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Journal Reviews

Posted in Journal Reviews on 12th Nov 2012

Editor’s Choice
A mutation for protection against Alzheimer’s disease

The perceived importance of amyloid in the pathogenesis of Alzheimer’s disease has fluctuated in the last 30 years. Deposition of amyloid is a pathological hallmark of the disease and suggests a central role for the protein in the disease.The association of Down’s syndrome, trisomy 21, with Alzheimer’s made the Amyloid Precursor Protein (APP) gene on chromosome 21 an obvious candidate gene for autosomal dominant Alzheimer’s disease. Initial genetic linkage studies excluded APP as the site of the causative mutation.The subsequent realisation that Alzheimer’s disease might be caused by more than one gene by John Hardy’s group led to a re-examination of linkage results and the discovery that APP mutations can cause autosomal dominant Alzheimer’s disease. Over 20 further pathological mutations in the APP gene have been described,however,APP mutations proved comparatively rare. Other genes, Presenilin 1 and APOE, stole much of the limelight. In Alzheimer’s disease drug development,there was a clear rationale to developing treatments that influenced amyloid metabolism or deposition. These treatments have been developed and shown initial promise but,so far, have disappointed.

This paper is another step in the Alzheimer/ amyloid story.Jonsson and colleagues utilised whole genome data from over 1500 Icelanders to look for sequence changes in the APP gene.They identified a coding mutation (A673T) which confers protection against Alzheimer’s disease in their cohort and show that this mutation reduces the production of amyloidogenic peptides in vitro.Their controls were elderly (over 85 years of age) and had passed a cognitive assessment. Jonsson and colleagues found that the A673T mutation was also rarer in patients with less specific“cognitive decline”.The results look robust and there seems little reason to suppose that they will not apply to a wider population than Iceland, but this remains to be shown. 0.6% of the control Icelandic population carry the mutation so the effect is significant although the protective allele may be rarer in other populations.This discovery will also encourage therapeutic approaches aimed at altering APP metabolism.

It is not surprising that these results apply also to patients with cognitive decline not diagnosed with AD.It highlights the spectrum that exists between the “normal”decline in memory with age,amnestic Mild Cognitive Impairment and Alzheimer’s disease. The result supports the theory that very mild Alzheimer’s pathology may be responsible for minor cognitive problems as people age.This observation highlights the question that already troubles Alzheimer specialists: of when a minor cognitive problem becomes a disease. – Dr Jeremy Brown, Addenbrooke’s Hospital and Queen Elizabeth Hospital, King’s Lynn.
Jonsson et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature: 488, 96–99. Date published: (02 August 2012)

miRNA and ASO – The initial approach to treating genetic diseases in a new way

One of the holy grails of treating genetic disorders of the CNS is to target the abnormal gene itself and by so doing effect a cure without having to worry about off target effects.There have been two recent papers which are worth highlighting in this regard – one using a microRNA approach, the other an anti-sense oligonucleotide (ASO) strategy and both involving autosomal dominant trinucleotide repeat disorders.

In the first paper by Miyazaki et al in Nature Medicine (with a wonderfully clear News and Views commentary on it by Christopher Pearson), they concentrated on spinal bulbar muscular atrophy (SBMA) which is a slowly progressive lower motor neuron disorder of men.The disease is characterised by a CAG expansion in the androgen receptor, which then causes motor neuronal cell dysfunction and death through translocation of the mutant receptor within the cell. This has in the past led to attempts to block translocation using anti-androgen agents, although as a clinical therapy this creates obvious problems. In this new paper the authors looked at a transgenic model of this condition and found that one endogenous microRNAs in particular (the imaginatively named miRNA-196a) was upregulated and that by overexpressing it they could slow down the disease process. This they did using an AAV delivery system that selectively targeted the motoneurons. They then showed that miR-196a mediated its effects on the mutant receptor through a protein that is involved with mRNA processing (CELF2). This beautiful work shows how miRNAs are coming of age not only in terms of how they regulate networks of intracellular processes but how they can be recruited for treating disease.

In the second study the disease under attack is Huntington’s disease,which has its CAG repeat in exon 1 of the huntingtin (htt) gene. This gene product causes extensive cell loss in the CNS but typically not until patients are in their 40s, although exactly when the disease process begins relative to clinical expression remains a subject of great interest (see TRACK-HD and PREDICT-HD studies). Obviously being able to switch off the mutant gene (mthtt) whilst leaving the normal htt to do its job has proven difficult, as has getting the silencing agent for the mutant htt in all cells for long period of times.This last point in particular has vexed the field but a recent paper by Kordasiewicz et al in Neuron (again accompanied by a lovely Preview by Lu and Yang) suggests that this might not be necessary as they showed that transiently knocking down mthtt could have long lasting benefits in animal models of disease.This implies that stopping the production of mthtt even if only for a short time may allow the cell to recover,regroup and fight another day,and thus whilst repeated injections of ASOs may be required, the frequency of administration may be less than once thought.

