Subtypes Of Frontotemporal Lobar Degeneration Research Articles

Cerebellar atrophy in pathological subtypes of Alzheimer’s disease and related dementias

AbstractBackgroundThe cerebellum is differentially affected in various neurodegenerative diseases (Gellersen et al., 2017), but associations of cerebellar atrophy with specific neuropathologies have not been systematically analyzed. We used brain imaging to examine cerebellar grey matter volume with patients with all major pathological subtypes of Alzheimer’s disease and related dementias (ADRD).MethodWe applied voxel‐based morphometry to the earliest structural magnetic resonance imaging scans of autopsy‐proven ADRD cases (n = 309), and age‐, sex‐, and education‐matched healthy controls (n = 80). Seventy‐seven AD cases, 74 cases with mixed Lewy body disease and AD (LBD‐AD), and 158 frontotemporal lobar degeneration (FTLD) cases were included in this study. Patients with FTLD were further classified into FTLD major molecular classes and subtypes: FTLD‐TDP [FTLD‐TDP type A (TDP‐A) (n = 21), FTLD‐TDP type B (TDP‐B) (n = 21), FTLD‐TDP type C (TDP‐C) (n = 26)] and FTLD‐tau [Pick’s disease (n = 25), corticobasal degeneration (CBD) (n = 32), progressive supranuclear palsy (PSP) (n = 33)]. Clinical function was assessed with the Clinical Dementia Rating Scale (CDR) (Morris, 1993; Hughes et al., 1982) at the time of MRI scan, with global score ranging from 0 (normal), 0.5 (very mildly impaired), 1 (mildly impaired), 2 (moderately impaired) to 3 (severely impaired).ResultsCompared with controls, distinct patterns of cerebellar atrophy were observed in all pathological subtypes spanning bilateral hemispheres and vermis (PFWE‐corr<0.05, >100 contiguous voxels). Significant cerebellar grey matter changes were even found in the early stage (CDR ≦ 1) of all subtypes, with the exception of TDP‐B, and in the very early stage (CDR 0‐0.5) of AD, LBD‐AD, TDP‐A and PSP. Degree of cortical atrophy positively predicted degree of cerebellar atrophy in all subtypes.ConclusionThis study is the first to identify distinct early patterns of cerebellar atrophy across pathological subtypes of ADRD, and to show a direct relationship between cerebellar and cortical grey matter volume. These results clarify the cerebellar involvement in ADRD and underscore the potential for cerebellar neuroimaging to be a non‐invasive biomarker for differential diagnosis among pathologies and disease monitoring.

Epigenetic Age Acceleration in Frontotemporal Lobar Degeneration: A Comprehensive Analysis in the Blood and Brain.

Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge, and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD.

Case report of a patient with unclassified tauopathy with molecular and neuropathological features of both progressive supranuclear palsy and corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are distinct clinicopathological subtypes of frontotemporal lobar degeneration. They both have atypical parkinsonism, and they usually have distinct clinical features. The most common clinical presentation of PSP is Richardson syndrome, and the most common presentation of CBD is corticobasal syndrome. In this report, we describe a patient with a five-year history of Richardson syndrome and a family history of PSP in her mother and sister. A tau PET scan (18F-APN-1607) revealed low-to-moderate uptake in the substantia nigra, globus pallidus, thalamus and posterior cortical areas, including temporal, parietal and occipital cortices. Neuropathological evaluation revealed widespread neuronal and glial tau pathology in cortical and subcortical structures, including tufted astrocytes in the motor cortex, striatum and midbrain tegmentum. The subthalamic nucleus had mild-to-moderate neuronal loss with globose neurofibrillary tangles, consistent with PSP. On the other hand, there were also astrocytic plaques, a pathological hallmark of CBD, in the neocortex and striatum. To further characterize the mixed pathology, we applied two machine learning-based diagnostic pipelines. These models suggested diagnoses of PSP and CBD depending on the brain region – PSP in the motor cortex and superior frontal gyrus and CBD in caudate nucleus. Western blots of insoluble tau from motor cortex showed a banding pattern consistent with mixed features of PSP and CBD, whereas tau from the superior frontal gyrus showed a pattern consistent with CBD. Real-time quaking-induced conversion (RT-QuIC) using brain homogenates from the motor cortex and superior frontal gyrus showed ThT maxima consistent with PSP, while reaction kinetics were consistent with CBD. There were no pathogenic variants in MAPT with whole genome sequencing. We conclude that this patient had an unclassified tauopathy and features of both PSP and CBD. The different pathologies in specific brain regions suggests caution in diagnosis of tauopathies with limited sampling.

