Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Removing outliers from the normative database improves regional atrophy detection in single-subject voxel-based morphometry.

PURPOSE: Single-subject voxel-based morphometry (VBM) compares an individual T1-weighted MRI to a sample of normal MRI in a normative database (NDB) to detect regional atrophy. Outliers in the NDB might result in reduced sensitivity of VBM. The primary aim of the current study was to propose a method for outlier removal ("NDB cleaning") and to test its impact on the performance of VBM for detection of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). METHODS: T1-weighted MRI of 81 patients with biomarker-confirmed AD (n = 51) or FTLD (n = 30) and 37 healthy subjects with simultaneous FDG-PET/MRI were included as test dataset. Two different NDBs were used: a scanner-specific NDB (37 healthy controls from the test dataset) and a non-scanner-specific NDB comprising 164 normal T1-weighted MRI from 164 different MRI scanners. Three different quality metrics based on leave-one-out testing of the scans in the NDB were implemented. A scan was removed if it was an outlier with respect to one or more quality metrics. VBM maps generated with and without NDB cleaning were assessed visually for the presence of AD or FTLD. RESULTS: Specificity of visual interpretation of the VBM maps for detection of AD or FTLD was 100% in all settings. Sensitivity was increased by NDB cleaning with both NDBs. The effect was statistically significant for the multiple-scanner NDB (from 0.47 [95%-CI 0.36-0.58] to 0.61 [0.49-0.71]). CONCLUSION: NDB cleaning has the potential to improve the sensitivity of VBM for the detection of AD or FTLD without increasing the risk of false positive findings.

The use of synaptic biomarkers in cerebrospinal fluid to differentiate behavioral variant of frontotemporal dementia from primary psychiatric disorders and Alzheimer's disease.

BACKGROUND: Lack of early molecular biomarkers in sporadic behavioral variants of frontotemporal dementia (bvFTD) and its clinical overlap with primary psychiatric disorders (PPD) hampers its diagnostic distinction. Synaptic dysfunction is an early feature in bvFTD and identification of specific biomarkers might improve its diagnostic accuracy. Our goal was to understand the differential diagnostic potential of cerebrospinal fluid (CSF) synaptic biomarkers in bvFTD versus PPD and their specificity towards bvFTD compared with Alzheimer's disease (AD) and controls. Additionally, we explored the association of CSF synaptic biomarkers with social cognition, cognitive performance, and disease severity in these clinical groups. METHODS: Participants with probable bvFTD (n = 57), PPD (n = 71), AD (n = 60), and cognitively normal controls (n = 39) with available CSF, cognitive tests, and disease severity as frontotemporal lobar degeneration-modified clinical dementia rating scale (FTLD-CDR) were included. In a subset of bvFTD and PPD cases, Ekman 60 faces test scores for social cognition were available. CSF synaptosomal-associated protein 25 (SNAP25), neurogranin (Ng), neuronal pentraxin 2 (NPTX2), and glutamate receptor 4 (GluR4) were measured, along with neurofilament light (NfL), and compared between groups using analysis of covariance (ANCOVA) and logistic regression. Diagnostic accuracy was assessed using ROC analyses, and biomarker panels were selected using Wald's backward selection. Correlations with cognitive measures were performed using Pearson's partial correlation analysis. RESULTS: NPTX2 concentrations were lower in the bvFTD group compared with PPD (p < 0.001) and controls (p = 0.003) but not compared with AD. Concentrations of SNAP25 (p < 0.001) and Ng (p < 0.001) were elevated in patients with AD versus those with bvFTD and controls. The modeled panel for differential diagnosis of bvFTD versus PPD consisted of NfL and NPTX2 (AUC = 0.96, CI: 0.93-0.99, p < 0.001). In bvFTD versus AD, the modeled panel consisted of NfL, SNAP25, Ng, and GluR4 (AUC = 0.86, CI: 0.79-0.92, p < 0.001). In bvFTD, lower NPTX2 (Pearson's r = 0.29, p = 0.036) and GluR4 (Pearson's r = 0.34, p = 0.014) concentrations were weakly associated with worse performance of total cognitive score. Lower GluR4 concentrations were also associated with worse MMSE scores (Pearson's r = 0.41, p = 0.002) as well as with worse executive functioning (Pearson's r = 0.36, p = 0.011) in bvFTD. There were no associations between synaptic markers and social cognition or disease severity in bvFTD. CONCLUSION: Our findings of involvement of NTPX2 in bvFTD but not PPD contribute towards better understanding of bvFTD disease pathology.

