Research Provides First Whole Genome Map Of Genetic Variability In Parkinson's Disease

From Mayo Clinic

Mayo Clinic researchers in collaboration with scientists at Perlegen Sciences, Inc. and funded by the Michael J. Fox Foundation for Parkinson's Research have produced the first large-scale whole genome map of genetic variability associated with Parkinson's disease. Their results highlight changes in 12 genes that may increase the risk for Parkinson's disease in some people.

Mayo Clinic and Perlegen Sciences will report their findings in The American Journal of Human Genetics. The paper was published online Friday, Sept. 9 (www.ajhg.org) and will appear in the November 2005 print issue.

Significance of the Findings
Both the findings and the technology that produced them are groundbreaking, representing one of the most comprehensive genetic studies of Parkinson's disease to date with nearly 200 million genetic tests (genotypes) completed. To accomplish this, researchers initially studied the association of about 200,000 single-letter variations in the genome known as single nucleotide polymorphisms, or "SNPs" (pronounced "snips") in patients with Parkinson's disease. The study examined DNA from 775 people with Parkinson's disease (cases) and from 775 people without Parkinson's disease (controls).

"To be most effective, a whole genome association study requires accurate testing of a large number of SNP markers that are distributed across the human genome in a dense and informative pattern," says Dr. Maraganore. "In this respect, our collaborators at Perlegen have set a new standard."

Noteworthy findings include:
Confirmation that variation in two previously known regions of the genome, PARK10 and PARK11, are likely associated with Parkinson's disease susceptibility.

Identification of 10 additional SNPs that appear to be associated with Parkinson's disease susceptibility. Some of these are in or near genes with direct biological relevance to the disease. For instance, one of these, the SEMA5A gene, may play an important role in both the development and programmed death of dopamine-producing nerve cells in the brain. Selective degeneration of dopamine neurons in the brain is a hallmark feature of Parkinson's disease.

Susceptibility genes are genes that may make some people more or less likely to develop a disease but that do not necessarily cause the disease directly. The authors note that in this study, the size of the effect was small for any single SNP; combinations of gene variants or interactions with environmental factors may be necessary to develop Parkinson's disease.

New Study Shows SARS Can Infect Brain Tissue

From Infectious Diseases Society of America

Severe acute respiratory syndrome (SARS), by its very name, indicates a disease of the respiratory tract. But SARS can also infiltrate brain tissue, causing significant central nervous system problems, according to an article in the Oct. 15 issue of Clinical Infectious Diseases, now available online.

SARS, a potentially fatal illness caused by a coronavirus, was first reported in Asia in February of 2003. The disease is usually transmitted by contact with coronavirus-laden droplets sprayed into the air by an infected person’s coughing. Other symptoms can include high fever, headache, body aches, and pneumonia. However, some patients also exhibit central nervous system ailments. In a new study, the researchers report the case of a 39-year-old doctor who treated SARS patients in China during the 2003 outbreak and became infected himself.

He showed the usual symptoms of SARS--fever, chills, headache, muscle pain--but after hospitalization, he developed vision problems, then progressively worse central nervous system symptoms, like restlessness and delirium. A computed tomography scan indicated brain damage. He died about a month after being hospitalized, and his brain tissue was examined and found to contain the SARS coronavirus. The researchers also discovered a high level of Mig, a type of immune system regulator called a chemokine, in the man’s bloodstream and brain, which may have resulted from the central nervous system infection. The researchers speculated that Mig could also have contributed to his brain damage by attracting immunological cells to the site of the viral infection in the brain, where their inflammatory effects may have done more harm than good.

Four to five percent of SARS patients treated at the Guangzhou Institute of Respiratory Diseases experienced central nervous system symptoms, said Dr. Xu; therefore, physicians need to be aware of the potential for brain infection when evaluating patients with the disease. Immunosuppressive drugs should be administered carefully and on an individual basis, as they may allow amplification of the SARS coronavirus in the brain. “Superinfection” with other pathogens could also contribute to SARS’ harmful effects on the brain. “Physicians should pay more attention to the prevention of brain damage if [SARS patients] are superinfected with other conditional pathogens,” according to Dr. Xu and Dr. Jiang.

