Muscle Biomarkers Correlate With Severity in SBMA

Neurofilament Light Chain [NfL]

Image: BestPractice

Wikipedia describes Neurofilaments this way: NF are intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring approximately 10 nm in diameter and many micrometers in length. Together with microtubules and microfilaments, they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. Neurofilaments are found in vertebrate neurons in especially high concentrations in axons, where they are all aligned in parallel along the long axis of the axon forming a continuously overlapping array. In addition to their structural role in axons, neurofilaments are also cargoes of axonal transport. Most of the neurofilament proteins in axons are synthesized in the nerve cell body, where they rapidly assemble into neurofilament polymers within about 30 minutes. These assembled neurofilament polymers are transported along the axon on microtubule tracks powered by microtubule motor proteins. 

Below is a portion of the abstract from a study published February 20th. You can read the entire study (PDF) at Neurology.org . 

Muscle and not neuronal biomarkers correlate with severity in spinal and bulbar muscular atrophy

Objective: To determine whether blood biomarkers of neuronal damage (neurofilament light chain [NfL]), muscle damage (creatine kinase [CK]), and muscle mass (creatinine) are altered in spinal bulbar muscular atrophy (SBMA aka Kennedy's Disease) and can be used as biomarkers for disease severity.

Methods: In this multicenter longitudinal prospective study, plasma and serum were collected from 2 cohorts of patients with SBMA in London, United Kingdom (n = 50), and Padova, Italy (n = 43), along with disease (amyotrophic lateral sclerosis [ALS]) and healthy controls, and levels of plasma and serum NfL, CK, and creatinine were measured. Disease severity was assessed by the SBMA Functional Rating Scale and the Adult Myopathy Assessment Tool at baseline and 12 and 24 months.

Results: Blood NfL concentrations were increased in ALS samples, but were unchanged in both SBMA cohorts, were stable after 12 and 24 months, and were not correlated with clinical severity. Normal NfL levels were also found in a well-established mouse model of SBMA. Conversely, CK concentrations were significantly raised in SBMA compared with ALS samples, and were not correlated to the clinical measures. Creatinine concentrations were significantly reduced in SBMA, and strongly and significantly correlated with disease severity.

Conclusions: While muscle damage and muscle mass biomarkers are abnormal in SBMA, axonal damage markers are unchanged, highlighting the relevant primary role of skeletal muscle in disease pathogenesis. Creatinine, but not CK, correlated with disease severity, confirming its role as a valuable biomarker in SBMA.

Note: The KDA just posted the research on their website. There was also a note from Pietro Fratta, who spoke about his biomarker research at last year's conference:

This work uses blood samples from 93 Kennedy’s patients, alongside controls and samples from models of disease, to look for traces of neuron and muscle damage in Kennedy’s disease. It finds that muscle damage is prominent, whilst neuron damage is below detection levels. This work highlights the role of muscle damage in Kennedy’s disease, which is extremely important for how therapies are designed. Further, this study supports the use of a specific biomarker, creatinine, for Kennedy’s disease clinical trials.

This study was possible only thanks to the incredibly strong participation to research of patients attending the Kennedy’s Clinic at the National Hospital in London and the University of Padova.

Biomarkers of Spinal and Bulbar Muscle Atrophy

This report was published in Frontiers of Neurology three days ago. Excerpts are below and the entire report ban be read by following the link.

Biomarkers of Spinal and Bulbar Muscle Atrophy (SBMA): A Comprehensive Review

Biomarkers in SBMA

A biomarker is a parameter that can be measured accurately and reproducibly and used as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (WHO definition, 1998). An ideal biomarker should have a predictive value and capture subtle changes over relatively short periods of time. Additional requirements to biomarkers include cost-effectiveness, non-invasiveness, and reproducibility. It is generally agreed that no single biomarker is suitable for diagnostic, prognostic and monitoring roles and a panel of several markers may be better suited as multirole indicators. SBMA is a rare and slowly progressing condition, therefore the development of sensitive outcome measures would enable smaller sample-size and shorter duration of pharmaceutical trials.

Biomarkers of Neurological Involvement in SBMA

In recent years, an unprecedented interest has developed in the standardized assessment of neuromuscular performance in SBMA, evaluation of novel therapeutic strategies and in the launch of national SBMA registries. Many of the commonly used instruments, such as the MRC score, respiratory function parameters, the modified Norris scale, ALSFRS-r, Quantitative Myasthenia Gravis Score etc. are non-specific to SBMA, yet remain widely utilized. As these tools have been developed for other conditions, new batteries of tests have been recently proposed to specifically appraise disability in SBMA.

