CSF biomarkers in frontotemporal lobar degeneration with known pathology

Hong, Bo; Swieten, John van; Leight, Susan; Massimo, Lauren; Wood, Elisabeth McCarty; Forman, Mark S.; Moore, Peachie; Koning, Inge de; Clark, Christopher M.; Rosso, SM; Trojanowski, John Q.; Lee, V. M.-Y.; Grossman, Murray

doi:10.1212/01.wnl.0000311445.21321.fc

Cited by 201 publications

(159 citation statements)

References 47 publications

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“…1,19 Patients were classified as AD or FTLD using an autopsy-validated t-tau: A␤ 1-42 ratio cutoff of 0.34 (table 1). This cutoff revealed 100% sensitivity and 91% specificity for discriminating between AD and non-AD, 3 where t-tau:A␤ 1-42 Ն0.34 was associated with AD and where t-tau:A␤ 1-42 Ͻ0.34 was associated with non-AD.…”

Section: Csf Analysis Csf Was Obtained At the Time Of Clinical Andmentioning

confidence: 99%

“…Total-tau (t-tau), ␤-amyloid (A␤ ), and other CSF analytes support in vivo diagnosis, with t-tau:A␤ ratio showing superior discriminating power in autopsy-confirmed studies. [1][2][3] However, CSF collection is invasive, costly, and limited in availability. Structural MRI of gray matter (GM) [4][5][6] and diffusion tensor imaging (DTI) of white matter (WM) 4 are less invasive and widely available candidate biomarkers.…”

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confidence: 99%

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White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration

McMillan¹,

Brun²,

Siddiqui³

et al. 2012

Neurology

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Objective: To evaluate the distribution of white matter (WM) disease in frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) and to evaluate the relative usefulness of WM and gray matter (GM) for distinguishing these conditions in vivo.Methods: Patients were classified as having FTLD (n ϭ 50) or AD (n ϭ 42) using autopsy-validated CSF values of total-tau:␤-amyloid (t-tau:A␤ 1-42 ) ratios. Patients underwent WM diffusion tensor imaging (DTI) and volumetric MRI of GM. We employed tract-specific analyses of WM fractional anisotropy (FA) and whole-brain GM density analyses. Individual patient classification was performed using receiver operator characteristic (ROC) curves with FA, GM, and a combination of the 2 modalities.Results: Regional FA and GM were significantly reduced in FTLD and AD relative to healthy seniors. Direct comparisons revealed significantly reduced FA in the corpus callosum in FTLD relative to AD. GM analyses revealed reductions in anterior temporal cortex for FTLD relative to AD, and in posterior cingulate and precuneus for AD relative to FTLD. ROC curves revealed that a multimodal combination of WM and GM provide optimal classification (area under the curve ϭ 0.938), with 87% sensitivity and 83% specificity. Conclusions: FTLD and AD have significant WM and GM defects. A combination of DTI and volumetric MRI modalities provides a quantitative method for distinguishing FTLD and AD in vivo.Neurology ® 2012;78:1761-1768 GLOSSARY A␤ 1-42 ϭ ␤-amyloid; AD ϭ Alzheimer disease; CC ϭ corpus callosum; CST ϭ corticospinal tract; DTI ϭ diffusion tensor imaging; DWI ϭ diffusion-weighted image; FA ϭ fractional anisotropy; FDR ϭ false discovery rate; FTLD ϭ frontotemporal lobar degeneration; GM ϭ gray matter; IFO ϭ inferior fronto-occipital; ILF ϭ inferior longitudinal fasciculus; MMSE ϭ MiniMental State Examination; MPRAGE ϭ magnetization-prepared rapid gradient echo; PBAC ϭ Philadelphia Brief Assessment of Cognition; ROC ϭ receiver operator characteristic; SLF ϭ superior longitudinal fasciculus; t-tau ϭ total-tau; TSA ϭ tractspecific analysis; UNC ϭ uncinate fasciculus; WM ϭ white matter.

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Section: Csf Analysis Csf Was Obtained At the Time Of Clinical Andmentioning

confidence: 99%

mentioning

confidence: 99%

White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration

McMillan¹,

Brun²,

Siddiqui³

et al. 2012

Neurology

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“…CSF amyloid beta 1‐42 (A β 1‐42 ) and tau distinguish FTLD from Alzheimer's disease (AD),3 but they are not consistently abnormal in FTD2, 4, 5 and are largely unexplored as predictors of changes in FTD disease severity. Recent studies in FTD suggest that serum and CSF neurofilament‐light chain (NfL), an intermediate cytoskeletal element that elevates upon neuronal injury,6 is a reliable marker of disease onset,7 clinical severity,7, 8, 9 disease prognosis,7, 10 and brain atrophy rates 7, 9.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Ljubenkov

