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Published in final edited form as: Mol Neurobiol. 2020 May 30;57(7):3143–3149. doi: 10.1007/s12035-020-01951-0

Plasma neurofilament light chain as a translational biomarker of aging and neurodegeneration in dogs

Wojciech K Panek 1, Margaret E Gruen 1, David M Murdoch 2, Robert D Marek 2, Alexandra F Stachel 1, Freya M Mowat 1,3, Korinn E Saker 1, Natasha J Olby 1,*
PMCID: PMC7529326  NIHMSID: NIHMS1599357  PMID: 32472519

Abstract

Age is a primary risk factor for multiple comorbidities including neurodegenerative diseases. Pet dogs and humans represent two populations that have experienced a significant increase in average life expectancy over the last hundred years. A higher prevalence of age-related neurodegenerative diseases has been observed across both species and human diseases, such as Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS), have canine analogues, Canine Cognitive Dysfunction (CCD) and Degenerative Myelopathy (DM) respectively. In humans, protein biomarkers have proved useful in the prediction and diagnosis of neurodegeneration. Molecular signatures of many proteins are highly conserved across species. In this study, we explored the potential of the neuronal cytoskeletal protein neurofilament light chain (NfL) as a biomarker of neuro-aging in dogs using an ultrasensitive single molecule array assay to measure plasma concentrations. Healthy dogs of different ages and dogs affected with CCD and DM were evaluated. The mean plasma NfL concentrations in the different age groups of the healthy population were: 4.55±1.70 pg/mL in puppy/junior group (0.43–2 years), 13.51±6.8 pg/mL in adult/mature group (2.1– 9 years), and 47.1±12.68 pg/mL in geriatric/senior group (9.3–14.5 years). Concentrations in dogs with DM (7.5–12.6 years) and CCD (11.0–15.6 years) were 84.17±53.57 pg/mL and 100.73±83.72 pg/mL, respectively. Plasma NfL increases in an age-dependent manner and is significantly elevated in dogs diagnosed with neurodegenerative disease. This work identified plasma NfL as a key clinical index of neuro-aging and neurodegeneration in pet dogs. Our findings mirror recent reports from human neurodegenerative diseases.

Keywords: canine, cognitive dysfunction, Alzheimer’s disease, amyotrophic lateral sclerosis, degenerative myelopathy

INTRODUCTION

Improvements in healthcare, nutrition and lifestyle have contributed to an increased life expectancy in both dogs and humans [1–3]. Unfortunately, extended lifespan has been paralleled by a concurrent increase in clinical diagnosis of neurodegenerative diseases [4]. Disorders, such as Alzheimer’s disease (AD), significantly impact quality of life in the elderly and have high mortality rates [5]. Proper understanding of the pathophysiology of age-related neurodegenerative processes requires reliable disease models, which is challenging in these complex diseases in which the passage of time also plays an important role [6]. Coupled with this is a need for non-invasive, reliable biomarkers that indicate particular disease stage, ideally the pre-clinical onset disease stage [7]. Among human companion animals, pet dogs enjoy unique privileges within the human society and, in many cases, are considered family members. As a result, pet dogs and their owners share the same living environment with exposure to the same potential neurotoxins. The neurodegenerative diseases such as AD and superoxide dismutase associated Amyotrophic Lateral Sclerosis (SOD1-ALS), have canine analogs, Canine Cognitive Dysfunction (CCD) and Degenerative Myelopathy (DM), respectively [8, 9]. Dogs with CCD exhibit signs of dementia, such as disorientation, anxiety, loss of learned behaviors and changes in sleep cycles associated with neuronal loss and corresponding cortical atrophy within brain areas such as the prefrontal and frontal cortex, hippocampus and limbic system [10–12]. The marked similarity of amyloid beta pathology between dogs and humans has led to the adoption of the dog as a model of early Alzheimer’s disease [13–19]. As another parallel, dogs with DM develop an upper motor neuron paraparesis that progresses to generalized lower motor neuron tetraplegia over a period of 18 – 24 months. Onset of signs is in senior dogs and is associated with a mutation in the SOD1 gene that results in accumulation of SOD1 protein within neurons [9]. This naturally occurring model of SOD1-ALS is now being used to evaluate novel ALS therapies [20, 21].

