Neurotrophic factors and Alzheimer's disease: are we focusing on the wrong molecule?

Brain derived neurotrophic factor (BDNF) promotes cholinergic neuron function and survival. In Alzheimer's disease, BDNF mRNA and protein are decreased in basal forebrain cholinergic neuron target tissues such as cortex and hippocampus. Using RT-PCR, we demonstrate that BDNF is synthesized in basal forebrain, supplying cholinergic neurons with a local as well as a target-derived source of this factor. BDNF mRNA levels are decreased 50% in nucleus basalis of Alzheimer disease patients compared to controls. Thus, not only do the basal forebrain cholinergic neurons have a reduced supply of target-derived BDNF, but also of local BDNF. We also show by Western blotting that human CNS tissue contains both proBDNF and mature BDNF protein. Moreover, we demonstrate a significant (2.25-fold) deficit in proBDNF protein in Alzheimer's disease parietal cortex compared to controls. Thus, reduced BDNF mRNA and protein levels in Alzheimer's disease suggests that BDNF administration may be an effective therapeutic strategy for this disorder.     

Nutrition and dementia: are we asking the right questions?

Alzheimer's disease (AD) has no cure or nullifying pharmacological interventions. Nutritional supplementation represents a systemic approach that in some studies has provided benefit and has augmented pharmacological approaches. However, additional studies report no benefit of supplementation. We review herein how studies of nutrition on dementia, including those combining nutrition and dementia, are inherently compromised. We also review studies with mice, which demonstrate that nutritional supplementation can alleviate multiple genetic risk factors for AD. An individual diagnosed with AD has by definition undergone considerable cognitive decline; anticipating restoration/maintenance of cognitive performance following nutritional supplementation alone may be misdirected. Nutrition declines in aging, and even more so in AD. While optimization of nutrition should ideally be initiated well before any cognitive decline, we present evidence that the systemic benefit alone of nutritional supplementation at the very minimum warrants initiation along with pharmacological intervention.     

RNAi and brain function: was McConnell on the right track?

RNA interference (RNAi), one of the hottest topics of molecular biology research today, has unique features that are eerily reminiscent of the phenomenon of "RNA-mediated memory transfer," a controversial line of work that was investigated with great enthusiasm in the 1960s. If not a coincidence, then this suggests taking a new look at RNA-mediated modulation of neural function and raises the possibility that RNAi might be one of the physiologic mechanisms that regulate long-term gene expression in the brain.     

The hippocampal debate: are we asking the right questions?

For years, the debate has been: "Is the hippocampus the cognitive map?" or "Is the hippocampus the core of memory?" These two hypotheses derived their original power from two key experiments--the cognitive map theory from the remarkable spatial correlates seen in recordings of hippocampal pyramidal cells and the memory theory from the profound amnesias seen in the patient H.M. Both of these key experiments have been reinterpreted over the years: hippocampal cells are correlated with much more than place and H.M. is missing much more than just his hippocampus. However, both theories are still debated today. The hippocampus clearly plays a role in both navigation and memory processing. The question that must be addressed is rather: "What is the role played by the hippocampus in the navigation and memory systems?" By looking at the navigation system as a whole, one can identify the major role played by the hippocampus as correcting for accumulation errors that occur within idiothetic navigation systems. This is most clearly experimentally evident as reorientation when an animal is lost. Carrying this over to a more general process, this becomes a role of recalling a context, bridging a contextual gap, or, in other words, it becomes a form of recognition memory. I will review recent experimental data which seems to support this theory over the more general spatial or memory theories traditionally applied to hippocampus.     

Dysconnectivity in schizophrenia: where are we now?

The disconnection hypothesis suggests that the core symptoms of schizophrenia (SZ) are related to aberrant, or ‘dys-’, connectivity between distinct brain regions. A proliferation of functional and structural neuroimaging studies have been conducted to investigate this hypothesis, across the full course of the disorder; from people at Ultra-High-Risk of developing psychosis to patients with chronic SZ. However the results of these studies have not always been consistent, and to date, there have been no attempts to summarise the results of both methodologies in conjunction. In this article, we systematically review both the structural and functional connectivity literature in SZ. The main trends to emerge are that schizophrenia is associated with connectivity reductions, as opposed to increases, relative to healthy controls, and that this is particularly evident in the connections involving the frontal lobe. These two trends appear to apply across all stages of the disorder, and to be independent of the neuroimaging methodology employed. We discuss the potential implications of these trends, and identify possible future investigative directions.     

Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the "right stuff"?

There has been a surge of interest in the functional consequences of neurocognitive deficits in schizophrenia. The published literature in this area has doubled in the last few years. In this paper, we will attempt to confirm the conclusions from a previous review that certain neurocognitive domains (secondary verbal memory, immediate memory, executive functioning as measured by card sorting, and vigilance) are associated with functional outcome. In addition to surveying the number of replicated findings and tallying box scores of results, we will approach the review of the studies in a more thorough and empirical manner by applying a meta-analysis. Lastly, we will discuss what we see as a key limitation of this literature, specifically, the relatively narrow selection of predictor measures. This limitation has constrained identification of mediating variables that may explain the mechanisms for these relationships.     

