Understanding the behavioral mechanisms of sensorimotor adaptation and learning is essential for designing rational rehabilitation interventions.

Recent findings

Adaptation is the trial-and-error process of adjusting movement to new demands and is now thought to be more than a simple error cancellation process. Instead, it may calibrate the brain’s prediction of how the body will move and takes into account costs associated with the new task demand. Damage of the cerebellum systematically disrupts adaptation, but damage to other brain regions often does not. Adapting to perturbations driven by a device like a robot or a treadmill leads to only partial generalization to unconstrained ‘real-world’ movements. Repeated adaptation can lead to learning a new motor calibration, but process of consolidation of this type of learning is less understood in patients.

Summary

Adaptation is inherently important for rehabilitation by making movement flexible, but can also be used to ascertain whether some patients can generate a more normal motor pattern. Repeated adaptation can lead to learning of a new, more permanent motor calibration. Though less understood, this type of learning is likely to be an important method for making long-term improvements in patients’ movement patterns.

Purpose of review

Advances in MR microscopy (MRM) make it practical to map gene variants responsible for structural variation in brains of many species, including mice and humans. We review results of a systematic genetic analysis of MRM data using as a case study a family of well-characterized lines of mice.

Recent advances

MRM has matured to the point that we can generate high contrast high-resolution images even for species as small as a mouse, with a brain merely 1/3000th the size of humans. We generated 21.5-micron data sets for a diverse panel of BXD mouse strains to gauge the extent of genetic variation, and as a prelude to comprehensive genetic and genomic analyses. Here we review (1) MRM capabilities and image segmentation methods; (2) heritability of brain variation; (3) covariation of the sizes of brain regions; and (4) correlations between MRM and classical histological data sets.

Summary

The combination of high throughput MRM and genomics will improve our understanding of the genetic basis structure-function correlations. Sophisticated mouse models will be critical in converting correlations into mechanisms and in determining genetic and epigenetic causes of differences in disease susceptibility.

Purpose of review:

This article reviews recent developments in the field of amyloid imaging using positron emission tomography (PET), specifically the ability to quantify the amount and distribution of brain Aβ, the protein that occupies a central position in leading theories of the pathogenesis of Alzheimer's disease (AD).

Recent Findings:

Several imaging-pathology correlations place the technique itself on a stronger footing by showing good agreement between in vivo and histological measures of Aβ deposition. Correlations between Aβ and other measures of dementia – cognition, brain atrophy, and glucose metabolism – appear to support a view that Aβ triggers a host of downstream alterations that are closely related to dementia severity and progression. However, associations between PET measures of β-amyloid and cognition are generally fairly weak. The implications for clinical use are still uncertain. It seems likely that amyloid imaging will be useful for differentiating dementias associated with Aβ from those that are not, but the utility of this approach will depend on the availability of effective Aβ-directed treatments. Similarly, amyloid imaging offers the potential for predicting which non-demented individuals will eventually develop AD although here again the measurement of downstream Aβ effects may be important.

Summary:

The ability to quantify the onset and progression of Aβ pathology in the brain offers the potential for investigating a host of questions concerning individual and neural vulnerability and the amyloid hypothesis of AD itself. These findings will have important basic and clinical implications.

Purpose of review:

This review will discuss how recent advances with induced pluripotent stem (iPS) cells have brought the science of stem cell biology much closer to clinical application for patients with retinal degeneration.

Recent findings:

The ability to generate embryonic stem (ES) cells by reprogramming DNA taken from adult cells was demonstrated by the cloning of Dolly the sheep by somatic cell nuclear transfer over ten years ago. Recently it has been shown that adult cells can be reprogrammed directly, without the need for a surrogate oocyte through the generation of induced pluripotent stem (iPS) cells. The method of reprogramming has since been optimised to avoid the use of retroviruses, making the process considerably safer. Last year human iPS cells were isolated from an 80 year old patient with neurodegenerative disease and differentiated into neurons in vitro.