Truncated TDP-43 proteoforms diagnostic of frontotemporal dementia with TDP-43 pathology.

INTRODUCTION: Biomarkers of TDP-43 pathology are needed to distinguish frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) from phenotypically related disorders. While normal physiological TDP-43 is not a promising biomarker, low-resolution techniques have suggested truncated forms of TDP-43 may be specific to TDP-43 pathology. To advance biomarker efforts for FTLD-TDP, we employed a high-resolution structural technique to characterize TDP-43 post-translational modifications in FTLD-TDP. METHODS: High-resolution mass spectrometry was used to characterize TDP-43 proteoforms in brain tissue from FTLD-TDP, non-TDP-43 dementias and neuropathologically unaffected cases. Findings were then verified in a larger cohort of FTLD-TDP and non-TDP-43 dementias via targeted quantitative mass spectrometry. RESULTS: In the discovery phase, truncated TDP-43 identified FTLD-TDP with 85% sensitivity and 100% specificity. The verification phase revealed similar findings, with 83% sensitivity and 89% specificity. DISCUSSION: The concentration of truncated TDP-43 proteoforms-in particular, in vivo generated C-terminal fragments-have high diagnostic accuracy for FTLD-TDP. HIGHLIGHTS: Discovery: Truncated TDP-43 differentiates FTLD-TDP from related dementias. Verification: Truncated TDP-43 concentration has high accuracy for FTLD-TDP. TDP-43 proteoforms <28 kDa have highest discriminatory power for TDP-43 pathology.

Survival in Incident Cases with Frontotemporal Lobar Degeneration: A Registry-Based Study.

Population-based registries represent a unique sample to estimate survival. The aim of the present study was to assess survival rates and predictors of outcome in incidental frontotemporal lobar degeneration (FTLD). Incident cases with FTLD, included between January 1, 2017 to December 31, 2017, have been followed for five years. Median survival was 8.16 years from disease onset and 5.38 years from diagnosis. Survival rates did not differ between phenotypes. Shorter disease duration from onset to diagnosis was associated with poorer outcome (p = 0.01). FTLD is a relatively homogeneous disease in terms of survival. Future multinational population-based studies are needed to confirm these findings.

Frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) is one of the most common causes of early-onset dementia and presents with early social-emotional-behavioural and/or language changes that can be accompanied by a pyramidal or extrapyramidal motor disorder. About 20-25% of individuals with FTLD are estimated to carry a mutation associated with a specific FTLD pathology. The discovery of these mutations has led to important advances in potentially disease-modifying treatments that aim to slow progression or delay disease onset and has improved understanding of brain functioning. In both mutation carriers and those with sporadic disease, the most common underlying diagnoses are linked to neuronal and glial inclusions containing tau (FTLD-tau) or TDP-43 (FTLD-TDP), although 5-10% of patients may have inclusions containing proteins from the FUS-Ewing sarcoma-TAF15 family (FTLD-FET). Biomarkers definitively identifying specific pathological entities in sporadic disease have been elusive, which has impeded development of disease-modifying treatments. Nevertheless, disease-monitoring biofluid and imaging biomarkers are becoming increasingly sophisticated and are likely to serve as useful measures of treatment response during trials of disease-modifying treatments. Symptomatic trials using novel approaches such as transcranial direct current stimulation are also beginning to show promise.

Limbic-predominant age-related TDP43 encephalopathy (LATE) neuropathological change in neurodegenerative diseases.

TAR DNA-binding protein 43 (TDP43) is a focus of research in late-onset dementias. TDP43 pathology in the brain was initially identified in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and later in Alzheimer disease (AD), other neurodegenerative diseases and ageing. Limbic-predominant age-related TDP43 encephalopathy (LATE), recognized as a clinical entity in 2019, is characterized by amnestic dementia resembling AD dementia and occurring most commonly in adults over 80 years of age. Neuropathological findings in LATE, referred to as LATE neuropathological change (LATE-NC), consist of neuronal and glial cytoplasmic TDP43 localized predominantly in limbic areas with or without coexisting hippocampal sclerosis and/or AD neuropathological change and without frontotemporal lobar degeneration or amyotrophic lateral sclerosis pathology. LATE-NC is frequently associated with one or more coexisting pathologies, mainly AD neuropathological change. The focus of this Review is the pathology, genetic risk factors and nature of the cognitive impairments and dementia in pure LATE-NC and in LATE-NC associated with coexisting pathologies. As the clinical and cognitive profile of LATE is currently not easily distinguishable from AD dementia, it is important to develop biomarkers to aid in the diagnosis of this condition in the clinic. The pathogenesis of LATE-NC should be a focus of future research to form the basis for the development of preventive and therapeutic strategies.

