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Tauopathies are a major type of proteinopathies underlying neurodegenerative diseases. Mutations in the tau-encoding MAPT-gene lead to hereditary cases of frontotemporal lobar degeneration (FTLD)-tau, which span a wide phenotypic and pathological spectrum. Some of these mutations, such as the N279K mutation, result in a shift of the physiological 3R/4R ratio towards the more aggregation prone 4R isoform. Other mutations such as V337M cause a decrease in the in vitro affinity of tau to microtubules and a reduced ability to promote microtubule assembly. Whether both mutations address similar downstream signalling cascades remains unclear but is important for potential rescue strategies. Here, we developed a novel and optimised forward programming protocol for the rapid and highly efficient production of pure cultures of glutamatergic cortical neurons from hiPSCs. We apply this protocol to delineate mechanisms of neurodegeneration in an FTLD-tau hiPSC-model consisting of MAPT N279K - or MAPT V337M -mutants and wild-type or isogenic controls. The resulting cortical neurons express MAPT-genotype-dependent dominant proteome clusters regulating apoptosis, ROS homeostasis and mitochondrial function. Related pathways are significantly upregulated in MAPT N279K neurons but not in MAPT V337M neurons or controls. Live cell imaging demonstrates that both MAPT mutations affect excitability of membranes as reflected in spontaneous and stimulus evoked calcium signals when compared to controls, albeit more pronounced in MAPT N279K neurons. These spontaneous calcium oscillations in MAPT N279K neurons triggered mitochondrial hyperpolarisation and fission leading to mitochondrial ROS production, but also ROS production through NOX2 acting together to induce cell death. Importantly, we found that these mechanisms are MAPT mutation-specific and were observed in MAPT N279K neurons, but not in MAPT V337M neurons, supporting a pathological role of the 4R tau isoform in redox disbalance and highlighting MAPT-mutation specific clinicopathological-genetic correlations, which may inform rescue strategies in different MAPT mutations., Competing Interests: Declaration of competing interest LK: none; AS: A patent application for the optimised forward programming protocol has been filed and submitted. CBS: none. LG: none. TK: none. AE: none. PD: none. MN: none. GS: none. SGM: none. HRS: none. HW: none. SK: none. MP: A patent application for the optimised forward programming protocol has been filed and submitted., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Due to the demographic change dementia is a common and dramatically increasing reason for medical presentations. In approximately 8% of cases dementia occurs before the age of 65 years. The psychosocial and economic consequences are often severe, particularly in younger patients. Clinicians face major diagnostic challenges. A rapid diagnosis is crucial for patient counselling and management., Objective: This review article presents the special features of dementia in younger people, the most important underlying diseases and a rational clinical diagnostic approach., Methods: Narrative review. The literature search was carried out in PubMed., Results: The differential diagnostic spectrum of dementia in younger people under the age of 65 years is very broad. The most common causes are Alzheimer's disease with typical or atypical clinical presentations and frontotemporal lobar degeneration. The younger the age of onset, the higher the proportion of treatable and potentially reversible causes of dementia., Conclusion: The diagnostics of primary neurodegenerative diseases have continuously improved, especially due to the availability of an increasing number of clinical, molecular and imaging biomarkers. Nevertheless, in order to avoid unnecessary and burdensome examinations, the diagnostic work-up of young onset dementia must be hypothesis-driven, i.e. following a precise clinical syndromic classification of the symptoms.

Background: Optical coherence tomography angiography (OCT-A) provides detailed visualization of the perfusion of the vascular network of the eye. While in other forms of dementia, such as Alzheimer's disease and mild cognitive impairment, reduced retinal perfusion was frequently reported, data of patients with frontotemporal dementia (FTD) are lacking. Objective: Retinal and optic nerve head perfusion was evaluated in patients with FTD with OCT-A. Quantitative OCT-A metrics were analyzed and correlated with clinical markers and vascular cerebral lesions in FTD patients. Methods: OCT-A was performed in 18 eyes of 18 patients with FTD and 18 eyes of 18 healthy participants using RTVue XR Avanti with AngioVue. In addition, patients underwent a detailed ophthalmological, neurological, and neuropsychological examination, cerebral magnetic resonance imaging (MRI), and lumbar puncture. Results: The flow density in the optic nerve head (ONH) and in the superficial capillary plexus (SCP) of the macula of patients was significantly lower compared to that of healthy controls (p < 0.001). Similarly, the VD in the deep capillary plexus (DCP) of the macula of patients was significantly lower compared to that of healthy controls (p < 0.001). There was no significant correlation between the flow density data, white matter lesions in brain MRI, cognitive deficits, and cerebrospinal fluid markers of dementia. Conclusions: Patients with FTD showed a reduced flow density in the ONH, and in the superficial and deep retinal capillary plexus of the macula, when compared with that of healthy controls. Quantitative analyses of retinal perfusion using OCT-A may therefore help in the diagnosis and monitoring of FTD. Larger and longitudinal studies are necessary to evaluate if OCT-A is a suitable biomarker for patients with FTD. [ABSTRACT FROM AUTHOR]