Discussion and Future Perspectives

Interest in SBMA biomarkers has grown steadily in recent years, fuelled both by accruing knowledge about pathogenesis and novel therapeutic strategies. SBMA is now widely recognized as a multisystem syndrome. A multitude of studies focus on multi-organ involvement, and the systemic phenotype is now considered just as relevant as the neurological manifestations. It is increasingly recognized that non-neurological features of the disease have an equally important impact on the patients' quality of life. Until now, clinical trials on SBMA focused almost exclusively on the treatment of motor symptoms, but a shift to targeted molecular therapies and focus on systemic processes are likely to be witnessed in the near future. From a clinical trial perspective, ideal biomarkers should undergo robust validation, sensitivity and specificity profiling, and sampling and measurement harmonization across different centers. Crucially, candidate markers should be able to detect the subtle changes expected after the administration of a specific treatment. Given the particularly slow progression rates observed in SBMA, the definition of an effective outcome measures is challenging. The integration of neurological, metabolic, and endocrine indicators seems essential into composite biomarker panels in addition to functional scales. Serum creatinine levels appear to correlate strongly with motor impairment and HOMA-IR index with disease duration. The convincing validation of these parameters and their use as effective outcome measures in clinical trials will require robust multicenter study designs.

Beyond motor neurons

This is a pretty good recap of what we know and what else might be of importance in finding a treatment or cure for Kennedy's Disease.

The entire post can be found here: 

Beyond motor neurons: expanding the clinical spectrum in Kennedy’s disease

The conclusions are shown below:

Conclusions

In SBMA, as in other genetic conditions caused by mutations in ubiquitously expressed genes, the clinical picture is the result of a complex interplay between differentially affected tissues, which struggle to cooperate to maintain homeostasis.

Extra-motor neuron features in SBMA, such as primary muscle atrophy or hormonal abnormalities, are emerging as clinically highly impactful in patients’ quality of life and disease progression. Their thorough investigations are proving critical for a number of reasons. First, they may provide important insights into common mechanisms of pathogenesis. Second, the peripheral abnormalities may offer the opportunity for direct functional assessments and repetitive samplings, therefore representing potentially exploitable biomarkers to track disease progression and/or response to therapy. Lastly, disentangling the underlying molecular mechanisms of this highly integrated inter-tissues cross-talk may offer unparalleled opportunities for therapeutic interventions in the near future.

Creatinine Biomarker in SBMA

On April 11, SMA News reported the results of a three-year study on biomarkers that can spot neurodegenerative disorders before symptoms appear in conditions like Kennedy's Disease. 

Muscle Waste Product Creatinine Might Be Used as SBMA Biomarker, Study Reports

Yasuhiro Hijikata, Atsushi Hashizume, Shinichiro Yamada, Tomonori Inagaki, Daisuke Ito, Akihiro Hirakawa, Keisuke Suzuki, Naoki Atsuta, Takashi Tsuboi, Makoto Hattori, Akihiro Hori, Haruhiko Banno, Gen Sobue and Masahisa Katsuno
 

“Blood levels of a waste product from muscle metabolism could be used to see how spinal and bulbar muscular atrophy (SBMA) develops before symptoms appear, a Japanese study reports.

The research on the waste product, creatinine, appeared in the journal Neurology. The title of the article is “Biomarker-based analysis of preclinical progression in spinal and bulbar muscular atrophy.”

Scientists have been trying to find biomarkers that can spot neurodegenerative disorders before symptoms appear. The work has led to promising biomarkers for Alzheimer’s and Huntington’s disease.

But little research has been done on biological changes over time that occur before neurodegenerative disease symptoms show up. SBMA is a neurodegenerative disease caused by a mutation of the androgen receptor gene.

The Japanese researchers had previously reported a link between levels of the creatinine that kidneys secrete to the blood and the severity of movement problems once SBMA symptoms appear. But the team had not looked at how creatinine levels change before symptoms show up.

They wondered if tracking changes in biochemical levels and body measurements before SBMA symptoms appeared could shed light on how it develops. They focused on changes before and after the start of patients’ muscle weakness.

The team used statistical methods to predict changes in disease markers. Then they compared the forecasts with changes in healthy men and in ALS and Parkinson’s patients. In addition, they analyzed the link between patients’ creatinine blood levels and the start of their symptoms.

Their study between October 2014 and October 2017 involved 40 men with SBMA, 25 with ALS, 20 with Parkinson’s, and 48 healthy controls. The SBMA patients, whose bulbar and limb muscles had weakened, were followed for a mean of 17.3 years, including 11.4 years before symptoms appeared. …”

Click here to continue reading the rest of the article

SBMA and Fatty Liver Disease - Follow up

This is a follow-up to an earlier article on this research. This article in Neurology Advisor has an important message for your doctor.

