Frontotemporal Lobar Dementia Research Articles

Analysis of convolutional neural networks for fronto-temporal dementia biomarker discovery.

Frontotemporal lobe dementia (FTD) results from the degeneration of the frontal and temporal lobes. It can manifest in several different ways, leading to the definition of variants characterised by their distinctive symptomatologies. As these variants are detected based on their symptoms, it can be unclear if they represent different types of FTD or different symptomatological axes. The goal of this paper is to investigate this question with a constrained cohort of FTD patients in order to see if the heterogeneity within this cohort can be inferred from medical images rather than symptom severity measurements. An ensemble of convolutional neural networks (CNNs) is used to classify diffusion tensor images collected from two databases consisting of 72 patients with behavioural variant FTD and 120 healthy controls. FTD biomarkers were found using voxel-based analysis on the sensitivities of these CNNs. Sparse principal components analysis (sPCA) is then applied on the sensitivities arising from the patient cohort in order to identify the axes along which the patients express these biomarkers. Finally, this is correlated with their symptom severity measurements in order to interpret the clinical presentation of each axis. The CNNs result in sensitivities and specificities between 83 and 92%. As expected, our analysis determines that all the robust biomarkers arise from the frontal and temporal lobes. sPCA identified four axes in terms of biomarker expression which are correlated with symptom severity measurements. Our analysis confirms that behavioural variant FTD is not a singular type or spectrum of FTD, but rather that it has multiple symptomatological axes that relate to distinct regions of the frontal and temporal lobes. This analysis suggests that medical images can be used to understand the heterogeneity of FTD patients and the underlying anatomical changes that lead to their different clinical presentations.

Computerized decision support is an effective approach to select memory clinic patients for amyloid-PET.

The use of amyloid-PET in dementia workup is upcoming. At the same time, amyloid-PET is costly and limitedly available. While the appropriate use criteria (AUC) aim for optimal use of amyloid-PET, their limited sensitivity hinders the translation to clinical practice. Therefore, there is a need for tools that guide selection of patients for whom amyloid-PET has the most clinical utility. We aimed to develop a computerized decision support approach to select patients for amyloid-PET. We included 286 subjects (135 controls, 108 Alzheimer's disease dementia, 33 frontotemporal lobe dementia, and 10 vascular dementia) from the Amsterdam Dementia Cohort, with available neuropsychology, APOE, MRI and [18F]florbetaben amyloid-PET. In our computerized decision support approach, using supervised machine learning based on the DSI classifier, we first classified the subjects using only neuropsychology, APOE, and quantified MRI. Then, for subjects with uncertain classification (probability of correct class (PCC) < 0.75) we enriched classification by adding (hypothetical) amyloid positive (AD-like) and negative (normal) PET visual read results and assessed whether the diagnosis became more certain in at least one scenario (PPC≥0.75). If this was the case, the actual visual read result was used in the final classification. We compared the proportion of PET scans and patients diagnosed with sufficient certainty in the computerized approach with three scenarios: 1) without amyloid-PET, 2) amyloid-PET according to the AUC, and 3) amyloid-PET for all patients. The computerized approach advised PET in n = 60(21%) patients, leading to a diagnosis with sufficient certainty in n = 188(66%) patients. This approach was more efficient than the other three scenarios: 1) without amyloid-PET, diagnostic classification was obtained in n = 155(54%), 2) applying the AUC resulted in amyloid-PET in n = 113(40%) and diagnostic classification in n = 156(55%), and 3) performing amyloid-PET in all resulted in diagnostic classification in n = 154(54%). Our computerized data-driven approach selected 21% of memory clinic patients for amyloid-PET, without compromising diagnostic performance. Our work contributes to a cost-effective implementation and could support clinicians in making a balanced decision in ordering additional amyloid PET during the dementia workup.

