Saliva Test May Flag Early Huntington’s Disease

 

SAN DIEGO — A simple saliva test that detects the protein huntintin (Htt), which plays a key role in Huntington’s disease, may provide an early marker of onset and progression of the disorder, new research shows.

“Overall, measurements of salivary Htt offer significant promise as a relevant, noninvasive disease biomarker for Huntington’s disease, and its use could be immediately implemented into both translational and clinical research applications,” senior author, Jody Corey-Bloom, MD, PhD, University of California, San Diego, told Medscape Medical News.

Huntington’s disease, a fatal neurodegenerative disease, is known to be caused by a CAG repeat expansion in the gene that encodes Htt, making Htt a leading target in ongoing efforts to develop therapies.

With no noninvasive methods currently available for identifying Htt in the central nervous system, saliva represents a potentially ideal, accessible biomarker and is safer than blood tests in terms of risk for hepatitis and HIV, Dr Corey-Bloom said.

The findings were presented here at the ANA 2017: 142nd Annual Meeting of the American Neurological Association.

Promise as a Noninvasive Biomarker

The investigators used enzyme-linked immunosorbent assay (ELISA) methods to measure Htt protein in the saliva of 178 individuals, including patients with manifest Huntington’s disease, gene-positive patients with pre-manifest Huntington’s disease, and age- and sex-matched normal controls.

Results showed significant increases in salivary Htt levels in patients with Huntington’s disease (mean, 0.775 ng/mL) compared with normal controls (mean, 0.359 ng/mL; P = .001).

Significant correlations were also observed between Htt levels and various important clinical measures, including total functional capacity (P = .04), motor score (P = .02), and the diagnostic confidence level (P = .02).

Mutant Htt was further shown, by use of different antibody combinations, to be higher in gene-positive patients with pre-manifest Huntington’s disease than in normal controls (P = .03).

Importantly, total salivary Htt did not vary in terms of the time of day or over several different days. There were also no associations with age or sex.

“The biggest surprise for us was that we were able to measure huntingtin (Htt) in saliva at all,” Dr Corey-Bloom said. “We ran the Western blot and detected a single band just above the 250 kDa marker, corresponding to the full-length Htt protein (about 350 kDa). We were also surprised at its stability — that [Htt levels] didn’t vary over time of day or over different days.”

The researchers also evaluated various stress and inflammation markers. They found C-reactive protein (CRP) to be significantly elevated in patients with pre-manifest Huntington’s disease (9548 pg/mL) compared with normal controls (3399 pg/mL). CRP levels in saliva were also associated with motor symptom scores (P = .02) in gene-positive patients.

“We conclude that salivary Htt and possibly other inflammation markers offer significant promise as relevant, noninvasive biomarkers of disease onset and progression in Huntington’s disease,” the authors reported.

Dr Corey-Bloom noted that increases in total Htt could be due to various scenarios.

“Increased salivary total Htt protein could reflect increased expression of mutant or wild-type Htt protein, but we will need additional follow-up studies specifically measuring mutant forms and different cleavage products of Htt, in order to shed light on this issue,” she said.

Future studies will also need to determine how the levels of Htt in saliva relate to those in other measures, Dr Corey-Bloom added.

“We demonstrated that Htt protein can be detected in saliva and that salivary Htt can be reproducibly measured using ELISA,” she said. “Importantly, however, we don’t yet know how levels of salivary Htt compare to what is occurring in blood and cerebrospinal fluid. It will be very important to understand those relationships.”

The ability to detect Huntington’s disease onset provides multiple essential benefits, Dr Corey-Bloom said.
“There is a great need to identify accessible biomarkers for Huntington’s disease that could be used to anticipate the onset of disease symptoms, monitor disease progression, stratify patients for clinical trials, and track potential therapeutics,” she said.

Neurologist Conrad C. Weihl, MD, PhD, an associate professor of neurology with Washington University School of Medicine, St. Louis, Missouri, agreed that simplified identification of biomarkers could clearly be of benefit but that the findings will need replication.

“Peripheral biomarkers for neurodegenerative diseases are essential to monitor disease progression but also to monitor potential therapies,” he told Medscape Medical News.

“This will need to be validated in larger cohorts and see if it tracks with disease progression.”

The authors and Dr Weihl have disclosed no relevant financial relationships.

ANA 2017: 142nd Annual Meeting of the American Neurological Association. Abstract MS262. Presented October 16, 2017.

