The study by Kl ppel and colleagues

The study by Klöppel and colleagues can decisively shape future functional neuroimaging research in HD and other neurodegenerative conditions, but we believe that there is much more to learn from this study. The rationale and design should also motivate psychiatric research, where there is still an urgent need of valid and reliable biological markers. In depression or schizophrenia, for example, where cognitive deficits are prominent and deleterious for clinical outcome, there has been substantial effort to map neural correlates of cognitive dysfunction and to define neural predictors of treatment response (). In both depression and schizophrenia, there is a long-standing debate if regionally increased activity is reflective of neural compensation, whether this may be efficient or not (). Surprisingly, there have been only a few attempts to integrate structural data into the functional data analyses (). At multiple levels of biology and symptom expression there are clear differences between depression/schizophrenia and HD. But there is a loss of polo like kinase volume over time in both depression and schizophrenia, as much as there is evidence for compensatory neural activity which is so far unexplained in terms of its underlying neurobiology. Functional changes could be primary in the sense that they are intrinsic to the disorder and not secondary to structural alterations. Alternatively, functional compensation for structural damage is a possible explanation (as much as other explanations may be plausible as well, such as compensation for aberrant neural transmission), yet this possibility has not been addressed so far in a theoretically convincing and explicitly model-driven approach. In this regard, the work provided by Klöppel and colleagues may foster integrative neuroimaging approaches using explicit models of neural compensation at various levels of model complexity. Clearly, in depression and schizophrenia genetic and environmental influences need to be considered (although recent data suggest that the very same applies to HD; ), and any “close-to-real-world” compensation model in these disorders will seek to account for these variables in advanced stages of research. But before doing so, why not start with the obvious, especially when the available neuroimaging data invites and justifies such an approach. In this sense, this paper paves the way for an innovative path that opens up novel avenues of research not only for neurodegeneration but also for several other mental disorders. Disclosure
Understanding the etiology of cognitive deficits in genetic disorders holds great promise for advancing disease-specific treatments. The availability of animal models has allowed detailed examination of molecular pathways underlying the cognitive phenotype in numerous Mendelian disorders, increasing optimism for mechanism-based treatments. One such disorder is neurofibromatosis type 1 (NF1), an autosomal dominant condition associated with high rates of neurocognitive deficits, academic failure, attention deficit hyperactivity disorder, psychosocial maladjustment and motor coordination problems (). Mutations in the gene result in decreased levels of neurofibromin; a negative regulator of the RAS signaling cascade. Ensuing RAS hyperactivation increases activity-dependent GABAergic neurotransmission and reduces synaptic plasticity, resulting in behavioral impairment (). Preclinical trials demonstrate that genetic and pharmacological interventions inhibiting RAS transforming activity can rescue these cellular abnormalities and reverse the murine behavioral phenotype, providing a rationale for human clinical trials (). Despite significant promise, early attempts at translating these preclinical findings in randomized controlled trials have unfortunately failed (). Translation of findings from bench to clinically relevant therapies is notoriously complex, and treatments for cognitive deficits in patients with NF1 appear to be no different. There are many reasons for this including lack of evidence for the appropriate treatment dose to inhibit RAS activity in the brain and, more importantly, minimal validation of the preclinical disease model in the human disease state. The relative contributions of aberrant RAS signaling, altered GABAergic neurotransmission and deficient synaptic plasticity to the NF1 cognitive phenotype in humans is also unknown.