Imaging Approaches in Dementia: A Retrospective Cohort Study of Cross-sectional Imaging in the Indian Population

Introduction: Dementia is a broad medical term that describes the progressive cognitive decline of brain function due to disease or impairment, resulting in interference with daily activities. Magnetic Resonance Imaging (MRI) is commonly used for the clinical diagnosis of dementia by identifying cerebral atrophy and structural alterations. Furthermore, Magnetic Resonance Spectroscopy (MRS) can detect biochemical abnormalities in dementia patients, which may be beneficial for early diagnosis and treatment. Aim: To provide a comprehensive protocol and a guidance tool for radiologists to effectively diagnose dementia and its subtypes {Alzheimer’s Disease (AD), frontotemporal lobe dementia, etc.} based on radiological findings coupled with volumetry, spectroscopy, and Arterial Spin Labelling (ASL) findings. Materials and Methods: A retrospective observational study was conducted in the Department of Radiology, Nanavati Max Superspeciality Hospital, Mumbai, Maharashtra, India, between June 2022 and June 2023. A total of 125 patients were analysed to observe the correlation between whole brain volume, Intracranial Volume (ICV) of different cortical regions, hippocampal atrophy, and MRS findings. Descriptive statistics were used, and results were expressed as means and standard deviations for continuous variables, and as frequencies and percentages for categorical variables. Results: Out of 125 patients, 71 (56.8%) were males, and 54 (43.2%) were females, with ages ranging from 41 to 96 years. The majority presented with Mild Cognitive Impairment (MCI) 36 patients (28.8%) and Vascular Dementia (VaD) (18 patients - 14.4%). Some clinical features and imaging findings overlapped, resulting in some cases being a combination of different types of dementia. MRI, MRS, and Medial Temporal Atrophy (MTA) played a crucial role in allowing clinicians to perform a differential diagnosis. Conclusion: The use of MR volumetry and spectroscopy aids in classifying the type of dementia, which, in turn, gives treating clinicians a better perspective for further treatment and its outcomes.

The autophagy of stress granules.

Our understanding of stress granule (SG) biology has deepened considerably in recent years, and with this, increased understanding of links has been made between SGs and numerous neurodegenerative diseases. One of the proposed mechanisms by which SGs and any associated protein aggregates may become pathological is based upon defects in their autophagic clearance, and so the precise processes governing the degradation of SGs are important to understand. Mutations and disease-associated variants implicated in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and frontotemporal lobar dementia compromise autophagy, whilst autophagy-inhibiting drugs or knockdown of essential autophagy proteins result in the persistence of SGs. In this review, we will consider the current knowledge regarding the autophagy of SG.

Novel characterization of Alzheimer’s disease genetic loci using long‐read sequencing

AbstractBackgroundAlzheimer’s disease (AD) is up to 60‐80% heritable, but less than ∼20% is explained by studies analyzing single nucleotide variants (SNVs). One limitation of short‐read whole‐genome sequencing (SRS) is the standard read length of 150 base pairs, which does not enable the detection of longer structural variants (SVs). Here we sequenced individuals using long‐read sequencing (LRS), which can sequence reads with an average length of ∼20 kilobases, allowing us to identify SVs previously uncaptured.MethodAll participants underwent whole‐genome LRS (∼15x coverage) and a subgroup (84%) underwent SRS. Out of 576 participants (47% males, age = 70.6±7.9 y.o.), 115 were diagnosed with AD or mild cognitive impairment, 365 were healthy controls, and 96 were diagnosed with a synucleinopathy (either Parkinson or Lewy Body disease). Eighty‐three index SNVs from loci associated with AD risk through GWAS (Bellenguez et al., Nature Genetics 2022) were genotyped with 30x coverage SRS, in addition to APOE2‐4. A 1Mbp window was defined around these SNVs to construct the discovery range for SVs (Sniffles2 population mode). Linkage disequilibrium (LD) was assessed between SNVs and SVs (CubeX).ResultA total of 14854 SVs were found across the AD risk loci (Figure1). After LD calculation, N = 197 SVs had a R2&gt;0.1 (Figure2). The SVs with the highest LD (R2&gt;0.7) are reported in Table1, among which there is a 322 bp deletion in the 3’ UTR region of the TMEM106B in high LD (R2 = 0.918) with the intronic SNV rs13237518. This TMEM106B locus has been previously associated with the risk of frontotemporal lobar dementia with TDP‐43 pathology in addition to AD, but the causative SNV has not been identified yet. This large deletion may mediate TMEM106B’s risk‐modulating role in AD and FTLD‐TDP (Chemparathy et al. medRxiv 2023). At the complex MAPT locus, three SVs showed a high LD with rs199515.ConclusionInsights into the role of SVs in neurodegenerative disorders have been hampered due to limitations with SRS. Using LRS in a large AD‐related sample, we characterized for the first time the genetic variation of SVs in known AD risk loci and provide a roadmap to identify potential causal SVs driving the AD association signal.

Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets.

Seven major neurodegenerative diseases and their variants share many overlapping biomarkers that are calmodulin-binding proteins: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD), Huntington's disease (HD), Lewy body disease (LBD), multiple sclerosis (MS), and Parkinson's disease (PD). Calcium dysregulation is an early and persistent event in each of these diseases, with calmodulin serving as an initial and primary target of increased cytosolic calcium. Considering the central role of calcium dysregulation and its downstream impact on calcium signaling, calmodulin has gained interest as a major regulator of neurodegenerative events. Here, we show that calmodulin serves a critical role in neurodegenerative diseases via binding to and regulating an abundance of biomarkers, many of which are involved in multiple neurodegenerative diseases. Of special interest are the shared functions of calmodulin in the generation of protein biomarker aggregates in AD, HD, LBD, and PD, where calmodulin not only binds to amyloid beta, pTau, alpha-synuclein, and mutant huntingtin but also, via its regulation of transglutaminase 2, converts them into toxic protein aggregates. It is suggested that several calmodulin binding proteins could immediately serve as primary drug targets, while combinations of calmodulin binding proteins could provide simultaneous insight into the onset and progression of multiple neurodegenerative diseases.

Immunity impacts cognitive deficits across neurological disorders.

Cognitive deficits are a common comorbidity with neurological disorders and normal aging. Inflammation is associated with multiple diseases including classical neurodegenerative dementias such as Alzheimer's disease (AD) and autoimmune disorders such as multiple sclerosis (MS), in which over half of all patients experience some form of cognitive deficits. Other degenerative diseases of the central nervous system (CNS) including frontotemporal lobe dementia (FTLD), and Parkinson's disease (PD) as well as traumatic brain injury (TBI) and psychological disorders like major depressive disorder (MDD), and even normal aging all have cytokine-associated reductions in cognitive function. Thus, there is likely commonality between these secondary cognitive deficits and inflammation. Neurological disorders are increasingly associated with substantial neuroinflammation, in which CNS-resident cells secrete cytokines and chemokines such as tumor necrosis factor (TNF)α and interleukins (ILs) including IL-1β and IL-6. CNS-resident cells also respond to a wide variety of cytokines and chemokines, which can have both direct effects on neurons by changing the expression of ion channels and perturbing electrical properties, as well as indirect effects through glia-glia and immune-glia cross-talk. There is significant overlap in these cytokine and chemokine expression profiles across diseases, with TNFα and IL-6 strongly associated with cognitive deficits in multiple disorders. Here, we review the involvement of various cytokines and chemokines in AD, MS, FTLD, PD, TBI, MDD, and normal aging in the absence of dementia. We propose that the neuropsychiatric phenotypes observed in these disorders may be at least partially attributable to a dysregulation of immunity resulting in pathological cytokine and chemokine expression from both CNS-resident and non-resident cells.

Young-onset dementia in memory clinics in the Netherlands: Study design and description of PRECODE-GP.

The disease trajectory and healthcare requirements of patients with young-onset dementia (YOD) differ from those of older patients. Accurate data about YOD is crucial to improve diagnosis and optimize care. PRECODE-GP aims to set up a prospective national database of patients with YOD to gain insight into the occurrence and characteristics of patients with YOD in memory clinics in the Netherlands. The national database includes data from dementia patients aged <70 years at diagnosis, collected by local memory clinics (MCs). Data included demographic information, clinical variables, and (etiological) diagnoses. Between July 2019 and December 2022, 781 patients with a mean age of 62±6y at diagnosis (range 37 to 69y) were included from 39 MCs. Most (n = 547,70%)were diagnosed with dementia due to Alzheimer's disease (AD). Patients with Frontotemporal lobe dementia (FTD, n = 87, 11%) were youngest (61±6.0y). Over half (55%) of patients were experiencing symptoms for ≥2 years. We initiated a Dutch national YOD database to improve diagnosis and care for this underrepresented and vulnerable patient group. The database provides a basis for future in-depth studies on YOD.

