Distinguishing Frontotemporal Dementia From 'Phenocopy' Mimics

Susan Kreimer for Medscape

January 24, 2022

The study covered in this summary was published on medRxiv.org as a preprint and has not yet been peer reviewed.

Key Takeaways

  • This study proved very useful in distinguishing cerebrospinal fluid neurofilament (NfL) from phenocopy nonprogressor variants, at baseline, with a significant degree of accuracy in a real-world clinical setting.

  • The outcome has important clinical implications for patients and clinicians in this difficult predicament, as well as for healthcare services and trials.

  • Additional research would be necessary to explore heterogeneity within the nonprogressor group and potential diagnostic algorithms.

  • Prospective studies to assess plasma NfL are in progress.

Why This Matters

  • One of the most challenging clinical conundrums involves differentiating behavioral variant frontotemporal dementia (bvFTD) from non-neurodegenerative nonprogressor, 'phenocopy' mimics of frontal lobe dysfunction. NfL — a biomarker of neuronal injury — could decrease the likelihood of misdiagnosis and avert delay.

  • Patients still encounter several years of diagnostic uncertainty, misdiagnosis, and delay, even in centers with gold-standard multidisciplinary and multimodal trials.

  • The most significant diagnostic delay occurs in patients with younger onset (before age 65) dementia who often present with psychiatric or behavioral symptoms. It can be particularly challenging to differentiate behavioral, personality, and executive dysfunction symptoms of behavioral variant frontotemporal dementia (bvFTD) from primary psychiatric symptoms and other non-neurodegenerative causes of frontal lobe dysfunction.

  • Individuals can appear clinically to have bvFTD, meet established diagnostic criteria for bvFTD, but not experience the anticipated clinical, neuropsychological, and neuroimaging progression over time, according to a growing body of literature.

Study Design

  • In patients with an initial diagnosis of bvFTD, investigators evaluated cerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total tau (T-tau), and phosphorylated tau (P-tau) levels.

  • Based on this data, they classified patients as progressors. They subtyped nonprogressors into phenocopy nonprogressors (non-neurological/neurodegenerative final diagnosis) and static nonprogressors (static deficits, not fully explained by non-neurological/neurodegenerative causes).

Key Results

  • The study consisted of 43 patients: 20 progressors and 23 nonprogressors (15 phenocopy, 8 static), as well as 20 controls.

  • NfL concentrations were lower in nonprogressors (nonprogressors, M = 554 pg/mL, phenocopy nonprogressors M = 459 pg/mL, static nonprogressors M = 730 pg/mL, compared with bvFTD progressors (M = 2397 pg/mL).

  • NfL differentiated progressors from nonprogressors with the greatest accuracy (area under the curve 0.92, 90% / 87% sensitivity/specificity, 86% / 91% positive/negative predictive value, 88% accuracy).

  • T-tau and P-tau levels were likely to be higher in static nonprogressors compared with phenocopy nonprogressors.

Limitations

  • The authors acknowledged that his study is limited by its relatively small cohort size, even though total case numbers were superior or comparable to several other retrospective cohort studies, and add to the paucity of literature in this field, especially regarding biomarkers.

  • The retrospective design is an inherent limitation, but it is mitigated by the consistency of multidisciplinary and multimodal assessments within a single tertiary service, and rigorous file review blinded to biomarkers and conducted by two investigators separately.

  • While investigators followed the cohort for several years and utilized serial, gold-standard multidisciplinary and multimodal assessments and diagnosis based on set diagnostic criteria, it is plausible that longer follow-up could have uncovered more insights.

  • The study included complex patients with multifaceted symptoms, comorbidities and psychiatric histories that merited referral to a tertiary neuropsychiatry service for assessment and diagnosis. The data obtained from them may not be generalizable.

Study Disclosures

  • The authors have declared no competing interest.

This is a summary of a preprint research study, "Cerebrospinal fluid neurofilament light chain differentiates behavioral variant frontotemporal dementia progressors from 'phenocopy' non-progressors," by Dhamidhu Eratne, MBChB, and colleagues from Royal Melbourne Hospital, Parkville, Australia, provided to you by Medscape. This study

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