IMPORTANCE The positron emission tomography (PET) tracer [ 18 F]flortaucipir allows in vivo quantification of paired helical filament tau, a core neuropathological feature of Alzheimer disease (AD), but its diagnostic utility is unclear. OBJECTIVE To examine the discriminative accuracy of [ 18 F]flortaucipir for AD vs non-AD neurodegenerative disorders. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, 719 participants were recruited from 3 dementia centers in South Korea, Sweden, and the United States between June 2014 and November 2017 (160 cognitively normal controls, 126 patients with mild cognitive impairment [MCI], of whom 65.9% were amyloid-β [Aβ] positive [ie, MCI due to AD], 179 patients with AD dementia, and 254 patients with various non-AD neurodegenerative disorders).EXPOSURES The index test was the [ 18 F]flortaucipir PET standardized uptake value ratio (SUVR) in 5 predefined regions of interest (ROIs). Cut points for tau positivity were determined using the mean +2 SDs observed in controls and Youden Index for the contrast AD dementia vs controls. MAIN OUTCOMES AND MEASURESThe reference standard was the clinical diagnosis determined at the specialized memory centers. In the primary analysis, the discriminative accuracy (ie, sensitivity and specificity) of [ 18 F]flortaucipir was examined for AD dementia vs all non-AD neurodegenerative disorders. In secondary analyses, the area under the curve (AUC) of [ 18 F]flortaucipir SUVR was compared with 3 established magnetic resonance imaging measures (hippocampal volumes and AD signature and whole-brain cortical thickness), and sensitivity and specificity of [ 18 F]flortaucipir in MCI due to AD vs non-AD neurodegenerative disorders were determined. RESULTS Among 719 participants, the overall mean (SD) age was 68.8 (9.2) years and 48.4% were male. The proportions of patients who were amyloid-β positive were 26.3%, 65.9%, 100%, and 23.8% among cognitively normal controls, patients with MCI, patients with AD dementia, and patients with non-AD neurodegenerative disorders, respectively. [ 18 F]flortaucipir uptake in the medial-basal and lateral temporal cortex showed 89.9% (95% CI, 84.6%-93.9%) sensitivity and 90.6% (95% CI, 86.3%-93.9%) specificity using the threshold based on controls (SUVR, 1.34), and 96.8% (95% CI, 92.0%-99.1%) sensitivity and 87.9% (95% CI, 81.9%-92.4%) specificity using the Youden Index-derived cutoff (SUVR, 1.27) for distinguishing AD dementia from all non-AD neurodegenerative disorders. The AUCs for all 5 [ 18 F]flortaucipir ROIs were higher (AUC range, 0.92-0.95) compared with the 3 volumetric MRI measures (AUC range, 0.63-0.75; all ROIs P < .001). Diagnostic performance of the 5 [ 18 F]flortaucipir ROIs were lower in MCI due to AD (AUC range, 0.75-0.84).CONCLUSIONS AND RELEVANCE Among patients with established diagnoses at a memory disorder clinic, [ 18 F]flortaucipir PET was able to discriminate AD from other neurodegenerative diseases. The accuracy and potential utility of this test in patient care require further rese...

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

The diagnostic performance of second-generation tau positron emission tomographic (PET) tracers is not yet known. OBJECTIVE To examine the novel tau PET tracer RO948 F 18 ([ 18 F]RO948) performance in discriminating Alzheimer disease (AD) from non-AD neurodegenerative disorders. DESIGN, SETTING, AND PARTICIPANTS In this diagnostic study, 613 participants in the Swedish BioFINDER-2 study were consecutively enrolled in a prospective cross-sectional study from September 4, 2017, to August 28, 2019. Participants included 257 cognitively unimpaired controls, 154 patients with mild cognitive impairment, 100 patients with AD dementia, and 102 with non-AD neurodegenerative disorders. Evaluation included a comparison of tau PET tracer [ 18 F]RO948 with magnetic resonance imaging (MRI) and cerebrospinal fluid and a head-to-head comparison between [ 18 F]RO948 and flortaucipir F 18 ([ 18 F]flortaucipir) in patients with semantic variant primary progressive aphasia (svPPA). EXPOSURES [ 18 F]RO948 (all patients) and [ 18 F]flortaucipir (3 patients with svPPA) tau PET; MRI (hippocampal volume, composite temporal lobe cortical thickness, whole-brain cortical thickness) and cerebrospinal fluid measures (p-tau181 and amyloid Aβ42 and Aβ40 ratio [Aβ42/Aβ40], and Aβ42/p-tau181 ratio). MAIN OUTCOMES AND MEASURES Standard uptake value ratios (SUVRs) in 4 predefined regions of interest (ROIs) reflecting Braak staging scheme for tau pathology and encompass I-II (entorhinal cortex), III-IV (inferior/middle temporal, fusiform gyrus, parahippocampal cortex, and amygdala), I-IV, and V-VI (widespread neocortical areas), area under the receiver operating characteristic curve (AUC) values, and subtraction images between [ 18 F]RO948 and [ 18 F]flortaucipir. RESULTS Diagnostic groups among the 613 participants included cognitively unimpaired (mean [SD] age, 65.8 [12.1] years; 117 men [46%]), mild cognitive impairment (age, 70.8 [8.3] years; 82 men [53%]), AD dementia (age, 73.5 [6.7] years; 57 men [57%]), and non-AD disorders (age, 70.5 [8.6] years; 41 men [40%]). Retention of [ 18 F]RO948 was higher in AD dementia compared with all other diagnostic groups. [ 18 F]RO948 could distinguish patients with AD dementia from individuals without cognitive impairment and those with non-AD disorders, and the highest AUC was obtained using the I-IV ROI (AUC = 0.98; 95% CI, 0.96-0.99 for AD vs no cognitive impairment and AUC = 0.97; 95% CI, 0.95-0.99 for AD vs non-AD disorders), which outperformed MRI (highest AUC = 0.91 for AD vs no cognitive impairment using whole-brain thickness, and AUC = 0.80 for AD vs non-AD disorders using temporal lobe thickness) and cerebrospinal fluid measures (highest AUC = 0.94 for AD vs no cognitive impairment using Aβ42/p-tau181, and AUC = 0.93 for AD vs non-AD disorders using Aβ42/Aβ40). Generally, tau PET positivity using [ 18 F]RO948 was observed only in Aβ-positive cases or in MAPT R406W mutation carriers. Retention of [ 18 F]RO948 was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temp...

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

ObjectiveWidespread 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.Methods 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.ResultsNeurogranin 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.Interpretation 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.