Case Report of Drug-Induced Parkinsonism with Gait Disturbance Treated with Adjuvant Korean Therapy

Objective: This case study reported the effectiveness of adjuvant Korean therapy on gait disturbances induced by drug-induced Parkinsonism.Method: A patient suffering from frontotemporal lobe dementia was diagnosed with drug-induced Parkinsonism and treated with adjuvant Korean therapy, including herbal medicine and pharmaco-acupuncture. The evaluation was performed by monitoring the length of time and number of steps during an 8 m gait, using the Unified Parkinson’s Disease Rating Scale (UPDRS).Results: After 17 days of adjuvant Korean therapy, the UPDRS score improved from 32 to 16. The length of time for the 8 m gait improved from 20 seconds to 14 seconds. The patient also showed a decrease in the number of steps during the 8 m gait from 43 to 22.Conclusion: This case suggests that adjuvant Korean therapy can be effective for drug-induced Parkinsonism.

Functional near-infrared spectroscopy in elderly patients with four types of dementia.

Functional near-infrared spectroscopy (fNIRS) is commonly used to study human brain function by measuring the hemodynamic signals originating from cortical activation and provides a new noninvasive detection method for identifying dementia. To investigate the fNIRS imaging technique and its clinical application in differential diagnosis of subtype dementias including frontotemporal lobe dementia, Lewy body dementia, Parkinson's disease dementia (PDD) and Alzheimer's disease (AD). Four patients with different types of dementia were examined with fNIRS during two tasks and a resting state. We adopted the verbal fluency task, working memory task and resting state task. Each patient was compared on the same task. We conducted and analyzed the fNIRS data using a general linear model and Pearson's correlation analysis. Compared with other types of dementias, fNIRS showed the left frontotemporal and prefrontal lobes to be poorly activated during the verbal fluency task in frontotemporal dementia. In Lewy body dementia, severe asymmetry of prefrontal lobes appeared during both verbal fluency and working memory tasks, and the patient had low functional connectivity during a resting state. In PDD, the patient's prefrontal cortex showed lower excitability than the temporal lobe during the verbal fluency task, while the prefrontal cortex showed higher excitability during the working memory task. The patient with AD showed poor prefrontal and temporal activation during the working memory task, and more activation of frontopolar instead of the dorsolateral prefrontal cortex. Different hemodynamic characteristics of four types of dementia (as seen by fNIRS imaging) provides evidence that fNIRS can serve as a potential tool for the diagnosis between dementia subtypes.

Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling.

Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau. Methods: We analyzed genes differentially expressed in induced pluripotent stem cell-derived neurons (iPSC-neurons) that represent the three major categories of MAPT mutations: splicing (IVS10 + 16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. The genes that were commonly differentially expressed in MAPT IVS10 + 16, p.P301L, and p.R406W neurons were enriched in trans-synaptic signaling, neuronal processes, and lysosomal function. Many of these pathways are sensitive to disruptions in calcium homeostasis. One gene, CALB1, was significantly reduced across the three MAPT mutant iPSC-neurons and in a mouse model of tau accumulation. We observed a significant reduction in calcium levels in MAPT mutant neurons compared with isogenic controls, pointing to a functional consequence of this disrupted gene expression. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from MAPT mutation carriers and to a lesser extent in brains from sporadic Alzheimer disease and progressive supranuclear palsy, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and lysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.

A Novel Neurofilament Light Chain ELISA Validated in Patients with Alzheimer's Disease, Frontotemporal Dementia, and Subjective Cognitive Decline, and the Evaluation of Candidate Proteins for Immunoassay Calibration.

Neurofilament light chain (Nf-L) is a well-known biomarker for axonal damage; however, the corresponding circulating Nf-L analyte in cerebrospinal fluid (CSF) is poorly characterized. We therefore isolated new monoclonal antibodies against synthetic peptides, and these monoclonals were characterized for their specificity on brain-specific intermediate filament proteins. Two highly specific antibodies, ADx206 and ADx209, were analytically validated for CSF applications according to well-established criteria. Interestingly, using three different sources of purified Nf-L proteins, a significant impact on interpolated concentrations was observed. With a lower limit of analytical sensitivity of 100 pg/mL using bovine Nf-L as the calibrator, we were able to quantify the Nf-L analyte in each sample, and these Nf-L concentrations were highly correlated to the Uman diagnostics assay (Spearman rho = 0.97, p < 0.001). In the clinical diagnostic groups, the new Nf-L ELISA could discriminate patients with Alzheimer’s disease (AD, n = 20) from those with frontotemporal lobe dementia (FTD, n = 20) and control samples with subjective cognitive decline (SCD, n = 20). Henceforth, this novel Nf-L ELISA with well-defined specificity and epitopes can be used to enhance our understanding of harmonizing the use of Nf-L as a clinically relevant marker for neurodegeneration in CSF.

