New CSF Biomarker Distinguishes Frontotemporal Dementia From Other Neurodegenerative Disorders

Oskar Hansson, MD, PhD

New research suggests that placental growth factor (PIGF) is a promising diagnostic biomarker for frontotemporal dementia (FTD), able to distinguish the neurodegenerative disease with high accuracy from other dementias.

The findings are significant as differential diagnosis of FTD is challenging due to its heterogenous clinical presentation, with symptoms that overlap with several other neurodegenerative disorders, especially early on in presentation. While symptomatic and imaging biomarkers provide important diagnostic clues, there is a need for quicker, more cost-efficient biomarkers to help improve the rate of earlier, more accurate diagnosis.

Investigators led by Oskar Hansson, MD, PhD, of Lund University in Sweden, recruited a total of 278 individuals with various forms of dementia and mild cognitive impairment (MCI), as well as 50 cognitively normal controls for the discovery cohort. The study also included a validation cohort of 22 patients with FTD and 18 healthy controls.

Cerebrospinal fluid (CSF) levels of PIGF were analyzed for all participants; notably, CSF PIGF levels were higher in men than in women, and did not differ between APOE e4 allele carriers and noncarriers.

Based on univariate analysis adjusted for age and sex, CSF PIGF levels were elevated in patients with stable MCI (P =.019), MCI-Alzheimer disease (P =.005), Alzheimer disease dementia (AD) (P <.001), dementia with Lewy bodies-Parkinson disease dementia (DLB-PDD) (P <.001), vascular dementia (VaD) (P <.001), and FTD (P <.001) compared with cognitively normal controls. Compared with patients with AD, DLB-PDD, or VaD, those with FTD had 1.8-2.1-fold greater PIGF levels (all P <.001). A similar increase was observed between patients with FTD and stable MCI or MCI-AD.

On its own, PIGF demonstrated high accuracy, sensitivity, and specificity for differentiating FTD from controls, as well as patients with stable MCI. When combined with tau and amyloid-beta 42, differential diagnosis for FTD was significantly improved over tau/amyloid-beta 42 alone for distinguishing FTD from MCI-AD and AD (area under the curve [AUC] 0.972 vs 0.932; P <.01), as well as DLB-PDD (AUC 0.954 vs 0.897; P <.05) and VaD (AUC 0.941 vs 0.850; P <.05).

A subcohort analysis (n=267) comparing diagnostic accuracy of PIGF alone, with tau, and with tau and amyloid-beta 42 to neurofilament light chain demonstrated higher accuracies for PIGF for differentiating FTD from other dementia, including AD.

The results were confirmed in the validation cohort, with PIGF levels in patients with FTD greater than in controls, though the investigators did note that differences in PIGF levels between groups were less pronounced in the validation cohort. In addition, PIGF levels were found to be increased in patients with behavioral-variant FTD compared with those with semantic dementia. PIGF concentrations from 5 presymptomatic patients with known GRN mutation were nearly as high as in patients with behavioral-variant FTD.

“In contrast to CSF Ab42 and tau, PlGF showed very high accuracy when discriminating FTD patients from controls and even sMCI patients (AUCs >0.95), with the performance similar to CSF NfL,” the investigators wrote. “Although CSF NfL is a promising biomarker of neuronal damage in neurodegenerative disorders and disease severity in FTD, it does not provide significant added value to CSF Ab42 and tau for differential diagnosis of FTD because CSF levels of NfL are also elevated in many other dementias, for example, progressive supranuclear palsy and VaD.”

“These results suggest that PlGF offers significant promise as diagnostic biomarker of FTD and merit further studies in larger clinical cohorts,” they concluded.

REFERENCE

Hansson O, Santillo AF, Meeter LH, et al. CSF placental growth factor-a novel candidate biomarker of frontotemporal dementia. Ann Clin Transl Neuro. doi: 10.1002/acn3.763. Published March 29, 2019.