These papers highlight once more the skill of researchers to get to the heart of disease, and their ingenuity in how to do this.Obviously the challenge still remains as to how one can translate such findings into a much larger, longer living human patient – but slowly we are moving towards therapies that seek to truly switch off disease causing genes and their products.
– Roger Barker, Cambridge Centre for Brain Repair.
Pearson CE. Co-opting endogenous microRNAs for therapy.
NATURE MEDICINE 2012;18:1011-2. Miyazaki Y, Adachi H, Katsuno M et al.
Viral delivery of miR-196a ameliorates
the SBMA phenotype via the silencing of CELF2.
NATURE MEDICINE 2012;18:1136-1141.
X-H Lu & X.W Yang. “Huntingtin Holiday”: progress toward an antisense therapy for Huntington’s disease.
NEURON 2012;74:964-6.
Kordasiewicz HB, Stanek LM, Wancewicz EV et al. Sustained Therapeutic Reversal of Huntington’s Disease by Transient Repression of Huntingtin Synthesis.
NEURON 2012;74:1031-44.

Intramuscular midazolam for status epilepticus

Large studies of status epilepticus which change practice are hard to come by but this is one such.The study compared the outcome of treatment of status epilepticus with IM midazolam and IV lorazepam, which has been the gold standard since 1998. This massive effort included 3114 paramedics and 79 hospitals. Children estimated to be over 13Kg and adults were included and were treated if convulsive seizures had been continuing for over five minutes. Patients were excluded with major trauma, hypoglycaemia, cardiac arrest or HR<40. Essentially the question is does speed of access with an IM injection of midazolam 10mg in adults, using an auto- injector make up for speed of distribution of IV access of IV lorazepam 4mg (smaller doses were given to little people) given also that it is a different drug being administered. The short answer to the question is yes, which means that we should be looking to change practice for emergency management to IM midazolam.

The primary outcome of the study was termination of seizures before arrival in the emergency department without the need for the paramedics to provide rescue therapy. The key secondary outcome was time from opening the box containing treatment to the termination of seizures. 448 patients were assigned to IM midazolam of whom 443 received the drug. 445 were assigned to IV lorazepam of whom 297 received the drug. Of the remainder, seizures stopped anyway in 95,before the drug was given and in 42 IV access could not be achieved. In the intention to treat analysis, treatment failure occurred in 26.6% of midazolam patients and 36.6% of lorazepam patients. Per protocol figures were 25.1% and 35.7% respectively. Midazolam also fared better on all secondary measures, except slightly longer hospital stays. Seizure recurrence within 12 hours was similar and only around 10% in both groups and hypotension was also similar. Although the time from giving the injection to cessation of seizures was slightly longer with midazolam, this was more than relative speed of IM access compared with IV access for lorazepam. The authors cautiously state that IM midazolam is non-inferior to IV lorazepam. With these data one might go further.– Mark Manford, Addenbrooke’s and Bedford Hospitals.
Silbergleit R, Durkalski V, Lowenstien D et al. Intramuscular versus intravenous therapy for pre-hospital status epilepticus. NEJM 2012;366:591-600.

A View to a Kill: Oligodendrocytes in ALS

It is the glia that are to blame, again. Recent revelations that astrocytes can trigger neuronal degeneration in amyotrophic lateral sclerosis (ALS) came as a surprise. Now, it seems that astrocytes are not alone in serving as a primary cause in neurodegeneration. Oligodendrocytes, normally providing insulation and nutritional support for axons, have currently come into the spotlight. Their primary involvement in multiple sclerosis has been long evident, leading to axonopathy and cortical neuronal loss following the disruption of the myelin sheath. However, their relatively normal initial appearance in neurodenerative disease has perhaps masked their significance in pathogenesis. A new paper published by Jeffery Rothstein’s group reports a mechanism by which oligodendrocytes may contribute to early neurodegeneration in ALS patients, but somewhat unexpectedly, without the loss of myelin.