The Evaluation of North Wales SPiCE: Special Preparation in CASC Examination

AimsAs part of the effort to support core psychiatry trainees in North Wales to prepare for their CASC (Clinical Assessment and Skill Competency) exam, the North Wales SPiCE (Special Preparation in CASC Examination) Project has been initiated. This article aims to evaluate the SPiCE based on medical educational principles.MethodsA total of five candidates preparing for the CASC exam expressed interest and an organising committee was set up. Examiners consisted of a consultant and four specialist registrars while role players were recruited from non-exam sitting junior trainees. Five mock CASC stations were written and role-players were calibrated accordingly. The stations included: History taking for a patient with FTD (frontotemporal lobe dementia), MSE (Mental state examination) of a patient with mania and psychosis, explanation of CBT (cognitive-behavioural therapy), breaking bad news of NMS (neuroleptic malignant syndrome), and explanation of ECT (electroconvulsive therapy). The mock exam was conducted virtually using Microsoft TeamsTM. The specialist registrars’ performances in feedback provision were assessed for their teaching using the AOT (Assessment of Teaching) form by the consultants. For core trainees who had played the part of organising committee members and role players, their volunteerism and educational management experience were assessed using the DONCS (Direct Observation of Non-clinical Skill) form by specialist trainees.ResultsAll five candidates passed all the stations (consists of both borderline pass, pass) in the mock exam with 25% improvements in confidence level were seen among candidates in four stations, i.e. ECT explanation, breaking bad news of NMS, CBT explanation, and MSE of a patient with mania and psychosis. All candidates feel the SPiCE programme was useful in helping their final preparation and they would recommend it to other candidates. Four of the candidates sat for the immediate CASC diet after the SPiCE received a pass result. All specialist registrars received positive AOT feedback for their teaching and all non-exam sitting junior trainees received positive DONCS feedback for their spirit of volunteerism and collaborative teamwork.ConclusionThe main strength of the SPiCE project is it utilises existing resources and volunteerism of the organising committee while its main limitation is it has only five stations rather than 16 stations in the real exam. Although the mock exam has improved the confidence of candidates and the majority of candidates pass the exam immediately after that, the causal link between the SPiCE and candidates’ results cannot be conclusively established given all candidates have a good baseline.

PINK1‐Mediated Neuroprotection Against Mutant Tau Pathology

Protein accumulation, mislocalization and dendritic atrophy are pathological features of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Frontotemporal lobar dementia (FTLD). Postmortem samples from patients with AD or FTLD reveal Tau pathology, wherein aberrant Tau accumulates as oligomers and hyperphosphorylated species. Our preliminary data show that mutant Tau (Tau‐A152T), which is linked to increased risk of AD and FTLD, causes dendritic simplification in cultured neurons. While aberrant Tau accumulation is linked to disease severity in AD and FTLD, endogenous factors that can prevent Tau toxicity remain unknown. We and others have shown that PTEN‐induced Kinase 1 (PINK1) is protective in a wide range of genetic and toxin‐based models of neurodegeneration. Elevating PINK1 levels in vitro enhances dendrite length, while loss of PINK1 causes dendrite simplification. Moreover, using our own cohort of AD, FTD and 4R‐tauopathies, we confirmed published observations of decreased PINK1 mRNA and protein expression in the brains of patients with AD. In this work, we test the potential of elevating PINK1 to protect against mutant Tau pathology. We hypothesize that elevated PINK1 expression can protect against dendrite simplification caused by mutant Tau. To test this hypothesis, mouse primary cortical neurons and cortical neurons differentiated from control human iPSC lines (ic‐neurons) were transfected with GFP only or co‐transfected with Tau‐A152T. To elevate PINK1 levels, cultures were co‐transfected with PINK1‐GFP or treated with a pharmacological inhibitor of PINK1 degradation (BC1464). Through neurite length and Sholl analysis, we found that increased PINK1 levels protects neuronal cultures against mutant Tau‐mediated dendritic simplification. To determine the mechanism of PINK1‐mediated protection, we sought to test whether PINK1 elevation promotes Tau clearance. SH‐SY5Y cells were transfected with Tau‐A152T and treated with either DMSO (vehicle) or BC1464. A six‐hour cycloheximide chase assay was performed, and we found that Tau‐A152T levels decreased with BC1464 treatment, but not in vehicle‐treated cultures. Endogenous, wild type Tau levels were not significantly affected. We recently discovered that PINK1 interacts with Valosin‐Containing Protein (VCP, p97), a critical regulator of proteostasis pathways, to modulate dendritic morphology. Ongoing work is aimed at studying the underlying mechanism(s) of PINK1‐mediated Tau‐A152T clearance and identify the signaling partners with which PINK1 interacts to promote neuroprotection.

