Cerebrospinal Fluid Biomarkers In Frontotemporal Lobar Degeneration And Alzheimer Disease With Known Pathology

Objective:Frontotemporal lobar degeneration(FTLD)is an early-onset progressive neurodegenerative condition.The most common presenting features include language dysfunction or a disorder of social comportment,executive functioning,and personality.FTLD is the second most common cause of dementia in individuals younger than 65 and is almost as common as Alzheimer's disease(AD)within this age group.AD is a progressive neurodegenerative disorder characterized by memory decline,and it is the most common cause of dementia in aging people.It is important to distinguish between progressive neurodegenerative conditions such as frontotemporal lobar degeneration(FTLD)and Alzheimer's disease(AD)for many reasons.They appear to have distinct underlying causes that may require different etiologically-based treatments,for example,and patient counseling would benefit since clinical features such as survival may differ in these conditions.Both diseases have distinct pathological changes.Two broad pathological subdivisions of FTLD are recognized in a recent classification scheme based on biochemical features:Tau-positive pathology due to the accumulation of various forms of the microtubule-associated protein tau,such as FTLD with Pick bodies and corticobasal degeneration;and tau-negative pathology such as frontotemporal lobar degeneration with ubiquitin/TDP-43-immunoreactive inclusions.Both tau-positive and tau-negative subtypes of FTLD differ from AD where pathological tau filaments accumulate as neurofibrillary tangles together with extracellular deposits ofβ-amyloid(Aβ).Diagnosis may be difficult because of atypical presentations, such as frontal variant AD or FTLD presenting with memory difficulty.Etiologically-based treatments aim to target the mechanisms underlying the accumulation of these abnormal proteins in these conditions.It is essential for us to develop biomarkers that support the accurate diagnosis of the specific diseases causing FTLD.These biomarkers also can be useful in assessing efficacy during treatment trials.In this study,we examine the usefulness of cerebrospinal fluid(CSF) biomarkers obtained during life at distinguishing patients with autopsy evidence or with a genetic mutation causing known FTLD pathology from AD.Among currently available CSF biochemical markers of neurodegenerative diseases,the protein tau appears most promising for differentiating FTLD from AD.Attempts to distinguish FTLD and AD during life also have focused on cognitive biomarkers.AD is characterized by memory decline,for example,while changes in personality/behavior and progressive aphasia are the most prominent features of FTLD.Neuropsychological measures such as category naming fluency, confrontation naming and episodic memory appear to differ in autopsy-proven FTLD and AD,so we also assessed whether neuropsychological results can improve the diagnostic value of CSF biomarkers.Methods:Patients with FTLD(n=30)and AD(n=19)were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center.The clinical diagnosis of an FTLD spectrum disorder or AD was established through a consensus mechanism following a clinical evaluation by an experienced neurologist and was consistent with the results of serum studies,the absence of clinically significant magnetic resonance imaging or computed tomography changes suggesting vascular pathology or hydrocephalus,normal clinical studies of CSF and functional neuroimaging studies.In the FTLD series,histopathologic and genetic mutation diagnoses were as follows:13 tau-positive patients,and 17 tau-negative patients,CSF from 13 cognitively normal seniors established the range of normal CSF tau and Aβ₄₂.All patients and their legally authorized caregivers participated in an informed consent procedure approved by the Institutional Review Board at the University of Pennsylvania or Erasmus University Medical Centre.CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42(Aβ₄₂).Patients also were assessed with a brief neuropsychological battery including Working memory, Letter category naming fluency,Confrontation naming,Animal category naming fluency,Geometric figure copy,Verbal Serial List Learning TestWe established diagnoses according to consensus criteria including the recent Workgroup on Frontotemporal Dementia and Pick's Disease,.Statistical AnalysisAll statistical analyses were performed using SPSS version 12.0(SPSS, Chicago,IL).Descriptive statistics were used to characterize the entire cohort,as well as each pathological subgroup.Student t-tests were used to investigate differences in demographics and levels CSF tau,Aβ₄₂and ratio of tau/Aβ₄₂ between the two pathological