Youngjin Lee and colleagues have demonstrated that monocarboxylate transporter 1 (MCT1) is specifically enriched in oligodendrocytes in the mouse brain and spinal cord, providing potential energy support to neurons in the form of lactate. In vitro, the inhibition of MCT1 in oligodendocytes, either by antisense or

by pharmacological methods, leads to selective motoneuron death in organotypic spinal cord slice cultures. This highlights the possibility that the inhibition of lactate transport by oligodendrocytes to neurones could be solely responsible for a neurotoxic effect. Indeed, the replacement of lactate in the culture medium reversed neurotoxicity. Similar results were noted also in vivo when MCT1 expression was downregulated by a specific small hairpin RNA (shRNA) packaged by a lentivirus.

Could the failure of providing lactate by oligodendrocytes play a primary role in toxicity in neurodegenerative diseases? The elegant series of experiments, in which MCT1 downregulation was induced selectively in oligodendrocytes,have provided proof of their direct involvement. The similar features of axon pathology seen in the mouse ALS model (SOD1 transgenic mice) and in mice affected by a single MCT1 allele deletion lent further support to such a notion.Thus it did not come as a surprise to learn that the motor cortex of human ALS patients show more than a 50% decline in MCT1 expression, similar to that seen in the spinal cords of the SOD1 transgenic mice.

This corroborating evidence may add another layer to the complexity of ALS pathogenesis, shifting the view to another potential killer cell in neurodegenerative disease. Perhaps there is more than meets the eye, and one may speculate that protective approaches designed to directly target neurones may not be sufficient. – Andras Lakatos, Cambridge Centre for Brain Repair and Addenbrooke’s Hospital, Cambridge.
Youngjin Lee et al.
Oligodendroglia metabolically support axons and contribute to neurodegeneration.
NATURE, Published online on 11 July 2012.

Infection and autoimmunity – an overlap in the brain?

NMDA-receptor antibody related encephalitis is now a well-recognised, clinically distinctive condition often seen in younger individuals with a good response to immunotherapies. Patients frequently develop fever and headache prior to, or during, their illness. Importantly,the antibodies are of the IgG class.

Pruss et al retrospectively show antibodies of IgG, IgA and IgM classes which are directed against the NMDA receptor in 13 of 44 (30%) patients with proven HSV encephalitis (HSVE).The diagnosis of HSVE appears robust in that patients had the typical symptomatology, CSF HSV PCR positivity plus a pronounced lymphocytosis, and classical temporal lobe changes on imaging.

Although the timing of available serum and CSF samples was understandably rather patchy and variable,it was apparent that some patients had NMDAR-Igs as early as four days after their diagnosis of HSV. By contrast, in other patients, NMDAR-Igs only appeared many weeks or months after the HSV symptom onset. This may suggest that in some cases, and slightly surprisingly, the antibodies are present in HSVE very early in the illness. In others, the antibodies may be part of a secondary immune response to the HSV-induced cell lysis.

However, the serum-CSF compartmentalisation of the antibodies, time-course of their appearance and the NMDA classes were often difficult to predict or pathophysiologically model. For example, one patient only had serum NMDAR-IgM ten days into their illness, these persisted and were accompanied by serum NMDAR-IgA after around one year but serum NMDAR-IgG or CSF NMDAR- IgG/A/M were never detected.Another case had serum and CSF NMDAR-IgA two weeks into their illness, the serum NMDAR-IgA persisted for an additional fortnight, and at around one year CSF showed no NMDAR- IgG/A/M and only serum NMDAR-IgM was present.

These data provide one potential rationale for the use of steroids in HSVE. They also suggest that infectious and autoimmune encephalitis may coexist. Although headache, fever and cognitive deficits do overlap, there are marked differences between many clinical and paraclinical features of HSVE and ‘typical’ NMDAR- IgG antibody encephalitis. While the presence of these antibodies in the setting of HSVE is intriguing, their role remains unclear. Nevertheless, these antibodies should certainly be measured in a prospectively collected series of HSVE. Reproducible findings may mean that in the future steroids are routinely added to acyclovir in the setting of HSVE. – Sarosh Irani, Neurosciences Building, University of California, San Francisco.
Prüss H, Finke C, Höltje M, et al.
NMDA receptor antibodies in herpes simplex encephalitis.
ANNALS OF NEUROLOGY. Accepted manuscript online: 16 JUL 2012, DOI: 10.1002/ana.23689.

Panel of reviewers

Dr Jeremy Brown, Addenbrooke’s Hospital and
Queen Elizabeth Hospital, King’s Lynn.

Roger Barker, Cambridge Centre for Brain Repair.

Mark Manford, Addenbrooke’s and Bedford Hospitals.

Andras Lakatos, Cambridge Centre for Brain Repair and Addenbrooke’s Hospital, Cambridge.

Sarosh Irani, Neurosciences Building, University of California, San Francisco.

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