Locus Coeruleus hypopigmentation in frontotemporal lobar degeneration and its relation to cerebrovascular injury biomarkers

AbstractBackgroundIncreasing evidence suggests that degeneration of Locus Coeruleus (LC) neurons is a common feature of various neurodegenerative diseases. Including patients neuropathologically diagnosed with frontotemporal lobar degeneration (FTLD). Based on the histopathological patterns FTLD has been categorized into three distinct subtypes; FTLD with tau immunoreactivity inclusion (FTLD‐tau), FTLD with TDP‐43 (transactive response DNA‐binding protein 43 kDa) immunoreactivity inclusion (FTLD‐TDP), and FTLD with other than tau and TDP‐43 immunoreactivity inclusion (FTLD‐Others). However, the significance of LC degeneration as a marker of the FTLD subtypes has not been fully explored. The purpose of this study was to investigate if the graded LC hypopigmentation can be used as a biomarker to separate distinct subtypes of FTLD.MethodThe sample included 63 participants from the National Alzheimer’s Coordinating Center’s (NACC) data sets who had ante mortem neuropathological and CSF data. LC pigmentation was graded as 0 = none, 1 = mild, 2 = moderate, and 3 = severe. The relationship between LC gross anatomy (hypopigmentation) and CSF A‐beta and Tau levels was explored. Also, the relationship between LC hypopigmentation and FTLD type was investigated. Moreover, markers of cerebrovascular diseases, including infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy, were investigated for their correlation with LC hypopigmentation.ResultThe hypopigmentation of LC is highly correlated with FTLD‐tau, then with a lower degree with FTLD‐TDP and less correlated with FTLD‐Other. Both LC and Substantia Nigra damage was correlated with CSF tau. We did not find statistically significant correlations between FTLD and cerebrovascular disease markers.ConclusionAnte mortem LC hypopigmentation could be used as a biomarker to differentiate underlying FTLD‐tauopathies from clinically similar FTLD‐TDP proteinopathies.

Transcriptome wide correlations with neuropathological hallmarks in the frontal cortex of FTLD patients

AbstractBackgroundA key pathological event in frontotemporal lobar degeneration (FTLD) is the alteration of the RNA metabolism. Despite this, no study has characterized the diversity of RNA species using high‐throughput sequencing approaches and correlated them with the main neuropathological hallmarks across FTLD subtypes.MethodTotal and small RNA sequencing was performed in the frontal cortex of patients neuropathologically diagnosed with FTLD‐TDP (including non‐mutation carriers [sFTLD‐TDP;n = 9], and carriers of the C9orf72 repeat expansion [FTLD‐C9;n = 11]), FTLD‐tau (n = 13, six carrying the p.P301L mutation in MAPT) and controls without neuropathological alterations in the same brain region (n = 7). Gene and miRNA co‐expression modules were identified using WGCNA. Cell‐type proportions were estimated through cell‐type deconvolution using MuSiC. Gene ontology enrichment analyses were performed using Metascape. We assessed in the frontal cortex the presence of pTDP43 (in sFTLD‐TDP and FTLD‐C9), dipeptide repeats and RNA foci (in FTLD‐C9), and tau aggregates (in FTLD‐tau) through quantitative immunohistochemistry and correlated their density with transcriptome‐wide RNA alterations.ResultOur results indicate statistically significant correlations between gene and miRNA co‐expression modules, neuropathological changes and cell‐type proportions specific for each FTLD subtype. The most significant findings include: in sFTLD‐TDP, the density of pTDP43 positively correlated with a gene co‐expression module (R = 0.9,p = 0.04) enriched with splicing functions (p<1×10−8), which directly correlated with a miRNA co‐expression module (R = 0.77,p = 5×10−4) and the proportion of a microglial subpopulation (R = 0.69,p = 4×10−3). In FTLD‐C9, the density of poly(GP) repeats inversely correlated with the proportion of a neuronal subpopulation (R = ‐0.62,p = 0.041), and negatively correlated with a gene co‐expression module (R = ‐0.67,p = 0.024) enriched with protein phosphorylation functions (p<1×10−4). In FTLD‐tau, the density of tau aggregates negatively correlated with the proportion of a neuronal subpopulation (Fig.1A;R = ‐0.77,p = 0.003) and positively correlated with a miRNA (Fig.1B;R = 0.88,p = 8.8×10−5) and a gene (Fig.1C;R = 0.65,p = 0.016) co‐expression module enriched in genes with neuron ensheathing functions (Fig.1D;p<1×10−20).ConclusionOur data demonstrate selective vulnerability of cell‐subtypes to neuropathological changes. In addition, we describe striking correlations between the main neuropathological hallmarks of each FTLD subtype and specific gene and miRNA co‐expression modules, including their hub genes and miRNAs which might be used as biomarkers to identify the FTLD neuropathological substrate in vivo, and reveal novel molecular mechanisms amenable for therapeutic intervention in FTLD.