Are we witnessing the disappearance of catatonic schizophrenia?

The decrease in the frequency of diagnosed catatonic subtypes among schizophrenic disorders as a whole during the last 50 years has long been regarded as an established fact. Until now the factors responsible for this development have been under discussion. As it is not clear if there is a true decrease or an ostensible one due to other factors such as changed diagnostic habits or neuroleptic treatment, we examined 174 consecutively admitted schizophrenic patients from three different psychiatric institutions diagnosed according to DSM-IV and Leonhard's criteria. It turned out that-depending on the diagnostic system-the rates of diagnosed catatonias were 10.3% (DSM-IV) and 25.3% (Leonhard's criteria). Comparison of the two original Leonhard cohorts (1938 to 1968, 1969 to 1986) with our own (1994 to 1999) shows a decrease in the frequency of catatonias from 35% to 25%, which-albeit statistically significant-is much less pronounced than in studies that used a narrower definition of catatonia. Here, besides sociocultural developments, the use of neuroleptics seems to effect the decrease in the frequency of catatonias in two ways: on one hand, they cause a decrease of hyperkinesia, excitement, or impulsivity; while on the other hand, they themselves produce motor abnormalities like rigidity, effects that favor the attribution of motoric symptoms to neuroleptics.     

A note on the association of schizophrenia after head injury: Causal or coincidental?

It has long been assumed on the basis of clinical reports that when schizophrenia is diagnosed after traumatic head injury there is a causal relationship. However, caution is urged in the medico-legal setting before assuming such causality. This recommendation is based on the experiential nature of previous clinical reserach, the relative frequency of both conditions, the tendency of patients and relatives to idealise pre-injury functioning, the challenge of establishing the time of onset of schizophrenia, the absence of a 'biological gradient' or consistentcy of localisation of injury, and the emergence of rigorous large-number epidemiological studies that have cast considerable doubt on the hitherto presumed association.     

Genetics in schizophrenia: where are we and what next?

Understanding the genetic basis of schizophrenia continues to be major challenge. The research done during the last two decades has provided several candidate genes which unfortunately have not been consistently replicated across or within a population. The recent genome-wide association studies (GWAS) and copy number variation (CNV) studies have provided important evidence suggesting a role of both common and rare large CNVs in schizophrenia genesis. The burden of rare copy number variations appears to be increased in schizophrenia patients. A consistent observation among the GWAS studies is the association with schizophrenia of genetic markers in the major histocompatibility complex (6p22.1)-containing genes including NOTCH4 and histone protein loci. Molecular genetic studies are also demonstrating that there is more overlap between the susceptibility genes for schizophrenia and bipolar disorder than previously suspected. In this review we summarize the major findings of the past decade and suggest areas of future research.     

Are we on the right track in DBS surgery for dystonic head tremor? Polymyography is a promising answer

The clinical benefit of Deep Brain Stimulation (DBS) is associated with electrode positioning accuracy. Intraoperative assessment of clinical effect is therefore key. Evaluating this clinical effect in patients with dystonic head tremor, as opposed to limb tremor, is challenging because the head is fixed in a stereotactic frame. To clinically assess head tremor during surgery, surface electromyography (EMG) electrodes were bilaterally applied to the sternocleidomastoid and cervical paraspinal muscles. This case shows that intraoperative polymyography is an easy and useful tool to assess the clinical effect of DBS electrode positioning.     

Can we track the impact of Australian mental health research?

OBJECTIVE: Arguments are being made to increase research and development funding for mental health research in Australia. Consequently, the methods used to measure the results of increased investment require review. This study aimed to describe the status of Australian mental health research and to propose potential methods for tracking changes in research output. Specifically, we describe the research output of nations, Australian states, Australian and New Zealand institutions and Australian and New Zealand researchers using citation rates. METHOD: Information on research output was sourced from two international databases (Institute for scientific information [ISI] Essential Science Indicators and ISI Web of Science) and the ISI list of Highly Cited Researchers. RESULTS: In an international setting, Australia does not perform as well as other comparable countries such as New Zealand or Canada in terms of research output. Within Australia, the scientific performance of institutions apparently relates to the strength of some individual researchers or consolidated research groups. Highly cited papers are evident in the fields of syndrome definition, epidemiology and epidemiological methods, cognitive science and prognostic or longitudinal studies. CONCLUSIONS: Australian researchers need to consider the success of New Zealand and Canadian researchers, particularly given the relatively low investment in health and medical research in New Zealand. Although citation analyses are fraught with difficulties, they can be effectively complemented by other measures of responsiveness to clinical or population needs and community expectations and should be conducted regularly and independently to monitor the status of Australian mental health research.