___________

“… Patients with spinal-bulbar muscular atrophy (SBMA) are at high risk for nonalcoholic liver disease as well as elevated glucose, serum triglycerides, and insulin, according to study findings published in Neurology.”

“… Although the researchers indicate that previous research has demonstrated elevations of serum cholesterol in patients with SBMA, the small sample size of 14 in the second group limits the study's detection power for this variable.

Because of the liver's prominent role in drug metabolism, the investigators suggest healthcare practitioners "prescribing medications or evaluating candidate therapeutics for patients with SBMA should be aware of the risk for fatty liver disease and monitor hepatic function." …”

Nonalcoholic fatty liver disease in spinal and bulbar muscular atrophy

Nonalcoholic fatty liver disease in spinal and bulbar muscular atrophy

Robert D. Guber, BS*, Varun Takyar, MD*, Angela Kokkinis, BSN, RN, Derrick A. Fox, MD, Hawwa Alao, MD, Ilona Kats, BA, Dara Bakar, BA, Alan T. Remaley, MD, PhD, Stephen M. Hewitt, MD, PhD, David E. Kleiner, MD, PhD, Chia-Ying Liu, PhD, Colleen Hadigan, MD, Kenneth H. Fischbeck, MD, Yaron Rotman, MD and Christopher Grunseich, MD
Correspondence to Dr. Grunseich: christopher.grunseich{at}nih.gov

ABSTRACT

Objective: To determine the prevalence and features of fatty liver disease in spinal and bulbar muscular atrophy (SBMA).

Methods: Two groups of participants with SBMA were evaluated. In the first group, 22 participants with SBMA underwent laboratory analysis and liver imaging. In the second group, 14 participants with SBMA were compared to 13 female carriers and 23 controls. Liver biopsies were done in 4 participants with SBMA.

Results: Evidence of fatty liver disease was detected by magnetic resonance spectroscopy in all participants with SBMA in the first group, with an average dome intrahepatic triacylglycerol of 27% (range 6%–66%, ref ≤5.5%). Liver dome magnetic resonance spectroscopy measurements were significantly increased in participants with SBMA in the second group relative to age- and sex-matched controls, with average disease and male control measurements of 17% and 3%, respectively. Liver biopsies were consistent with simple steatosis in 2 participants and nonalcoholic steatohepatitis in 2 others.

Conclusions: We observed evidence of nonalcoholic liver disease in nearly all of the participants with SBMA evaluated. These observations expand the phenotypic spectrum of the disease and provide a potential biomarker that can be monitored in future studies.

Photo:  https://www.quora.com/What-is-liver-failure

A Biomarker … What is that?

Yesterday Ed Meyertholen, KDA board member and resident guru for explaining anything complicated, hosted the chat room.  The topic was an update on the Gordon Conference.

It wasn’t long, however, before the topic shifted to biomarkers … what they are and why they are important.  The key takeaway was that biomarkers can help determine if you have a disease before any symptoms show up.  For example, a biomarker could show that a person has cancer forming before any other physical signs are evident (i.e., a tumor, nagging cough, blood in stool, decline in red blood cells, etc.).


I found the subject so interesting that I wanted to learn more so I went to Wikipedia for answers.

Wikipedia defines a biomarker as:

 

In medicine, a biomarker is a term often used to refer to a protein measured in blood whose concentration reflects the severity or presence of some disease state. More generally a biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism.

A biomarker is a parameter that can be used to measure the progress of disease or the effects of treatment. The parameter can be chemical, physical or biological. In molecular terms biomarker is "the subset of markers that might be discovered using genomics, proteomics technologies or imaging technologies. Biomarker help in early diagnosis, disease prevention, drug target identification, drug response etc. Several diseased based biomarker had been identified for many diseases such as serum LDL for cholesterol, blood pressure, P53 gene and MMPs for cancer etc.

Uses for Biomarkers

 

For chronic diseases, whose treatment may require patients to take medications for years, accurate diagnosis is particularly important, especially when strong side effects are expected from the treatment. In these cases, biomarkers are becoming more and more important, because they can confirm a difficult diagnosis or even make it possible in the first place.  

A number of diseases, such as Alzheimer’s disease or rheumatoid arthritis, often begin with an early, symptom-free phase. In such symptom-free patients there may be more or less probability of actually developing symptoms. In these cases, biomarkers help to identify high-risk individuals reliably and in a timely manner so that they can either be treated before onset of the disease or as soon as possible thereafter.

In Kennedy’s Disease, our CAG count is an indicator of a gene mutation, but not a biomarker.  By the time twitches, cramping, high creatinine levels, etc. start showing up the progression has already began.

Warning:  Wednesday’s snap quiz could contain questions on biomarkers, so be prepared.