Autoimmunity and Frontotemporal Lobar Degeneration: From Laboratory Study to Clinical Practice.

Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases with heterogenous clinical, genetic, and pathological characteristics that show similar impairment of areas in the frontal and/or temporal lobes. Prime doctors' lack of awareness of this complex disease makes early identification and accurate intervention difficult. Autoimmune diseases and autoantibodies are manifestations of different levels of autoimmune reactions. This review presents research findings examining the relationship between autoimmunity and FTLD in terms of autoimmune diseases and autoantibodies with a focus on identifying potential diagnosis and treatment approaches. The findings indicate that the same or similar pathophysiological mechanisms may exist from clinical, genetic, and pathological perspectives. However, the existing evidence is not sufficient to extract substantial conclusions. On the basis of the current situation, we propose future research patterns using prospective studies on large populations and combined clinical and experimental research. Autoimmune reactions or, more generally, inflammatory reactions should receive increased attention from doctors and scientists of all disciplines.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Blood Biomarkers for the Diagnosis of Neurodegenerative Dementia: A Systematic Review.

IMPORTANCE: Accurately diagnosing neurodegenerative dementia is often challenging due to overlapping clinical features. Disease specific biomarkers could enhance diagnostic accuracy. However, CSF analysis procedures and advanced imaging modalities are either invasive or high-priced, and routinely unavailable. Easily accessible disease biomarkers would be of utmost value for accurate differential diagnosis of dementia subtypes. OBJECTIVE: To assess the diagnostic accuracy of blood-based biomarkers for the differential diagnosis of AD from Frontotemporal Lobar Degeneration (FTLD), or AD from Dementia with Lewy Bodies (DLB). METHODS: Systematic review. Three databases (PubMed, Scopus, and Web of Science) were searched. Studies assessing blood-based biomarkers levels in AD versus FTLD, or AD versus DLB, and its diagnostic accuracy, were selected. When the same biomarker was assessed in three or more studies, a meta-analysis was performed. QUADAS-2 criteria were used for quality assessment. RESULTS: Twenty studies were included in this analysis. Collectively, 905 AD patients were compared to 1262 FTLD patients, and 209 AD patients were compared to 246 DLB patients. Regarding biomarkers for AD versus FTLD, excellent discriminative accuracy (AUC >0.9) was found for p-tau181, p-tau217, synaptophysin, synaptopodin, GAP43 and calmodulin. Other biomarkers also demonstrated good accuracy (AUC = 0.8-0.9). For AD versus DLB distinction, only miR-21-5p and miR-451a achieved excellent accuracy (AUC >0.9). CONCLUSION: Encouraging results were found for several biomarkers, alone or in combination. Prospective longitudinal designs and consensual protocols, comprising larger cohorts and homogeneous testing modalities across centres, are essential to validate the clinical value of blood biomarkers for the precise etiological diagnosis of dementia.

Improved Alzheimer's Disease versus Frontotemporal Lobar Degeneration Differential Diagnosis Combining EEG and Neurochemical Biomarkers: A Pilot Study.

BACKGROUND: Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy. OBJECTIVE: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis. METHODS: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aß1-42, T-tau, P-tau181, and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG). RESULTS: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95%. Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD. CONCLUSION: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools.

Classification accuracy of blood-based and neurophysiological markers in the differential diagnosis of Alzheimer's disease and frontotemporal lobar degeneration.