Clinical, radiologic, and pathologic features of the globular glial tauopathy subtype of frontotemporal lobar degeneration in right temporal variant frontotemporal dementia with salient features of Geschwind syndrome

ABSTRACT Globular Glial Tauopathy (GGT) is a rare form of Frontotemporal Lobar Degeneration (FTLD) consisting of 4-repeat tau globular inclusions in astrocytes and oligodendrocytes. We present the pathological findings of GGT in a previously published case of a 73-year-old woman with behavioral symptoms concerning for right temporal variant frontotemporal dementia with initial and salient features of Geschwind syndrome. Clinically, she lacked motor abnormalities otherwise common in previously published GGT cases. Brain MRI showed focal right anterior temporal atrophy (indistinguishable from five FTLD-TDP cases) and subtle ipsilateral white matter signal abnormalities. Brain autopsy showed GGT type III and Alzheimer’s neuropathologic changes. .

Cerebrospinal Fluid Biomarkers in Autopsy-Confirmed Alzheimer Disease and Frontotemporal Lobar Degeneration.

Background and ObjectivesTo determine how fully automated Elecsys CSF immunoassays for β-amyloid (Aβ) and tau biomarkers and an ultrasensitive Simoa assay for neurofilament light chain (NFL) correlate with neuropathologic changes of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD).MethodsWe studied 101 patients with antemortem CSF and neuropathology data. CSF samples were collected a mean of 2.9 years before death (range 0.2–7.5 years). CSF was analyzed for Aβ40, Aβ42, total tau (T-tau), tau phosphorylated at amino acid residue 181 (P-tau), P-tau/Aβ42 and Aβ42/Aβ40 ratios, and NFL. Neuropathology measures included Thal phases, Braak stages, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores, AD neuropathologic change (ADNC), and primary and contributory pathologic diagnoses. Associations between CSF biomarkers and neuropathologic features were tested in regression models adjusted for age, sex, and time from sampling to death.ResultsCSF biomarkers were associated with neuropathologic measures of Aβ (Thal, CERAD score), tau (Braak stage), and overall ADNC. The CSF P-tau/Aβ42 and Aβ42/Aβ40 ratios had high sensitivity, specificity, and overall diagnostic performance for intermediate-high ADNC (area under the curve range 0.95–0.96). Distinct biomarker patterns were seen in different FTLD subtypes, with increased NFL and reduced P-tau/T-tau in FTLD–TAR DNA-binding protein 43 and reduced T-tau in progressive supranuclear palsy compared to other FTLD variants.DiscussionCSF biomarkers, including P-tau, T-tau, Aβ42, Aβ40, and NFL, support in vivo identification of AD neuropathology and correlate with FTLD neuropathology.Classification of EvidenceThis study provides Class II evidence that distinct CSF biomarker patterns, including for P-tau, T-tau, Aβ42, Aβ40, and NFL, are associated with AD and FTLD neuropathology.