Within these models, there is a need for biomarkers of neurodegenerative disease for use in the diagnosis and monitoring of disease and outcome assessment in clinical trials. Ideally these biomarkers will be reliable, sensitive (particularly to the early stage of disease), non-invasive and inexpensive. To this end, we were interested in examining plasma concentrations of neurofilament light chain (NfL). Neurofilament light chain is a neuronal structural protein that is genetically conserved across human and canine species and is released into the CSF and blood upon neuronal degeneration or axonal damage. Recent scientific reports in the field of AD and ALS in humans suggest that plasma NfL concentrations are a sensitive biomarker of neurodegeneration, when assessed with ultrasensitive immune assays [22, 23]. In this study, we explored the potential application of measuring canine plasma NfL levels using single-molecule array immunoassay (Simoa, Quanterix) as a translational diagnostic biomarker for the aging and neurodegeneration of the CNS. The advantage of this technology lies in the ability to trap single molecules into the femtoliter-sized microwells, which then allows for the detection of substantially low concentrations of target molecules in plasma. We sought to analyze plasma NfL levels in a healthy population of pet dogs in different life stages and a population of dogs with CCD and dogs with DM. We found that NfL is detectable in canine plasma samples, and that its concentration increases in an age-dependent manner. In addition, dogs with CCD or with DM had higher concentrations of plasma NfL. Our novel canine data mirrors the dynamics of plasma NfL in human neurodegenerative diseases, thereby highlighting the translational potential of the aging pet dog. Clinical application of plasma NfL level testing may represent a highly-sensitive, minimally invasive, and costeffective means of monitoring neuro-aging in pet dogs.

METHODS

Animals

This study included 63 dogs recruited from the staff of the North Carolina (NC) State College of Veterinary Medicine and NC State Veterinary Hospital neurology service caseload, 36 healthy and 27 suffering from neurodegenerative conditions. Because of differences in life expectancy between different dogs breeds, dogs were stratified using life stage categories based on the American Animal Hospital Association (AAHA) canine life stage guidelines combined with breed lifespan by American Kennel Club (AKC) [24]. Inclusion criteria for the cohort of healthy dogs were normal physical and neurological examinations. Exclusion criteria were: history of or ongoing neurological conditions and use of drugs that might alter behavior (e.g. behavior modifying drugs such as fluoxetine or antineuropathic pain medications such as gabapentin).

Dogs classified as having CCD were participating in a longitudinal study of neuro-aging in pet dogs. All dogs underwent physical, orthopedic and neurological examinations and had no significant comorbidities and no evidence of focal neurological deficits. All dogs were visually intact and could hear, and were able to walk without assistance. Exclusion criteria were coexisting metabolic or neurological conditions such as epilepsy and use of drugs that might alter results of behavioral testing. Questionnaire-based assessment of cognitive status was performed using the Canine Dementia Scale (CADES) (Suppl. Fig1) [25]. The Canine Dementia Scale evaluates seventeen items, distributed into four domains associated with behavioral changes (spatial orientation, social interactions, sleep-wake cycles and house soiling) and grades (normal, mild, moderate and severe) are assigned for each item. The CADES score was used to classify dogs as normal (0–7), mild (8–23), moderate (24–44) or severe (45–95) cognitive impairment.

Dogs diagnosed with DM were participating in a longitudinal study or a clinical trial. Dogs diagnosed with DM had progressive tetraparesis with no evidence of compressive or inflammatory myelopathy on magnetic resonance imaging (MRI) of the spine and cerebrospinal fluid (CSF) analysis and were homozygous for the SOD1c.118A allele on genetic testing [8].

All owners were provided with details of the study, were given the opportunity to ask questions and signed an informed consent before participating. All of the study participants underwent physical and neurological examinations followed by blood draw. All procedures were performed in accordance with the North Carolina State University Institutional Animal Care and Use Committee. Data gathered on the dogs included age, breed, sex and health status. Table 1 summarizes the demographic and clinical information for participants grouped according to life stage and disease status.

