A 2-Step Cerebrospinal Algorithm for the Selection of Frontotemporal Lobar Degeneration Subtypes.
ABSTRACT: Importance:Cerebrospinal fluid (CSF) core Alzheimer disease (AD) biomarkers have shown an excellent capacity for the in vivo detection of AD. Previous studies have shown that CSF levels of phosphorylated tau (p-tau) also correlate with tau pathology in frontotemporal lobar degeneration (FTLD) after accounting for AD copathology. Objective:To develop an algorithm based on core AD CSF measures to exclude cases with AD pathology and then differentiate between FTLD-tau and FTLD transactive response DNA-binding protein of approximately 43kDa (FTLD-TDP). Design, Setting, and Participants:A case-control study at the University of Pennsylvania. Participants were selected from a database of 1796 patients included between 1992 and 2016 with different neurodegenerative diseases with available CSF. Three patient cohorts were included: a cohort of patients with sporadic, autopsy-confirmed FTLD and AD (n?=?143); a cohort of patients with frontotemporal degeneration (FTD) with TDP-associated or tau-associated mutations (n?=?60); and a living cohort of patients with syndromes highly predictive of FTLD (progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis; n?=?62). Main Outcomes and Measures:Cerebrospinal fluid values of amyloid ?1-42 (A?1-42), total tau (t-tau), and p-tau obtained using the INNO-BIA AlzBio3 (xMAP; Luminex) assay or INNOTEST enzyme-linked immunosorbent assay transformed using a previously validated algorithm. Sensitivities and specificities for differentiating AD from FTLD groups were calculated. Results:This autopsy cohort included FTLD-tau (n?=?27; mean [SD] age at onset, 60.8 [9.7] years), FTLD-TDP (n?=?13; mean [SD] age at onset, 62.4 [8.5] years), AD (n?=?89, mean [SD] age at onset, 66.5 [9.7] years); and mixed FTLD-AD (n?=?14, mean [SD] age at onset, 70.6 [8.5] years).The p-tau/A?1-42 ratio showed an excellent diagnostic accuracy to exclude AD cases in the autopsy cohort with single neurodegenerative pathologies (area under the curve [AUC], 0.98; 95% CI, 0.96-1.00). Cerebrospinal fluid p-tau levels showed a good AUC (0.87; 95% CI, 0.73-1.00) for discriminating pure FTLD-TDP from pure FTLD-tau. The application of an algorithm using cutpoints of CSF p-tau to A?1-42 ratio and p-tau allowed a good discrimination of pure FTLD-TDP cases from the remaining FTLD-tau and mixed FTLD cases. The diagnostic value of this algorithm was confirmed in an independent cohort of living patients with progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis (AUC, 0.9; 95% CI, 0.81-0.99). However, the algorithm was less useful in FTD cases carrying a pathogenic mutation (AUC, 0.58; 95% CI, 0.38-0.77) owing to elevated p-tau levels in TDP-associated mutation carriers. Conclusions and Relevance:Alzheimer disease CSF core biomarkers can be used with high specificity for the in vivo identification of patients with pure FTLD-TDP and FTLD-tau when accounting for comorbid AD and genetic status.
Project description:OBJECTIVES:The combination of high YKL-40 (a glial inflammatory marker) and low sAPP? (a soluble ? fragment of amyloid precursor protein) in cerebrospinal fluid (CSF) has been associated with frontotemporal lobar degeneration (FTLD) in clinical series. We investigate these biomarkers in a neuropathologically confirmed cohort of patients with FTLD. METHODS:CSF samples were selected from the Penn FTD Center (University of Pennsylvania). Participants were followed to autopsy and had a neuropathological diagnosis of FTLD-Tau (n=24), transactive response DNA-binding protein with 43 kDa (FTLD-TDP) (n=25) or Alzheimer's disease (AD, n=97). We compared levels of YKL-40 and sAPP? between groups and with cognitively normal controls (n=77), and assessed their diagnostic utility using receiver operating characteristic curves. We also investigated the effect of AD copathology and the correlation between these CSF markers and tau burden at autopsy. RESULTS:Both FTLD groups had lower levels of sAPP?, higher levels of YKL-40 and lower sAPP?:YKL-40 ratio in CSF compared with controls. The group of pure FTLD-Tau (without AD copathology) showed higher levels of YKL-40 than AD and than pure FTLD-TDP. YKL-40 levels correlated with pathological tau burden. The sAPP?:YKL-40 ratio had an area under the curve (AUC) of 0.91 (95% CI 0.86 to 0.96) to distinguish subjects with FTLD from controls, but lower values to distinguish FTLD from AD (AUC 0.70; 95% ?CI 0.61 to 0.79) and to discriminate FTLD-Tau from FTLD-TDP (AUC 0.67; 95% ?CI 0.51 to 0.82). CONCLUSIONS:Our study provides pathological confirmation that the combination of low sAPP? and high YKL-40 in CSF is associated with FTLD. These biomarkers could be useful in particular clinical settings when FTLD is suspected.