There are a few possibilities for curbing Mig’s possible role in causing brain damage in SARS patients with central nervous system infection, according to lead author Jun Xu, PhD, of the Guangzhou Institute of Respiratory Diseases and senior author Yong Jiang, PhD, of the Key Laboratory of Functional Proteomics of Guangdong Province. “There might be some ways of controlling the release of Mig, such as specific inhibitors that interfere [with] the signaling pathways involved,” Dr. Jiang said. “Other approaches, such as neutralizing antibodies [and] specific binding peptides, could be tried to block brain damage induced by Mig.”

The AD8

From NEUROLOGY 2005;65:559-564

The AD8: A brief informant interview to detect dementia

Background: Brief measures that accurately discriminate normal cognitive aging from very mild dementia are lacking. Cognitive tests often are insensitive to very mild dementia. Informant-based measures may be more sensitive in detecting early dementia.

Objective: To identify informant-reported clinical variables that differentiate cognitively normal individuals from those with very mild dementia.

Methods: A 55-item battery of informant queries regarding an individual's cognitive status was derived from a semistructured interview and a consensus panel of dementia experts. The battery was evaluated with informants for 189 consecutive participants of a longitudinal study of memory and aging and compared with an independently obtained Clinical Dementia Rating (CDR) score for the participant. Multiple regression and receiver operator characteristic curves assessed subsets of the items to discriminate between CDR 0 (no dementia) and CDR 0.5 (very mild dementia).

Results: The final version (AD8) querying memory, orientation, judgment, and function was administered to an additional sample of 112 CDR 0 and 68 CDR 0.5 participants. Using a cut-off of two items endorsed, the area under the curve was 0.834, suggesting good to excellent discrimination, sensitivity was 74%, and specificity was 86% (prevalence of 0.38 for very mild dementia). Inclusion of 56 additional individuals with mild to severe dementia (increasing dementia prevalence to 0.53) increased sensitivity to 85%.

Conclusions: The AD8 is a brief, sensitive measure that reliably differentiates between nondemented and demented individuals. Use of the AD8 in conjunction with a brief assessment of the participant could improve diagnostic accuracy in general practice.

Antibody responses against galactocerebroside are potential stage-specific biomarkers in multiple sclerosis

From Journal of Allergy and Clinical Immunology Volume 116, Issue 2 , August 2005, Pages 453-459

Background
Galactocerebroside, the major glycolipid of central nervous system myelin, is a known target for pathogenic demyelinating antibody responses in experimental allergic encephalomyelitis (EAE), the animal model of multiple sclerosis (MS).

Objective
To address the importance of anti-galactocerebroside (α-GalC) antibodies in MS and to evaluate them as biomarkers of disease.

Methods
α-GalC IgGs were quantified from sera of patients with MS and in marmoset EAE by a new immunosorbent assay.

Results
We report a significant difference in serum α-GalC IgG titers between patients with relapsing-remitting (RR)–MS and healthy controls (HCs; P < .001). The frequencies of α-GalC antibody-positive subjects (α-GalC titers ≥ mean HC titers + 3 SD) are also significantly elevated in RR-MS compared with HC (40% vs 0%; P = .0033). Immunoaffinity purified α-GalC IgGs from human serum bind to cultured human oligodendrocytes, indicating that the ELISA detects a biologically relevant epitope. Corroborating these findings, α-GalC antibody responses in marmoset EAE were similarly found to be specifically associated with the RR forms and not the peracute or progressive forms, in contrast with other anti-myelin antibodies (P = .0256).

Conclusion
(1) α-GalC antibodies appear MS-specific and are not found in healthy subjects, unlike antibodies against myelin proteins; (2) when present, α-GalC antibodies identify mostly RR-MS and may be an indicator of ongoing disease activity. This novel assay is a suitable and valuable method to increase accuracy of diagnosis and disease staging in MS.

Is motor neuron disease-inclusion dementia a forme fruste of amyotrophic lateral sclerosis with dementia?