Table. 1. Demographic and clinical features of study participants.

Mean (SD) and Median (range) have been used to present the NfL concentrations.

Number of dogs (n) Life Stage (AAHA) Age at the evaluation (years) Dementia Score (CADES) Plasma NfL conc. (pg/mL)
Mean SD 		Plasma NfL conc. (pg/mL)
Median (range)
Healthy Controls n =12 puppy/junior 0.40–2 Normal 4.55±1.70 4.41 (1.8–7.5)
n =14 adult/mature 2.1– 9 Normal 13.51±6.8 11.88 (5.8–22.0)
n =10 senior/geriatric 9.3–14.5 Normal 47.1±12.68 42.67 (31.2–68.04)
Canine Cognitive Dysfunction (CCD) n = 11 senior/geriatric 11.0–15.6 Mild, n=4 100.73±83.72 69.72 (30.6 – 327.2)
Moderate, n=2
Severe, n=5
Degenerative Myelopathy (DM) n = 16 senior/geriatric 7.5–12.6 N/A 84.17±53.57 71.77 (21.4 – 184.3)
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Acronyms: CCD – Canine Cognitive Dysfunction; DM – Degenerative Myelopathy; AAHA – American Animal Hospital Association; CADES – Canine Dementia Scale; plasma NfL – plasma neurofilament light chain; SD - standard deviation.

Measurement of plasma NfL levels

Blood samples were taken into purple top (EDTA) tubes and centrifuged at 2000 × g at 4 °C for 8 min within 2 h of collection. Plasma supernatant was collected, divided into aliquots, and frozen at − 80 °C until further use. Samples were thawed on ice before analysis and the concentration of neurofilament light chain (NfL) was measured using Single Molecule Array Assay kit (NF-light, Quanterix, Lexington, MA), following the manufacturer’s instructions using the Sr-X ultrasensitive biomarker detection system (Quanterix, Lexington, MA). This system has a reported coefficient of variation of < 10% and analytical sensitivity of 0.62 pg/mL.

Statistical Analysis

Statistical analyses were performed using JMP14 (SAS Institute, Cary, NC). Dogs were grouped according to life stage and disease status and summary data were prepared for each group on age, weight, sex and breed. The influence of age, body weight and sex on plasma NfL concentrations was examined using linear regression. Plasma NfL concentrations were compared between life stage groups using the Wilcoxon test for each pair. Given the influence of age on plasma NfL concentrations, a model was built to examine the effect of disease status (healthy, CCD or DM) and age on plasma NfL concentration using logistic regression. The relationship between CADES score and pNfL concentrations was examined in healthy senior/geriatric dogs and dogs diagnosed with (CCD) using logistic regression. All reported p values were considered to be statistically significant at p < 0.05, p < 0.01, p< 0.001 and p<0.0001.

RESULTS

Clinical Characteristics

Sixty-three pet dogs (39 males and 24 females) of various breeds (Beagle n=8, Boxer n=8, Border Collie n=4, Cairn Terrier n=2, Jack Russell Terrier n=3, German Shepherd Dog n=8, Golden Retriever n=1, Hound n=1, Labrador Retriever n=7, Mix Breed n=13, Pembroke Welsh Corgi n=5, Rhodesian Ridgeback n=1, Rottweiler n=2) and life stages (puppy/junior; adult/mature; senior/geriatric) were enrolled into this prospective study. Of these, 36 were healthy and 27 were diagnosed with Canine Cognitive Dysfunction (CCD, n=11) or Degenerative Myelopathy (DM, n=16). The ages of dogs ranged from 0.40–15.6 years. The population of healthy pet dogs included puppy/junior dogs (0.40–2 years, n=12), adult/mature dogs (2.1– 9 years, n=14) senior/geriatric dogs (9.3–14.5 years, n=10). All dogs with a neurodegenerative condition were senior/geriatric (CCD: 11.0–15.6 years; DM: 7.5–12.6 years). Demographic features of study participants and CADES dementia scores are presented in Table 1.