Project description:<h4>Introduction</h4>Reliable cerebrospinal fluid (CSF) biomarkers enabling identification of frontotemporal dementia (FTD) and its pathologic subtypes are lacking.<h4>Methods</h4>Unbiased high-resolution mass spectrometry-based proteomics was applied on CSF of FTD patients with TAR DNA-binding protein 43 (TDP-43, FTD-TDP, n = 12) or tau pathology (FTD-tau, n = 8), and individuals with subjective memory complaints (SMC, n = 10). Validation was performed by applying enzyme-linked immunosorbent assay (ELISA) or enzymatic assays, when available, in a larger cohort (FTLD-TDP, n = 21, FTLD-tau, n = 10, SMC, n = 23) and in Alzheimer's disease (n = 20), dementia with Lewy bodies (DLB, n = 20), and vascular dementia (VaD, n = 18).<h4>Results</h4>Of 1914 identified CSF proteins, 56 proteins were differentially regulated (fold change >1.2, P < .05) between the different patient groups: either between the two pathologic subtypes (10 proteins), or between at least one of these FTD subtypes and SMC (47 proteins). We confirmed the differential expression of YKL-40 by ELISA in a partly independent cohort. Furthermore, enzyme activity of catalase was decreased in FTD subtypes compared with SMC. Further validation in a larger cohort showed that the level of YKL-40 was twofold increased in both FTD pathologic subtypes compared with SMC and that the levels in FTLD-tau were higher compared to Alzheimer's dementia (AD), DLB, and VaD patients. Clinical validation furthermore showed that the catalase enzyme activity was decreased in the FTD subtypes compared to SMC, AD and DLB.<h4>Discussion</h4>We identified promising CSF biomarkers for both FTD differential diagnosis and pathologic subtyping. YKL-40 and catalase enzyme activity should be validated further in similar pathology defined patient cohorts for their use for FTD diagnosis or treatment development.
Project description:<h4>Objectives</h4>To validate the ability of candidate CSF biomarkers to distinguish between the 2 main forms of frontotemporal lobar degeneration (FTLD), FTLD with TAR DNA-binding protein 43 (TDP-43) inclusions (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau).<h4>Methods</h4>Antemortem CSF samples were collected from 30 patients with FTLD in a single-center validation cohort, and CSF levels of 5 putative FTLD-TDP biomarkers as well as levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) were measured using independent assays. Biomarkers most associated with FTLD-TDP were then tested in a separate 2-center validation cohort composed of subjects with FTLD-TDP, FTLD-Tau, Alzheimer disease (AD), and cognitively normal subjects. The sensitivity and specificity of FTLD-TDP biomarkers were determined.<h4>Results</h4>In the first validation cohort, FTLD-TDP cases had decreased levels of p-Tau181 and interleukin-23, and increased Fas. Reduced ratio of p-Tau181 to t-Tau (p/t-Tau) was the strongest predictor of FTLD-TDP pathology. Analysis in the second validation cohort showed CSF p/t-Tau ratio <0.37 to distinguish FTLD-TDP from FTLD-Tau, AD, and healthy seniors with 82% sensitivity and 82% specificity.<h4>Conclusion</h4>A reduced CSF p/t-Tau ratio represents a reproducible, validated biomarker for FTLD-TDP with performance approaching well-established CSF AD biomarkers. Introducing this biomarker into research and the clinical arena can significantly increase the power of clinical trials targeting abnormal accumulations of TDP-43 or Tau, and select the appropriate patients for target-specific therapies.<h4>Classification of evidence</h4>This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau.
Project description:No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.
Project description:Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are the two common forms of dementia. FTD syndromes are characterized by lobar atrophy (frontotemporal lobar degeneration or FTLD) and the presence of either cellular TDP43 (FTLD-TDP), tau (FTLD-tau), or FUS aggregates, while extracellular ?-amyloid plaques and hyperphosphorylated tau tangles develop in AD. Oxidative stress can induce these pathological modifications in disease models, and is thought to play a role in these syndromes. Apolipoprotein D (apoD) is a glial-expressed lipocalin known to protect against oxidative stress, with increased levels in AD, supporting a protective role. The expression of apoD has not been studied in FTLD. This study assesses apoD expression in FTLD-TDP and FTLD-tau in comparison to AD and controls. It also analyzes the effect of apoD on TARDBP (TDP43 gene) and ?-amyloid precursor protein (APP). The expression of apoD was analyzed by Western blotting in FTLD-TDP, FTLD-tau, AD, and control post-mortem brain tissue. An apoD-overexpressing cell model was used to study the impact of increased apoD on APP and TARDBP expression. We confirm that apoD expression was increased in AD but surprisingly it was not affected in either of the two main pathological forms of FTLD. Under oxidative stress conditions, apoD had no effect on TDP43 expression but it did decrease APP expression. This suggests that apoD does not act as a neuroprotective factor in FTLD in the same way as in AD. This could contribute to the more rapid degeneration observed in FTLD.