From NeuropathologyVolume 25 Issue 3 Page 214 - September 2005

Case Report

We report the autopsy findings of a 62-year-old man who exhibited progressive FTD 10 years before the appearance of muscle weakness and wasting, and who died approximately 11 years after onset of the symptoms. Degeneration and atrophy of the frontal and temporal lobes, which contained ubiquitin-positive neuronal inclusions and dystrophic neurites, were evident. Circumscribed degeneration affecting the hippocampal CA1-subiculum border zone was also a feature. Moreover, degeneration was present in both the upper and lower motor neuron systems, the latter being more severely affected. A few lower motor neurons were found to contain the cytoplasmic inclusions characteristic of ALS (i.e. Bunina bodies and ubiquitin-positive skeins). Also of interest was the presence of pallidonigroluysian atrophy, which appeared to be responsible for the chorea-like involuntary movements that developed in this patient approximately 2 months before death. The clinical and pathological features of our patient further support the idea that motor neuron disease-inclusion dementia (MND-ID), which has been classified as a pathological subgroup of FTD, is a forme fruste of ALS with dementia. In other words, if patients with MND-ID live long enough, they may develop ALS.

Alzheimer's disease: an intracellular movement disorder?

From Trends in Molecular Medicine, Volume 11, Issue 9, September 2005, Pages 391-393

Axonal transport is essential for maintaining the structure and function of nerve cells. Deficient axonal transport has been implicated in several neurodegenerative diseases, including Alzheimer's disease (AD). In addition to a disturbed cytoskeleton and other abnormalities observed in AD that are suggestive of axonal transport deficits, several AD-related proteins are implicated in the regulation of axonal transport. A recent study has demonstrated that the axonal transport deficit occurs early in the course of AD, preceding amyloid pathology substantially in mouse models of AD; more importantly, the study showed that reduced axonal transport leads to increased amyloid β production and deposition. These data place axonal transport deficits at a central point in the pathogenesis of AD.

New Dye Could Offer Early Test For Alzheimer's

From Massachusetts Institute of Technology

MIT scientists have developed a new dye that could offer noninvasive early diagnosis of Alzheimer's disease, a discovery that could aid in monitoring the progression of the disease and in studying the efficacy of new treatments to stop it.

The work will be published in the Aug. 26 issue of Angewandte Chemie. Today, doctors can only make a definitive diagnosis of Alzheimer's-currently the fourth-leading cause of death in the United States-through a postmortem autopsy of the brain.

To that end, Swager and postdoctoral associate Evgueni Nesterov, also from the MIT Department of Chemistry, worked with researchers at Massachusetts General Hospital and the University of Pittsburgh to develop a contrast agent that would first bind to the protein deposits, or plaques, in the brain that cause Alzheimer's, and then fluoresce when exposed to radiation in the near-infrared range. The new dye could allow direct imaging of Alzheimer's plaques through a patient's skull.

Some of the first noninvasive techniques for diagnosing Alzheimer's involved agents labeled with radioactive elements that could enter the brain and target disease plaque for imaging with positron emission tomography (PET). However, these methods were expensive and limited by the short working lifetime of the labeled agents.

Swager and colleagues developed the new dye, called NIAD-4, through a targeted design process based on a set of specific requirements, including the ability to enter the brain rapidly upon injection, bind to amyloid plaques, absorb and fluoresce radiation in the right spectral range, and provide sharp contrast between the plaques and the surrounding tissue. The compound provided clear visual images of amyloid brain plaques in living mice with specially prepared cranial windows.

To make the technique truly noninvasive, scientists must further refine the dye so it fluoresces at a slightly longer wavelength, closer to the infrared region. Light in the near-IR range can penetrate living tissue well enough to make brain structures visible. Swager likens the effect to the translucence produced when one holds a red laser pointer against the side of a finger.

"This procedure could be done in a chamber with a photodetector and a bunch of lasers, and it would be painless," he said, adding that infrared fluorescence and other optical techniques will lead to a whole new class of noninvasive medical diagnostics. Swager says fluorescing dyes like NIAD-4 could be ready for clinical trials in the near future.

"What we have is a dye that lights up when it binds to amyloids that form in the brains of people with Alzheimer's. It's a completely new transduction scheme-a way of translating a physical or chemical event that's invisible to the naked eye, into a recognizable signal. Further wavelength adjustments in these dyes will allow us to perform in vivo analysis through human tissue."

The new dye was developed as part of a broader effort in sensing technology at MIT's Institute for Soldier Nanotechnologies. In addition to its applications as a medical diagnostic, Swager says fluorescing dyes like NIAD-4 could work as signals in a wide variety of sensing schemes.