Functional genome-wide short hairpin RNA library screening identifies key molecules for extracellular vesicle secretion from microglia

SUMMARYActivated microglia release extracellular vesicles (EVs) as modulators of brain homeostasis and innate immunity. However, the molecules critical for regulating EV production from microglia are poorly understood. Here we establish a murine microglial cell model to monitor EV secretion by measuring the fluorescence signal of tdTomato, which is linked to tetraspanin CD63. Stimulation of tdTomato+ cells with ATP induces rapid secretion of EVs and a reduction in cellular tdTomato intensity, reflecting EV secretion. We generate a GFP+ tdTomato+ cell library expressing TurboGFP and barcoded short hairpin RNAs for genome-wide screening using next-generation sequencing. We identify Mcfd2, Sepp1, and Sdc1 as critical regulators of ATP-induced EV secretion from murine microglia. Small interfering RNA (siRNA-based) silencing of each of these genes suppresses lipopolysaccharide- and ATP-induced inflammasome activation, as determined by interleukin-1β release from primary cultured murine microglia. These molecules are critical for microglial EV secretion and are potential therapeutic targets for neuroinflammatory disorders.

TAR DNA‐binding protein 43 oligomers in physiology and pathology

TAR DNA-binding protein 43 (TDP-43) is an RNA/DNA-binding protein involved in RNA regulation and diseases. In 2006, TDP-43 inclusions were found in the disease lesions of several neurodegenerative diseases. It is the pathological hallmark in both amyotrophic lateral sclerosis and frontotemporal lobar dementia. It also presents in a large portion of patients with Alzheimer's disease. TDP-43 is prone to aggregate; however, the role of TDP-43 oligomers remains poorly understood in both physiological and pathological conditions. In this review, we emphasize the role of oligomeric TDP-43 in both physiological and pathological conditions and discuss the potential mechanisms of oligomer formation. Finally, we suggest therapeutic strategies against the TDP-43 oligomers in neurodegenerative diseases.

Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient‐derived pluripotent cell models

AbstractBackgroundMutations in the microtubule‐associated protein tau (MAPT) cause heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD‐tau). Yet the pathogenic events linked to disease remain poorly understood. This study aimed to identify genes and pathways that lead to FTLD‐tau.MethodTo identify the earliest genes and pathways that are dysregulated in FTLD‐tau, we identified differentially expressed genes in RNA‐seq data generated from induced pluripotent stem cell (iPSC)–derived cortical neurons carrying MAPT R406W, MAPT P301L, and MAPT IVS10+16 and isogenic, controls and brain tissue samples from progressive supranuclear palsy (PSP) and control brains. We then identified pathological pathways and drug targets that were enriched among the differentially expressed genes.ResultsWe identified 275 genes that were differentially expressed in iPSC–derived cortical neurons from MAPT R406W carriers compared to isogenic controls, MAPT IVS10+16 carriers compared to isogenic controls, and MAPT P301L carriers compared with isogenic controls. These commonly dysregulated genes were enriched for pathways involving synaptic function, neuronal development, and endolysosomal function. A subset of these genes were also changed in brains from human subjects with PSP compared to normal control brains. Finally, a subset of genes, enriched in glutamate receptor signaling, were altered across the mutant neurons and significantly changed with tau accumulation in a mouse model of tauopathy (Tau‐P301L mice).ConclusionThe results from this study demonstrate that iPSC‐derived neurons capture molecular processes that occur in human brains and can be used to model disease and point to common molecular pathways driven by 3 distinct MAPT mutations

Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient-derived pluripotent cell models.

