By Alon Seifan, MD, MS

Assistant Professor of Neurology, Memory Disorders Program, Weill Cornell Medical College

Dr. Seifan reports no financial relationships relevant to this field of study.

Synopsis: Cerebrospinal fluid (CSF) visinin-like protein 1 is a useful marker, along with CSF tau and phospho-tau measurements, to predict brain atrophy and neurodegeneration in patients who carry a clinical diagnosis of Alzheimer’s disease.

Source: Tarawneh R, et al. Cerebrospinal fluid markers of neurodegeneration and rates of brain atrophy in early Alzheimer’s disease. JAMA Neurology 2015;72:656-665. doi:10.1001/jamaneurol.2015.0202.

Currently accepted frameworks for biomarker progression in preclinical Alzheimer’s disease (AD) postulate that markers of amyloidosis are the first to become abnormal, followed by markers of neuronal injury, and ultimately measures of impaired cognition, function, and quality of life. In fact, biomarkers of amyloidosis and neuronal injury can stage individuals along the continuum from healthy (Stage 0) to asymptomatic amyloidosis (Stage 1) to neurodegeneration (Stage 2 and 3), even prior to overt clinical symptoms.1 At present, biomarkers available to detect neuronal injury include cerebrospinal fluid (CSF) tau and phosphorylated tau, as well as hypometabolism or atrophy on functional or structural neuroimaging. However, a significant percentage of persons can show evidence of neuronal injury prior to amyloidosis. In these individuals (up to 25% in some cohorts), cognitive impairment may be explained by pathologies unrelated to AD (such as other tauopathies), or by the possibility that some individuals (perhaps related to genetics) manifest a different sequence of biomarker abnormalities in preclinical AD.2 Complicating matters further, the underlying pathologies causing dementia are often mixed in older individuals and often heterogeneous in individuals at risk for atypical neurodegenerative diseases such as primary progressive aphasia. In the context of such uncertainty, the identification of biomarkers of neuronal injury specific to AD is particularly important.

To this end, Tarawneh et al recently investigated the usefulness of CSF visinin-like protein I (VILIP-1), as compared to traditional markers of neuronal injury (tau and phosphorylated-tau), in predicting rates of whole brain and hippocampal atrophy in individuals prior to moderate stages of dementia due to AD. VILIP-1 is a neuronal calcium sensor protein that becomes elevated in CSF in the presence of neuronal injury due to AD. This biomarker may be particularly useful because it may reflect AD-specific neuropathology. The investigators compared CSF and neuroimaging data of healthy, community-dwelling volunteers (n = 64) and individuals with mild AD (n = 20) who were being longitudinally followed at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University School of Medicine in St Louis. At each assessment over a mean duration of follow-up of 2.7 years, diagnoses were made using standard criteria, and dementia severity was rated using the Clinical Dementia Rating scale. CSF samples were analyzed from all participants.

At baseline, biomarker differences were present between the AD and control groups that were consistent with the known pathophysiological changes in AD. Specifically, the AD group included a higher proportion of amyloid-positive individuals and also higher baseline levels of CSF tau, lower Aß42 levels, and more global and regional atrophy in areas associated with AD. Longitudinally, rates of atrophy were different, as to be expected. In the AD group, rates of atrophy were 0.9% per year for whole brain and 4.3% per year for entorhinal cortex and hippocampus, compared to 0.4% and 1.3% per year in the control group. The AD group had higher levels of VILIP-1 at baseline. Baseline VILIP-1, tau, or phosphorylated-tau levels in the highest tertile (but not amyloid levels) predicted greater whole brain and regional atrophy, after adjusting for age, sex, imaging system type, and APOE epsilon 4 genotype. The findings suggest that CSF tau and VILIP-1 levels are closely associated with disease intensity and with rates of subsequent brain atrophy in early symptomatic AD.

Commentary

Important limitations of this study include small sample size and short duration of follow-up. An important strength of the study includes the fact that the center has a 92% postmortem confirmation rate of AD clinical diagnoses made in individuals who are followed longitudinally. Despite the limitations, the study by Tarawneh et al suggests that VILIP-1 could represent a useful measure to predict hippocampal or whole brain atrophy, at least in the short-term in individuals at risk for AD.

Identification of biomarkers specific to underlying pathology in the prodromal stages of neurodegenerative disease is especially important, not only for a better understanding of AD pathophysiology, but also for promoting more accurate characterization of individuals for AD prevention trials and better measurement of treatment response during neurodegenerative stages of disease due to AD. Future studies are required to determine whether VILIP-1 can provide additional value over existing, less-invasively obtained biomarkers, and, specifically, whether it can distinguish impending AD-related neurodegeneration from neurodegeneration due to other dementias, including synucleinopathies, other tauopathies, and vascular causes of cognitive decline.

References

  1. Jack CR Jr, et al. An operational approach to National Institute on Aging-Alzheimer’s Association criteria for preclinical Alzheimer disease. Ann Neurol 2012;71:765-775.
  2. Reiman EM, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci U S A 2004;101:284-289.