Objectives: Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome linked to diverse types of underlying neuropathology. Diagnosis is mainly based on clinical presentation and accurate prediction of underlying neuropathology remains difficult.Methods: We present a large cohort of patients with FTD spectrum diseases (n=84). All patients were thoroughly characterised by cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers, neuroimaging, neuropsychological testing and standardised apraxia screening.Results: A potential AD pathology was found in 43% of patients with FTD. CSF AD biomarker levels positively correlated with AD-typical apraxia scores in patients with FTD. The discriminative power of apraxia test results indicative of AD pathology was high (sensitivity: 90%, specificity: 66%).Conclusions: Apraxia is common in neurodegenerative dementias but under-represented in clinical workup and diagnostic criteria. Standardised apraxia screening may serve as bedside test to objectify an AD-typical apraxia profile as an early and robust sign of AD pathology in patients with FTD. [ABSTRACT FROM AUTHOR]

Background: Due to suboptimal sensitivity and specificity of structural and molecular neuroimaging tools, the diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging.Objective: Investigation of the sensitivity of diffusion tensor imaging (DTI) and fluorodeoxyglucose positron emission tomography (FDG-PET) to detect cerebral alterations in early stages of bvFTD despite inconspicuous conventional MRI.Methods: Thirty patients with early stages of bvFTD underwent a detailed neuropsychological examination, cerebral 3T MRI with DTI analysis, and FDG-PET. After 12 months of follow-up, all patients finally fulfilled the diagnosis of bvFTD. Individual FDG-PET data analyses showed that 20 patients exhibited a "typical" pattern for bvFTD with bifrontal and/or temporal hypometabolism (bvFTD/PET+), and that 10 patients showed a "non-typical"/normal pattern (bvFTD/PET-). DTI data were compared with 42 healthy controls in an individual and voxel-based group analysis. To examine the clinical relevance of the findings, associations between pathologically altered voxels of DTI or FDG-PET results and behavioral symptoms were estimated by linear regression analyses.Results: DTI voxel-based group analyses revealed microstructural degeneration in bifrontal and bitemporal areas in bvFTD/PET+ and bvFTD/PET- groups. However, when comparing the sensitivity of individual DTI data analysis with FDG-PET, DTI appeared to be less sensitive. Neuropsychological symptoms were considerably related to neurodegeneration within frontotemporal areas identified by DTI and FDG-PET.Conclusion: DTI seems to be an interesting tool for detection of functionally relevant neurodegenerative alterations in early stages of bvFTD, even in bvFTD/PET- patients. However, at a single subject level, it seems to be less sensitive than FDG-PET. Thus, improvement of individual DTI analysis is necessary. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder. The contribution of the immune system to its pathogenesis remains incompletely understood. In this study, we performed comprehensive immune cell profiling in the cerebrospinal fluid (CSF) and peripheral blood of patients with FTD. Thirty-two patients with behavioral variant frontotemporal dementia and 25 patients with primary progressive aphasia were included and compared to 14 healthy elderly controls. All patients underwent neuropsychological examination, magnetic resonance imaging, voxel-based diffusion tensor imaging, and peripheral blood and CSF immune cell profiling by multiparameter flow cytometry. The percentage of CSF monocytes was significantly increased specifically in patients with primary progressive aphasia. The proportion of monocytes in the CSF of the total FTD patient group directly correlated with semantic language impairment and microstructural temporal lesions. Increased intrathecal numbers of monocytes suggest a specific response of the innate immune system in a subset of patients with FTD. The findings are of clinical relevance since monocyte levels in the CSF were correlated with typical neuropsychological deficits and microstructural patterns of temporal degeneration. [ABSTRACT FROM AUTHOR]