Mutations in the microtubule-associated protein tau (MAPT) cause heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-tau). Yet, the pathogenic events linked to disease remain poorly understood. This study was aimed at identifying genes and pathways that drive to FTLD-tau. To identify the earliest genes and pathways that are dysregulated in FTLD-tau, we detected differentially expressed genes in RNA-seq data generated from induced pluripotent stem cell (iPSC)-derived cortical neurons carrying MAPT R406W, MAPT P301L, and MAPT IVS10+16 and isogenic, controls and 26 brain tissue samples (3 R406W carriers, 7 IVS10+16, 3 P301L, and 13 unrelated controls). We then identified pathological pathways and drug targets that were enriched among the differentially expressed genes. We identified 61 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT R406W carriers compared with isogenic, control neurons and replicated a subset of these genes in brain tissue from MAPT R406W carriers. We identified 15 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT IVS10+16 carriers compared with isogenic, control neurons and replicated a subset of these genes in brain tissue from MAPT IVS10+16 carriers. We identified 37 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT P301L carriers compared with isogenic, control neurons and replicated a subset of these genes in brain tissue from MAPT P301L carriers. Interestingly, there is little overlap among genes differentially expressed for MAPT R406W, MAPT P301L, and MAPT IVS10+16, which suggests that these mutations may lead to tau aggregation and neurodegeneration by different mechanisms. The results from this study demonstrate that iPSC-derived neurons capture molecular processes that occur in human brains and can be used to model disease.

The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration.

Ageing is an inevitable event in the lifecycle of all organisms, characterized by progressive physiological deterioration and increased vulnerability to death. Ageing has also been described as the primary risk factor of most neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and frontotemporal lobar dementia (FTD). These neurodegenerative diseases occur more prevalently in the aged populations. Few effective treatments have been identified to treat these epidemic neurological crises. Neurodegenerative diseases are associated with enormous socioeconomic and personal costs. Here, the pathogenesis of AD, PD, and other neurodegenerative diseases has been presented, including a summary of their known associations with the biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communications. Understanding the central biological mechanisms that underlie ageing is important for identifying novel therapeutic targets for neurodegenerative diseases. Potential therapeutic strategies, including the use of NAD+ precursors, mitophagy inducers, and inhibitors of cellular senescence, has also been discussed.

Real-Time Fluorescent Measurement of Synaptic Functions in Models of Amyotrophic Lateral Sclerosis.

Before neuronal degeneration, the cause of motor and cognitive deficits in patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobe dementia (FTLD) is dysfunction of communication between neurons and motor neurons and muscle. The underlying process of synaptic transmission involves membrane depolarization-dependent synaptic vesicle fusion and the release of neurotransmitters into the synapse. This process occurs through localized calcium influx into the presynaptic terminals where synaptic vesicles reside. Here, the protocol describes fluorescence-based live-imaging methodologies that reliably report depolarization-mediated synaptic vesicle exocytosis and presynaptic terminal calcium influx dynamics in cultured neurons. Using a styryl dye that is incorporated into synaptic vesicle membranes, the synaptic vesicle release is elucidated. On the other hand, to study calcium entry, Gcamp6m is used, a genetically encoded fluorescent reporter. We employ high potassium chloride-mediated depolarization to mimic neuronal activity. To quantify synaptic vesicle exocytosis unambiguously, we measure the loss of normalized styryl dye fluorescence as a function of time. Under similar stimulation conditions, in the case of calcium influx, Gcamp6m fluorescence increases. Normalization and quantification of this fluorescence change are performed in a similar manner to the styryl dye protocol. These methods can be multiplexed with transfection-based overexpression of fluorescently tagged mutant proteins. These protocols have been extensively used to study synaptic dysfunction in models of FUS-ALS and C9ORF72-ALS, utilizing primary rodent cortical and motor neurons. These protocols easily allow for rapid screening of compounds that may improve neuronal communication. As such, these methods are valuable not only for the study of ALS but for all areas of neurodegenerative and developmental neuroscience research.