Project description:<h4>Objective</h4>Frontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD-Tau) or TDP43 (FTLD-TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.<h4>Methods</h4>YKL40, FABP4, MFG-E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD-TDP (<i>n</i> = 30), FTLD-Tau (<i>n</i> = 20), AD (<i>n</i> = 30), DLB (<i>n</i> = 29), and nondemented controls (<i>n</i> = 29) obtained from two different centers. Models were validated in an independent CSF cohort (<i>n</i> = 188).<h4>Results</h4>YKL40 and catalase activity were increased in FTLD-TDP cases compared to controls. YKL40 levels were also higher in FTLD-TDP compared to FTLD-Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG-E8, tTau, and A<i>β</i> <sub>42</sub>; 78% sensitivity and 83% specificity) and non-FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD-TDP from FTLD-Tau (YKL40, MFGE-8, <i>β</i>HexA together with <i>β</i>HexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity.<h4>Interpretation</h4>This study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.
Project description:<h4>Aims</h4>The loss of von Economo neurons (VENs) and GABA receptor subunit theta (GABRQ) containing neurons is linked to early changes in social-emotional cognition and is seen in frontotemporal dementia (FTD) due to C9orf72 repeat expansion. We investigate the vulnerability of VENs and GABRQ-expressing neurons in sporadic and genetic forms of FTD with different underlying molecular pathology and their association with the presence and severity of behavioural symptoms.<h4>Methods</h4>We quantified VENs and GABRQ-immunopositive neurons in the anterior cingulate cortex (ACC) in FTD with underlying TDP43 (FTLD-TDP) (n = 34), tau (FTLD-tau) (n = 24) or FUS (FTLD-FUS) (n = 8) pathology, neurologically healthy controls (n = 12) and Alzheimer's disease (AD) (n = 7). Second, we quantified VENs and the GABRQ-expressing population in relation to presence of behavioural symptoms in the first years of disease onset.<h4>Results</h4>The number of VENs and GABRQ-expressing neurons and the ratio of VENs and GABRQ-expressing neurons over total Layer 5 neuronal population decreased in FTLD-TDP and FTLD-FUS, but not in FTLD-tau, compared to control and AD. The severity of early behavioural symptoms in all donors correlated with a lower VEN and GABRQ neuronal count.<h4>Conclusion</h4>We show that in FTD, a loss of VENs together with GABRQ-expressing pyramidal neurons is associated with TDP43 and FUS pathology. No significant loss was found in donors with FTLD-tau pathology; however, this could be due to the specific MAPT mutation studied and small sporadic FTLD-tau sample size. Overall, we show the GABRQ-expressing population correlates with behavioural changes and suggest they are key in modulating behaviour in FTD.
Project description:Widespread implementation of cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) in clinical settings requires improved accuracy for diagnosis of prodromal disease and for distinguishing AD from non-AD dementias. Novel and promising CSF biomarkers include neurogranin, a marker of synaptic degeneration, and YKL-40, a marker of neuroinflammation.CSF neurogranin and YKL-40 were measured in a cohort of 338 individuals including cognitively healthy controls and patients with stable mild cognitive impairment (sMCI), MCI who later developed AD (MCI-AD), AD dementia, Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), vascular dementia (VaD), and frontotemporal dementia (FTD). The diagnostic accuracy of neurogranin and YKL-40 were compared with the core AD biomarkers, β-amyloid (Aβ42 and Aβ40) and tau.Neurogranin levels were increased in AD and decreased in non-AD dementia compared with healthy controls. As a result, AD patients showed considerably higher CSF levels of neurogranin than DLB/PDD, VaD and FTD patients. CSF YKL-40 levels were increased in AD compared with DLB/PDD but not with VaD or FTD. Neither CSF neurogranin nor YKL-40 levels differed significantly between sMCI patients and MCI-AD patients. Both biomarkers correlated positively with CSF Aβ40 and tau. CSF neurogranin and YKL-40 could separate AD dementia from non-AD dementias (neurogranin, area under the curve [AUC] = 0.761; YKL-40, AUC = 0.604; Aβ42/neurogranin, AUC = 0.849; Aβ42/YKL-40, AUC = 0.785), but the diagnostic accuracy was not better compared to CSF Aβ and tau (Aβ42, AUC = 0.755; tau AUC = 0.858; Aβ42/tau, AUC = 0.895; Aβ42/Aβ40, AUC = 0.881). Similar results were obtained when separating sMCI from MCI-AD cases.CSF neurogranin and YKL-40 do not improve the diagnostic accuracy of either prodromal AD or AD dementia when compared to the core CSF AD biomarkers. Nevertheless, the CSF level of neurogranin is selectively increased in AD dementia, whereas YKL-40 is increased in both AD and FTD suggesting that synaptic degeneration and glial activation may be important in these neurodegenerative conditions.