groups.Chi-square statistics were used to compare gender ratios and to compare ratios across different CSF tau level and tau/Aβ₄₂ ratio groups.Performance on each measure of cognitive function was reported as a z-score relative to 25 age- and education-matched healthy seniors.Significance was set at -2.32,equivalent to p＜0.01(two-tailed),unless otherwise noted.The Spearman coefficient was used for correlation.ROC curves were used to evaluate the utility of various measures at distinguishing between groups.Results:Relative to AD patients,CSF total tau level[p＜0.01]and tau/Aβ₄₂ ratio[p＜0.001]were reduced in FTLD patients with known pathology.The CSF Aβ₄₂level was higher in FTLD than AD[p＜0.001].Similar findings were evident in an assessment of the subset of autopsy-confirmed patients,that is,lower CSF tau and lower tau/Aβ₄₂ratio in FTLD than AD[p＜0.01],and elevated CSF Aβ₄₂in FTLD relative to AD[p＜0.01].Both CSF tau level and tau/Aβ₄₂ratio were lower in tau-negative patients than AD patients[p＜0.01].Similarly,CSF tau level and tau/Aβ₄₂ratio were lower in tau-positive patients than AD patients[p＜0.01].CSF total tau,Aβ₄₂and tau/Aβ₄₂ratio were lower in tau-negative than tau-positive patients,but this difference was not significant.AD patients had elevated CSF tau level and tau/Aβ₄₂ratio and lower CSF Aβ₄₂level compared to the control group[p＜0.01],but FTLD and controls did not differ in these measures.ROC curves shows the area under the curve(AUC)for CSF tau was 0.79(p= 0.001).For tau/Aβ₄₂,the AUC was 0.93(p＜0.001).Using a cutoff value of 1.06, CSF tau/Aβ₄₂ratio has a sensitivity of 78.9%and a specificity of 96.6%at distinguishing FTLD from AD.Using a cutoff value of 403.05 pg/ ml,total CSF tau has a sensitivity of 68.4%and a specificity of 89.7%at distinguishing FTLD from AD.In evaluating FTLD and controls,the AUC for CSF tau was 0.52 (p=0.817),and the AUC for tau/Aβ₄₂ratio was 0.42(p=0.422)showing modest ability to distinguish FTLD from controls based on CSF biomarkers.An analysis of total CSF tau levels was performed in individual patients using z-scores derived from the control sample obtained using the same CSF analyses.Using these z-score values,we found that 4(13.3%)of the 30 FTLD patients have a significantly reduced CSF total tau level.A significantly reduced level of CSF tau was never seen in individual AD patients,according to these z-score analyses.However,a much higher proportion of AD patients(10 of 19,or 52.6%)had an elevated CSF total tau level compared to FTLD(3 of 30,or 10.0%) [p=0.002].An analysis of individual patient tau/Aβ₄₂ratios,using z-scores derived from the control sample,revealed that none of the FTLD patients have an elevated tau/Aβ₄₂ratio,while more than half(10 of 19,or 52.6%)of the AD patients have an elevated tau/Aβ₄₂ratio[p＜0.001].Using a z-score criterion of-2.32(p＜0.01)based on 25 healthy seniors,the mean z-score of confrontation naming is significantly impaired in FTLD but not in AD.In contrast,the z-score of visual constructions is impaired in AD but not FTLD.Animal category naming fluency and delayed free recall memory were significantly impaired in both FTLD and AD.There were several correlations between CSF biomarkers and neuropsychological tests in FTLD and AD.As summarized in Table 2,the ratio of tau/Aβ₄₂correlated with confrontation naming and delayed recall memory in FTLD.In AD,tau and the tau/Aβ₄₂ratio correlated with animal naming fluency output,and the ratio of tau/Aβ₄₂also correlated with confrontation naming accuracy.ROC curves for the Boston Naming test and animal naming fluency in FTLD and AD showed that the AUC for Boston Naming test was 0.62(p=0.22)and the AUC for animal fluency was 0.48(p=0.85).Thus,performance on these neuropsychological measures alone does not distinguish effectively between FTLD and AD.Only the combination of CSF total tau with confrontation naming improved the ROC marginally(AUC 0.81,p=0.002)compared to CSF tau alone.The combinations of tau/Aβ₄₂ratio with confrontation naming(AUC=0.81,p=0.002) and with animal category naming fluency(AUC=0.76,p=0.009)were statistically robust,but these combined measures showed no improvement compared to the tau/Aβ₄₂ratio alone.Conclusions:CSF total tau level and the ratio of CSF total tau to Aβ₄₂(tau/Aβ₄₂) were significantly lower in FTLD than in AD.Receiver operating characteristic curve analyses confirmed that the CSF tau/Aβ₄₂ratio is sensitive and specific at discriminating between FTLD and AD,and is more successful at this than CSF total tau alone.Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD,combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD.The ratio of CSF tau/Aβ₄₂is a sensitive and specific biomarker at discriminating FTLD from AD in patients with known pathology.