Staffaroni

Rojas

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThe prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau181, and amyloid beta1‐42 was examined in frontotemporal dementia subtypes.MethodsWe compared baseline biomarkers between 49 controls, 40 patients with behavioral variant frontotemporal dementia, 24 with semantic variant primary progressive aphasia, and 26 with nonfluent variant primary progressive aphasia. Linear mixed effect models were used to assess the value of baseline biomarkers in predicting clinical and radiographic change in patient cohorts over multiple yearly follow up visits.ResultsNeurofilament light chain concentrations were lowest in controls. Elevated baseline neurofilament light chain predicted faster worsening in clinical severity, frontotemporal volume and frontotemporal fractional anisotropy in patients with behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. High total tau similarly predicted faster progression in nonfluent variant primary progressive aphasia. In behavioral variant frontotemporal dementia, higher phosphorylated tau181 predicted faster clinical progression whereas lower amyloid beta1‐42 predicted faster volumetric and fractional anisotropy reduction. Neurofilament light chain and phosphorylated tau181 were of greater predictive value in patients with tau pathology as compared to TDP‐43 pathology. Baseline neurofilament light chain correlated with baseline clinical severity and frontotemporal volume in behavioral variant frontotemporal dementia. Baseline total tau correlated with baseline clinical severity in semantic variant primary progressive aphasia.InterpretationHigh cerebrospinal fluid neurofilament light chain predicts more aggressive disease in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Total tau, phosphorylated tau181, and amyloid beta1‐42 also predict some measures of disease aggressiveness in frontotemporal dementia.

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“…The diagnosis of each patient was confirmed through a consensus mechanism. Autopsy information became available in 6 patients (4 FTLD, 2 AD), using methods summarized previously, 13 whereas others underwent CSF evaluation for levels of AD biomarkers (total tau [t-tau] and ␤-amyloid [A␤42], n ϭ 67). Using a reference set of patients with autopsy diagnosis and genetically mediated disease, patients in the current study were considered to have CSF biomarkers consistent with AD if the CSF t-tau-to-A␤42 ratio was greater than 1.45, as empirically determined.…”

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Distinct cerebral perfusion patterns in FTLD and AD

et al. 2010

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Objective:We examined the utility of distinguishing between patients with frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) using quantitative cerebral blood flow (CBF) imaging with arterial spin labeled (ASL) perfusion MRI. Methods:Forty-two patients with FTLD and 18 patients with AD, defined by autopsy or CSFderived biomarkers for AD, and 23 matched controls were imaged with a continuous ASL method to quantify CBF maps covering the entire brain. Results:Patients with FTLD and AD showed distinct patterns of hypoperfusion and hyperperfusion. Compared with controls, patients with FTLD showed significant hypoperfusion in regions of the frontal lobe bilaterally, and hyperperfusion in posterior cingulate and medial parietal/precuneus regions. Compared with controls, patients with AD showed significant hypoperfusion in the medial parietal/precuneus and lateral parietal cortex, and hyperperfusion in regions of the frontal lobe. Direct comparison of patient groups showed significant inferior, medial, and dorsolateral frontal hypoperfusion in FTLD, and significant hypoperfusion in bilateral lateral temporal-parietal and medial parietal/precuneus regions in AD.Conclusions: Doubly dissociated areas of hypoperfusion in FTLD and AD are consistent with areas of significant histopathologic burden in these groups. ASL is a potentially useful biomarker for distinguishing patients with these neurodegenerative diseases. Neurology ® 2010;75:881-888 GLOSSARY A␤42 ϭ ␤-amyloid 1-42 ; AD ϭ Alzheimer disease; ASL ϭ arterial spin labeling; bvFTD ϭ behavioral-variant frontotemporal dementia; cASL ϭ continuous arterial spin labeling; CBS ϭ corticobasal syndrome; CBF ϭ cerebral blood flow; dACC ϭ dorsal anterior cingulate cortex; dlPFC ϭ dorsolateral prefrontal cortex; FDR ϭ false detection rate; FTLD ϭ frontotemporal lobar degeneration; GM ϭ gray matter; iFC ϭ inferior frontal cortex; MCI ϭ mild cognitive impairment; MNI ϭ Montreal Neurological Institute; mTC ϭ middle temporal cortex; OFC ϭ orbital frontal cortex; PC ϭ parietal cortex; PCA ϭ principal component analysis; PCC ϭ posterior cingulate cortex; PPA ϭ primary progressive aphasia; PRC ϭ precuneus; PVE ϭ partial volume effect; t-tau ϭ total tau; TE ϭ echo time; TI ϭ inversion time; TR ϭ repetition time; WM ϭ white matter.Frontotemporal lobar degeneration (FTLD) is the most common cause of progressive cognitive decline in young-onset dementia. Because Alzheimer disease (AD) accounts for 30% of cases presenting with a clinical diagnosis of primary progressive aphasia (PPA) or behavioral-variant frontotemporal dementia (bvFTD), 1,2 it is important to distinguish between FTLD and AD so that appropriate treatments can be initiated. This distinction is difficult on clinical grounds alone, because AD can mimic PPA and bvFTD, 1,2 and FTLD can present with a memory disorder.

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CSF biomarkers in frontotemporal lobar degeneration with known pathology

Cited by 201 publications

References 47 publications

White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration

White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Distinct cerebral perfusion patterns in FTLD and AD

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