Plasma NfL concentrations in healthy pet dogs increase with age

Plasma NfL concentrations for dogs in different life stages are presented in Table 1. Using logistic regression to examine the effect of age, weight and sex, we determined there was a direct relationship between plasma NfL concentrations and age in healthy pet dogs (r2 = 0.75, p<0.0001) (Fig. 1). However, plasma NfL concentrations were not affected by body weight (r2 = 0.07, p=0.19) or sex (r2 = 0.1, p=0.64). When healthy dogs were grouped according to life stage, and compared using Wilcoxon test for each pair, there was a significant difference between each group (Table 1) (p<0.0001 for senior/geriatric versus both other groups, and p<0.0004 for puppy/junior compared with adult/mature) (Fig. 2). Our results mirror the gradual increase in plasma NfL concentrations that occur in humans as they age.

Fig 1. Plasma NfL concentrations increase with age in the population of healthy pet dogs.

Fig 1.

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A multiple linear regression model was fitted using plasma NfL concentration as response variable and age, sex and body weight as dependent variables. There is a positive correlation between age and plasma NfL, (r2=0.75, p<0.0001).

Fig 2. Plasma NfL concentrations increase in an age-dependent manner in the population of healthy pet dogs stratified into different life stage groups.

Fig 2.

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P/J: puppy/junior (n=10); A/M: adult/mature (n=14); S/G: senior/geriatric (n=12). There was statistically significant difference between the groups and when each group was compared pairwise with the Wilcoxon Test. (*p< 0.001); (*** p< 0.0001).

Neurodegenerative disease is associated with high plasma NfL concentrations

Plasma samples from dogs affected with CCD and DM (analogs of Alzheimer’s disease and SOD1-ALS respectively) were tested and the results are reported in Table 1. When plotted against age using logistic regression, dogs with these neurodegenerative diseases combined had significantly higher plasma NfL concentrations than healthy dogs (p<0.01). The rate of change of NfL with age appears to be accelerated in dogs with CCD and DM when compared to healthy dogs (Fig. 3). While plasma NfL concentrations in dogs with CCD were higher than dogs with DM (Table 1), there was no significant difference between these groups when compared with a Wilcoxon Test (p=0.35). Using logistic regression, a positive correlation was found between plasma NfL concentrations and CADES scores in senior and geriatric dogs (dogs with degenerative myelopathy were not included in this evaluation) (r2:0.27; p<0.05) (Fig. 4).

Fig 3. The relationship between age and plasma NfL concentration in a population of healthy dogs (n=36) and dogs affected with neurodegenerative disease (n=27).

Fig 3.

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There was a significant difference between these groups of dogs when evaluated using logistic regression (p<0.01).

Fig 4. The relationship between plasma NfL concentrations and Canine Dementia Score (CADES) in healthy senior/geriatric dogs (n=10) and dogs with CCD (n=11).

Fig 4.

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Plasma NfL concentrations are associated with the CADES score when evaluated using logistic regression (r2= 0.27, p<0.05)

DISCUSSION

This study provides the first report of plasma NfL measurement in healthy pet dogs at different ages and in dogs with naturally occurring neurodegenerative disease. The main findings are that (1) plasma NfL can be successfully detected in pet dogs; (2) plasma NfL concentration increases in an age-dependent manner and is not influenced by body weight and sex; (3) neurodegenerative disease is associated with a significant increase in plasma NfL concentration; and (4) plasma NfL concentration positively correlates with CADES scores. Our findings support the use of canine plasma NfL concentration as a biomarker of neuroaging and neurodegeneration. Moreover, our findings mirror the dynamics of the plasma NfL changes that occur in human aging and neurodegenerative diseases, highlighting the promising translational potential of the aging pet dog as a model of human aging (Suppl. Fig 2).