BACKGROUND: In the last decade, non-invasive blood-based and neurophysiological biomarkers have shown great potential for the discrimination of several neurodegenerative disorders. However, in the clinical workup of patients with cognitive impairment, it will be highly unlikely that any biomarker will achieve the highest potential predictive accuracy on its own, owing to the multifactorial nature of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). METHODS: In this retrospective study, performed on 202 participants, we analysed plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau phosphorylated at amino acid 181 (p-Tau181) concentrations, as well as amyloid ß42 to 40 ratio (Aß1-42/1-40) ratio, using the ultrasensitive single-molecule array (Simoa) technique, and neurophysiological measures obtained by transcranial magnetic stimulation (TMS), including short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), and short-latency afferent inhibition (SAI). We assessed the diagnostic accuracy of combinations of both plasma and neurophysiological biomarkers in the differential diagnosis between healthy ageing, AD, and FTLD. RESULTS: We observed significant differences in plasma NfL, GFAP, and p-Tau181 levels between the groups, but not for the Aß1-42/Aß1-40 ratio. For the evaluation of diagnostic accuracy, we adopted a two-step process which reflects the clinical judgement on clinical grounds. In the first step, the best single biomarker to classify "cases" vs "controls" was NfL (AUC 0.94, p < 0.001), whilst in the second step, the best single biomarker to classify AD vs FTLD was SAI (AUC 0.96, p < 0.001). The combination of multiple biomarkers significantly increased diagnostic accuracy. The best model for classifying "cases" vs "controls" included the predictors p-Tau181, GFAP, NfL, SICI, ICF, and SAI, resulting in an AUC of 0.99 (p < 0.001). For the second step, classifying AD from FTD, the best model included the combination of Aß1-42/Aß1-40 ratio, p-Tau181, SICI, ICF, and SAI, resulting in an AUC of 0.98 (p < 0.001). CONCLUSIONS: The combined assessment of plasma and neurophysiological measures may greatly improve the differential diagnosis of AD and FTLD.

Plasma proteome profiling identifies changes associated to AD but not to FTD.

BACKGROUND: Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. METHODS: Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 ± 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 ± 7.9; 45% female), AD patients (n = 57; age = 65.5 ± 8.0; 39% female), and non-demented controls (n = 148; 61.3 ± 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 ± 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 ± 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 ± 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. RESULTS: Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. CONCLUSIONS: We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts.

Very early-onset behavioral variant frontotemporal dementia in a patient with a variant of uncertain significance of a FUS gene mutation.

The behavioral variant of Frontotemporal dementia (bvFTD) has typically a progressive course with cognitive and behavioral changes that manifests between 50 and 70 years. Very early-onset bvFTD with rapid progression is a rare syndrome under the frontotemporal lobar degeneration (FTLD) umbrella that has been associated with a variety of protein deposition and genetic mutations. We present a case of a 24-year-old man who developed behavioral symptoms and progressed with severe cognitive impairment and functional loss within months. Genetic testing identified a variant of uncertain significance (VUS) mutation in the FUS gene.

Locus Coeruleus Degeneration Differs Between Frontotemporal Lobar Degeneration Subtypes.

BACKGROUND: There are few studies on the locus coeruleus (LC) in frontotemporal lobar degeneration (FTLD) and the potential differences in the LC related to the underlying proteinopathy. OBJECTIVE: The aim of this study was to investigate the LC in FTLD subgroups. METHODS: Neuropathological cases diagnosed with FTLD were included. The subgroups consisted of FTLD with tau, transactive response DNA-binding protein 43 (TDP) and fused in sarcoma (FUS). Micro- and macroscopical degeneration of the LC were assessed with respect to the number of neurons and the degree of depigmentation. A group of cognitively healthy subjects and a group with vascular cognitive impairment (VCI) served as comparison groups. RESULTS: A total of 85 FTLD cases were included, of which 44 had FTLD-TDP, 38 had FTLD-tau, and three had FTLD-FUS. The groups were compared with 25 VCI cases and 41 cognitively healthy control cases (N = 151 for the entire study). All FTLD groups had a statistically higher microscopical degeneration of the LC compared to the controls, but the FTLD-tau group had greater micro- and macroscopical degeneration than the FTLD-TDP group. Age correlated positively with the LC score in the FTLD-tau group, but not in the FTLD-TDP group. CONCLUSION: A greater microscopical degeneration of the LC was observed in all FTLD cases compared to healthy controls and those with VCI. The LC degeneration was more severe in FTLD-tau than in FTLD-TDP. The macroscopically differential degeneration of the LC in FTLD subgroups may facilitate differential diagnostics, potentially with imaging.