Summary:

For stem cell therapies, the retina has the optimal combination of ease of surgical access, combined with an ability to observe transplanted cells directly through the clear ocular media. The question now is which retinal diseases are most appropriate targets for clinical trials using iPS cell approaches.

Purpose of review

Recent developments in the statistical physics of complex networks have been translated to neuroimaging data in an effort to enhance our understanding of human brain structural and functional networks. This review focuses on studies using graph theoretical measures applied to structural MRI, diffusion MRI, functional MRI, electroencephalography and magnetoencephalography data.

Recent findings

Complex network properties have been identified with some consistency in all modalities of neuroimaging data and over a range of spatial and time scales. Conserved properties include small-worldness, high efficiency of information transfer for low wiring cost, modularity, and the existence of network hubs. Structural and functional network metrics have been found to be heritable and to change with normal aging. Clinical studies, principally in Alzheimer’s disease and schizophrenia, have identified abnormalities of network configuration in patients. Future work will likely involve efforts to synthesize structural and functional networks in integrated models and to explore the inter-dependence of network configuration and cognitive performance.

Summary

Graph theoretical analysis of neuroimaging data is growing rapidly and could potentially provide a relatively simple but powerful quantitative framework to describe and compare whole human brain structural and functional networks under diverse experimental and clinical conditions.

Purpose of review

The molecular neuroscience revolution has begun to rekindle interest in fundamental neuroanatomy. Blending these disciplines may prove critical to our understanding of neurodegenerative diseases, which target specific anatomical systems. Recent research on frontotemporal dementia highlights the potential value of these approaches.

Recent findings

The behavioral variant of FTD (bvFTD) leads to progressive social-emotional processing deficits accompanied by anterior cingulate and frontal insular degeneration. These sites form a discrete human neural network and feature a class of Layer 5b projection neurons, von Economo neurons (VENs), found only in large-brained, socially complex mammals. VENs have been shown to represent an early target in bvFTD but not in Alzheimer’s disease.

Summary

Integrative approaches to selective vulnerability may help clarify neurodegenerative disease pathogenesis.

Purpose of review

The last decade has generated much interest in the genetics of developmental disorders. This interest, in part, is focused on two issues: the specificity/generality and the type/frequency of the genetic mechanisms involved.

Recent findings

First, it appears that studies are more fruitful and their results more replicable, broadly speaking, when they conceptualize disorders not holistically, as categorical units, but componentially, through various quantitative processes. Second, there have been several successful investigations of severe impairments in a number of isolated families with higher than typical frequencies of developmental disorders. Yet, it has been difficult to generalize the genetic mechanisms involved in these rare cases to the general population.

Summary

Current findings suggest the involvement of multiple genetic mechanisms in the manifestations of childhood-onset conditions. It is possible that each ‘facet’ (or component) of a disorder is controlled by a semi-independent set of genes. Numerous components appear to be deficient in more than one disorder, possibly explaining comorbidity. The genetic foundation of developmental disorders may be formed not by isolated genes, but rather by a combination of genes and the pathways that these genes regulate. These accumulating findings have direct implications for designing both diagnostic and treatment approaches to childhood-onset disorders.

Purpose of review

Diffusion tensor imaging (DTI) has a unique capability to delineate axonal tracts within the white matter, which has not been possible with previous noninvasive imaging techniques. In the past 10 years, we have witnessed a large increase in the use of DTI-based studies and a score of new anatomical knowledge and image analysis tools have been introduced in recent years. This review will provide an overview of the recent advancements in DTI-based studies and new image analysis tools.

Recent findings

DTI provided new dimensions for the characterization of white matter anatomy. This characterization of the white matter can be roughly divided into two categories. First, the white matter can be parcellated into constituent white matter tracts, based on pixel-by-pixel orientation and anisotropy information. Second, the DTI information can be extrapolated to obtain three-dimensional connectivity information. Based on these capabilities of DTI, many new image analysis tools are being developed to investigate the status of the white matter.

Summary

In the past, the white matter has often been treated as one compartment. With DTI and recently developed analysis tools, we can investigate the status of intra-white matter structures and deepen our understanding of white matter structures and their abnormalities under pathological conditions.