Neurofilaments (NFs) are cytoskeletal proteins that are particularly abundant in the axons of neurons and highly conserved across species. Within the central nervous system (CNS), there are four different NF subunits, light, medium, heavy chains, and α-internexin, which is replaced with peripherin in the peripheral nervous system [26]. They play important functions during the neurogenesis and are responsible for the radial growth and maintenance of axon caliber in later life as well as supporting axonal conduction [27, 28]. Upon neuro-axonal breakdown, the NF subunits are released into the CSF and both phosphorylated NF heavy chain (pNfH) and NfL have been detected in the plasma [29, 30]. Measurement of plasma NfL has generated a lot of interest due to its stability and long half-life (approximately 3 weeks) in the blood [31]. There have been numerous reports of the association between plasma NfL and severity of acute CNS injury such as stroke, as well as the presence and stage of neurodegenerative disease in humans [32, 33].

Due to extended life expectancy, age-related neurodegenerative diseases pose a major health crisis. More than 40 million people worldwide are affected by AD, and this number is growing dramatically [34, 35]. Similarly, the number of people affected with ALS constantly increases and it is expected to rise across the globe by approximately one third from 80,162 in 2015 to 105,693 in 2040 [36]. Development of effective treatments to prevent the onset or to delay progression of the disease course is an international multidisciplinary research priority [34, 37]. The assessment of the efficacy of novel therapies for AD and ALS requires proper models and sensitive biomarkers that would reflect particular life stage and presymptomatic phases of the disease in a condensed period of time. Aging pet dogs represent a valuable model of spontaneously occurring neurodegenerative diseases due to the similarities in neurobiology and molecular cascades, the shared environmental risk factors between pet dogs and humans, comparable clinical phenotypes and pathology, the ability to provide advanced medical care in a manner comparable to human medical care, the beneficial genetic make-up of dog breeds and the relatively truncated canine lifespan [8, 16, 18, 38].

The use of single molecule array assay (SIMOA) technology allowed detection of plasma NfL in the picomolar range in healthy dogs. There was a clear relationship between plasma NfL and age with plasma concentrations ranging from 1.8pg/ml in puppies to 68pg/ml in healthy senior dogs. Given the different life spans of different breeds of dog, and the short life span of dogs when compared to humans, dogs were then grouped according to life stage. Grouping in this manner allowed us to control for breed specific lifespan and showed an even stronger relationship between plasma NfL concentration and life stage, suggesting that aging of the CNS is influenced by the breed specific aging factors rather than simply reflecting the passage of time. This suggests that examination of the genetic basis of different rates of aging in different breeds will uncover important regulators of aging of the nervous system, highlighting again the potential of study of pet dogs to expand our understanding of the pathophysiology of aging in humans [39]. Plasma NfL concentrations are elevated in humans with AD and ALS, and the range of concentrations reported correlates well with the ranges we report here [23]. While individuals may vary considerably in their NfL concentration, the rate of change of concentration shows considerable promise in predicting onset of AD in humans [22]. Similarly, we show that the rate of change of NfL with age is accelerated in dogs with CCD and DM when compared to life-stage matched healthy individuals. We also found that plasma NfL concentration correlates with CADES scores reported by owners of dogs with CCD. Additional longitudinal work is needed to define the rate of change of NfL and the ability to predict onset of disease. This is particularly important in neurodegenerative diseases, where early detection is difficult but likely to be extremely important when considering therapeutic intervention before significant irreversible damage has been done.

This report provides additional evidence of shared pathophysiology of age-related neurodegenerative diseases between dogs and humans by providing a common plasma biomarker that reflects health status in the similar fashion. Our findings suggest that the dynamics of plasma NfL are comparable between dogs and humans and that plasma NfL is a sensitive biomarker for the existence of age-related normal and pathological neurodegenerative processes. We conclude that measurement of plasma NfL concentration represents a promising biomarker that can be monitored in clinical trials for newly developed therapies against age-related neurodegenerative disorders in humans and dogs.

Supplementary Material

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Acknowledgements

We would like to acknowledge Quanterix company representatives for technical support. We want to thank Jackie Blake and Beth Case for their help with obtaining the biological samples and the dogs and their owners for taking part in the study.

Funding Information

This work is supported by the Dr. Kady M Gjessing and Rhanna M Davidson Distinguished Chair of Gerontology. F.M. M is funded by NIH/NEI K08 EY028628.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

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Associated Data

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Supplementary Materials

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