Elecsys Cerebrospinal Fluid Assays Accurately Distinguish Alzheimer's Disease from Frontotemporal Lobar Degeneration.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are heterogeneous in their clinical presentation and underlying pathology, but they often have overlapping features. Diagnostic accuracy is critical for guiding patient management. Cerebrospinal fluid (CSF) diagnostic assays for the differentiation of AD and FTLD may increase diagnostic accuracy. OBJECTIVES: In this study, we aimed to understand the potential role of CSF biomarkers and biomarker ratios, measured using Elecsys® CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), in the differential diagnosis of AD and FTLD. DESIGN: This study was conducted at a single center in Munich, Germany between July 2019 and July 2020. Patient CSF samples were retrospectively collected from the study center biobank. PARTICIPANTS: A total of 130 patients with cognitive impairment were included in the study; 86 patients were diagnosed with AD and 44 with FTLD (behavioral variant frontotemporal dementia, semantic variant of primary progressive aphasia, and non-fluent variant of primary progressive aphasia), based on core clinical criteria and a non-CSF biomarker, a typical pattern of regional hypometabolism on [18F] fluorodeoxyglucose positron emission tomography. MEASUREMENTS: Patient CSF biomarker concentrations were measured using Elecsys CSF immunoassays. Receiver operating characteristic analyses were conducted to determine areas under the curve (AUCs) for CSF biomarker performance. Sensitivity and specificity analyses were conducted to evaluate the performance of established cut-offs (Aß42 ≤1000 pg/mL, pTau181/Aß42 ratio >0.024, and tTau/Aß42 ratio >0.28) and optimized cut-offs based on Youden's index. RESULTS: AUC-based performance was similarly good for the pTau181/Aß42 ratio (AUC=0.841; 95% CI: 0.759-0.923), pTau181/Aß40 ratio (AUC=0.837; 95% CI: 0.754-0.919), Aß42/Aß40 ratio (AUC=0.829; 95% CI: 0.746-0.912), tTau/Aß42 ratio (AUC=0.822; 95% CI: 0.736-0.908), pTau181/Aß42/Aß40 ratio (AUC=0.817; 95% CI: 0.734-0.901), and Aß42 (AUC=0.812; 95% CI: 0.722-0.902). Performance was slightly lower for the tTau/Aß42/Aß40 ratio (AUC=0.799; 95% CI: 0.713-0.885), pTau181 alone (AUC=0.793; 95% CI: 0.707-0.880), tTau/Aß40 ratio (AUC=0.751; 95% CI: 0.657-0.844), and tTau alone (AUC=0.706; 95% CI: 0.613-0.799). The highest qualitative performance was observed with the pTau181/Aß42 ratio with an established cut-off value of >0.024 and optimized cut-off value of >0.022: sensitivity and specificity values were 0.892 and 0.773, respectively. CONCLUSIONS: Elecsys CSF immunoassays demonstrate good diagnostic accuracy in differentiating patients with AD from those with FTLD. These immunoassays have the potential to support clinical decision making, i.e. in diagnosing patients with FTLD by excluding patients with amyloid positivity, which is indicative of underlying AD.

Behavioral Variant Frontotemporal Dementia.

PURPOSE OF REVIEW: This article reviews many of the complex facets of behavioral variant frontotemporal dementia (bvFTD) and frontotemporal lobar degeneration (FTLD). A particular focus is on improving diagnostic accuracy to reduce the arduous diagnostic odyssey that so many patients and families endure. Strategies to promote diagnostic accuracy and approach the management of problematic symptoms are also discussed. RECENT FINDINGS: Although the International Consensus Criteria for bvFTD were published more than a decade ago and clinicopathologic studies have confirmed their utility, diagnostic confusion continues. This article presents updated data along with illustrative cases to emphasize the clinical pearls that are most useful for clinicians. Although accurate prediction of the underlying proteinopathy remains a challenge, the ability to differentiate bvFTD from atypical Alzheimer disease, psychiatric disorders, and other mimickers has improved. Knowledge about the genetic underpinnings in a significant minority of individuals with familial FTLD is enabling early and accurate diagnosis. Therapeutic optimism has also increased, particularly in familial FTLD, with a few clinical trials in progress and several more planned, some of which are designed to slow progression or delay the onset of symptoms, or both. SUMMARY: The diagnosis and management of bvFTD is challenging for clinicians and particularly for patients and their families. Although much progress has been gained over recent years, several key research questions persist. Treatments that significantly improve symptoms or alter the course of FTLD remain elusive, but optimism is increasing as pathobiology is better understood and novel therapies are being developed.

Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations.

Frontotemporal dementia comprises a group of clinical syndromes that are characterised by progressive changes in behaviour, executive function, or language. The term frontotemporal lobar degeneration encompasses the neurodegenerative diseases that give rise to these clinical syndromes and involve proteinopathies associated with frontotemporal network dysfunction. Improvements in clinical, genetic, and molecular characterisation have provided new insights into frontotemporal dementia and frontotemporal lobar degeneration, with a much broader range of signs and symptoms at presentation than has been previously considered. Accurate and early diagnosis of frontotemporal dementia is now a possibility due to development of neuropsychological measures with a special focus on social cognition. Advances in plasma and CSF biomarkers, and innovations in structural and functional imaging, will prove useful for future clinical trials in people with frontotemporal dementia.