Project description:<h4>Objective</h4>Diagnosis of frontotemporal dementia (FTD) is complicated by the overlap of clinical symptoms with other dementia disorders. Development of robust fluid biomarkers is critical to improve the diagnostic work-up of FTD.<h4>Methods</h4>CSF concentrations of placental growth factor (PlGF) were measured in the discovery cohort including patients with FTD (<i>n</i> = 27), Alzheimer disease (AD) dementia (<i>n</i> = 75), DLB or PDD (<i>n</i> = 47), subcortical vascular dementia (VaD, <i>n</i> = 33), mild cognitive impairment that later converted to AD (MCI-AD, <i>n</i> = 34), stable MCI (sMCI, <i>n</i> = 62), and 50 cognitively healthy controls from the Swedish BioFINDER study. For validation, CSF PlGF was measured in additional independent cohort of FTD patients (<i>n</i> = 22) and controls (<i>n</i> = 18) from the Netherlands.<h4>Results</h4>In the discovery cohort, MCI, MCI-AD, AD dementia, DLB-PDD, VaD, and FTD patients all showed increased CSF levels of PlGF compared with controls (sMCI <i>P</i> = 0.019; MCI-AD <i>P</i> = 0.005; AD dementia, DLB-PDD, VaD, and FTD all <i>P</i> < 0.001). PlGF levels were 1.8-2.1-fold higher in FTD than in AD, DLB-PDD and VaD (all <i>P</i> < 0.001). PlGF distinguished with high accuracy FTD from controls and sMCI performing better than tau/A<i>β</i>42 (AUC 0.954-0.996 versus 0.564-0.754, <i>P</i> < 0.001). A combination of PlGF, tau, and A<i>β</i>42 (tau/A<i>β</i>42/PlGF) was more accurate than tau/A<i>β</i>42 when differentiating FTD from a group of other dementias (AUC 0.972 vs. 0.932, <i>P</i> < 0.01). Increased CSF levels of PlGF in FTD compared with controls were corroborated in the validation cohort.<h4>Interpretation</h4>CSF PlGF is increased in FTD compared with other dementia disorders, MCI, and healthy controls and might be useful as a diagnostic biomarker of FTD.
Project description:OBJECTIVES:To determine the clinical, anatomical, genetic and pathological features of dual frontotemporal lobar degeneration (FTLD) pathology: FTLD-tau and FTLD-TDP-43 in a large clinicopathological cohort. METHODS:We selected subjects with mixed FTLD-TDP and FTLD-tau from 247 FTLD cases from the University of California, San Francisco, Neurodegenerative Disease Brain Bank collected between 2000 and 2016 and compared their clinical, anatomical, genetic, imaging and pathological signatures with those of subjects with pure FTLD. RESULTS:We found nine cases (3.6%) with prominent FTLD-TDP and FTLD-tau. Six cases were sporadic, whereas one case had a C9ORF72 expansion, another had a TARDBP A90V variant, and the other had an MAPT p.A152T variant. The subtypes of FTLD-TDP and FTLD-tau varied. Mixed FTLD cases were older and tended to show a higher burden of Alzheimer disease pathology (3/9, 33%). The neuroimaging signature of mixed cases, in general, included more widespread atrophy than that of pure groups. Specifically, cases of mixed corticobasal degeneration (CBD) with FTLD-TDP showed more prominent asymmetric left-sided atrophy than did those of pure CBD. However, the clinical phenotype of mixed cases was similar to that seen in pure FTLD. CONCLUSIONS:Although patients with mixed FTLD-TDP and FTLD-tau are rare, in-depth clinical, pathological and genetic investigations may shed light on the genetic and biochemical pathways that cause the accumulation of multiple proteinaceous inclusions and inform therapeutic targets that may be beneficial to each one of these abnormal protein misfoldings.