), which plays a key role in Huntington’s disease, may provide an early marker of onset and progression of the disorder, new research shows.

“Overall, measurements of salivary Htt offer significant promise as a relevant, noninvasive disease biomarker for Huntington’s disease, and its use could be immediately implemented into both translational and clinical research applications,” senior author, Jody Corey-Bloom, MD, PhD, University of California, San Diego, told Medscape Medical News.

Huntington’s disease, a fatal neurodegenerative disease, is known to be caused by a CAG repeat expansion in the gene that encodes Htt, making Htt a leading target in ongoing efforts to develop therapies.

With no noninvasive methods currently available for identifying Htt in the central nervous system, saliva represents a potentially ideal, accessible biomarker and is safer than blood tests in terms of risk for hepatitis and HIV, Dr Corey-Bloom said.

The findings were presented here at the ANA 2017: 142nd Annual Meeting of the American Neurological Association.

Promise as a Noninvasive Biomarker

The investigators used enzyme-linked immunosorbent assay (ELISA) methods to measure Htt protein in the saliva of 178 individuals, including patients with manifest Huntington’s disease, gene-positive patients with pre-manifest Huntington’s disease, and age- and sex-matched normal controls.

Results showed significant increases in salivary Htt levels in patients with Huntington’s disease (mean, 0.775 ng/mL) compared with normal controls (mean, 0.359 ng/mL; P = .001).

Significant correlations were also observed between Htt levels and various important clinical measures, including total functional capacity (P = .04), motor score (P = .02), and the diagnostic confidence level (P = .02).

Mutant Htt was further shown, by use of different antibody combinations, to be higher in gene-positive patients with pre-manifest Huntington’s disease than in normal controls (P = .03).

Importantly, total salivary Htt did not vary in terms of the time of day or over several different days. There were also no associations with age or sex.

“The biggest surprise for us was that we were able to measure huntingtin (Htt) in saliva at all,” Dr Corey-Bloom said. “We ran the Western blot and detected a single band just above the 250 kDa marker, corresponding to the full-length Htt protein (about 350 kDa). We were also surprised at its stability — that [Htt levels] didn’t vary over time of day or over different days.”

The researchers also evaluated various stress and inflammation markers. They found C-reactive protein (CRP) to be significantly elevated in patients with pre-manifest Huntington’s disease (9548 pg/mL) compared with normal controls (3399 pg/mL). CRP levels in saliva were also associated with motor symptom scores (P = .02) in gene-positive patients.

“We conclude that salivary Htt and possibly other inflammation markers offer significant promise as relevant, noninvasive biomarkers of disease onset and progression in Huntington’s disease,” the authors reported.

Dr Corey-Bloom noted that increases in total Htt could be due to various scenarios.

“Increased salivary total Htt protein could reflect increased expression of mutant or wild-type Htt protein, but we will need additional follow-up studies specifically measuring mutant forms and different cleavage products of Htt, in order to shed light on this issue,” she said.

Future studies will also need to determine how the levels of Htt in saliva relate to those in other measures, Dr Corey-Bloom added.

“We demonstrated that Htt protein can be detected in saliva and that salivary Htt can be reproducibly measured using ELISA,” she said. “Importantly, however, we don’t yet know how levels of salivary Htt compare to what is occurring in blood and cerebrospinal fluid. It will be very important to understand those relationships.”

The ability to detect Huntington’s disease onset provides multiple essential benefits, Dr Corey-Bloom said.
“There is a great need to identify accessible biomarkers for Huntington’s disease that could be used to anticipate the onset of disease symptoms, monitor disease progression, stratify patients for clinical trials, and track potential therapeutics,” she said.

Neurologist Conrad C. Weihl, MD, PhD, an associate professor of neurology with Washington University School of Medicine, St. Louis, Missouri, agreed that simplified identification of biomarkers could clearly be of benefit but that the findings will need replication.

“Peripheral biomarkers for neurodegenerative diseases are essential to monitor disease progression but also to monitor potential therapies,” he told Medscape Medical News.

“This will need to be validated in larger cohorts and see if it tracks with disease progression.”

The authors and Dr Weihl have disclosed no relevant financial relationships.

ANA 2017: 142nd Annual Meeting of the American Neurological Association. Abstract MS262. Presented October 16, 2017.

Source: https://www.medscape.com/viewarticle/887463

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