C9orf72 hexanucleotide repeat expansion leads to altered neuronal and dendritic spine morphology and synaptic dysfunction

Frontotemporal lobar degeneration (FTLD) comprises a heterogenous group of progressive neurodegenerative syndromes. To date, no validated biomarkers or effective disease-modifying therapies exist for the different clinical or genetic subtypes of FTLD. The most common genetic cause underlying FTLD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in the C9orf72 gene (C9-HRE). FTLD is accompanied by changes in several neurotransmitter systems, including the glutamatergic, GABAergic, dopaminergic, and serotonergic systems and many clinical symptoms can be explained by disturbances in these systems. Here, we aimed to elucidate the effects of the C9-HRE on synaptic function, molecular composition of synapses, and dendritic spine morphology. We overexpressed the pathological C9-HRE in cultured E18 mouse primary hippocampal neurons and characterized the pathological, morphological, and functional changes by biochemical methods, confocal microscopy, and live cell calcium imaging. The C9-HRE-expressing neurons were confirmed to display the pathological RNA foci and DPR proteins. C9-HRE expression led to significant changes in dendritic spine morphologies, as indicated by decreased number of mushroom-type spines and increased number of stubby and thin spines, as well as diminished neuronal branching. These morphological changes were accompanied by concomitantly enhanced susceptibility of the neurons to glutamate-induced excitotoxicity as well as augmented and prolonged responses to excitatory stimuli by glutamate and depolarizing potassium chloride as compared to control neurons. Mechanistically, the hyperexcitation phenotype in the C9-HRE-expressing neurons was found to be underlain by increased activity of extrasynaptic GluN2B-containing N-methyl-d-aspartate (NMDA) receptors. Our results are in accordance with the idea suggesting that C9-HRE is associated with enhanced excitotoxicity and synaptic dysfunction. Thus, therapeutic interventions targeted to alleviate synaptic disturbances might offer efficient avenues for the treatment of patients with C9-HRE-associated FTLD.

Calsyntenin‐1 is a cerebrospinal fluid marker of frontotemporal dementia‐related synapse degeneration

AbstractBackgroundFrontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD), a surrogate marker of synapse loss could aid the early diagnosis of FTD. The aim of this study was to evaluate the diagnostic performance of a panel of 9 synaptic proteins in cerebrospinal fluid (CSF) for FTLD in a neuropathological cohort.MethodWe included cognitively normal controls (n=35, 69 years+/‐7) and patients with neuropathological confirmation of FTLD (n=49, mean age‐at‐CSF 67 years+/‐10) or AD (n=25, 73 years+/‐6) from the Penn FTD Center. Subsets of the FTLD group included FTLD‐TDP (n=25) and FTLD‐Tau (n=24) neuropathological subtypes and “pure FTLD” (neurofibrillary tangle score of B0/B1 according to the NIA‐AA classification; n=39). We quantified the synaptic panel by targeted mass spectrometry using isotopically‐labeled proteotypic peptides as internal standards. We used linear regression with Dunnett’s post‐hoc tests to compare group differences, receiver‐operating characteristic curves to assess diagnostic accuracy (AUC) and linear regression adjusting for age‐at‐death and sex to assess the association with tau burden.ResultOf the 9 synaptic proteins, CSF Calsyntenin‐1 showed the strongest association with disease etiology (r2 =.12, p=.0006). Calsyntenin‐1 was lower in FTLD compared to controls (p=.03) and AD (p=.0008), particularly in “pure FTLD” (p=.02 vs controls, p=.0004 vs AD). Calsyntenin‐1 levels were comparable between AD and controls (p=.33) and between neuropathological FTLD subtypes (p=.66). Calsyntenin‐1 did not correlate with age‐at‐CSF analysis in controls (p=.74), FTLD (p=.07) or AD (p=.40). Calsyntenin‐1 showed the best diagnostic accuracy for differentiating FTLD from AD (AUC=73.4%) and showed similar accuracy in “pure FTLD” (AUC=75.7%) and in FTLD‐TDP (AUC=76.0%) and FTLD‐Tau (AUC=70.4%). Calsyntenin‐1 directly correlated with global pathological tau burden in FTLD (r2=.22; p=0.005) and in “pure FTLD” (r2=.17; p=0.02).ConclusionLow CSF levels of the post‐synaptic modulator, Calsyntenin‐1, is specific to FTLD, particularly in cases with little or no tau pathology and could aid the early diagnosis of FTD and the differential diagnosis from AD and other tauopathies.

Metabolic positron-emission tomography/magnetic resonance imaging in primary progressive aphasia and frontotemporal lobar degeneration subtypes: Reassessment of expected [18F]-fluorodeoxyglucose uptake patterns.

Clinical assessment of frontotemporal lobar degeneration (FTLD)/primary progressive aphasia (PPA) patients is challenging, given that common cognitive assessments rely extensively on language. Since asymmetry in neuroimaging biomarkers is often described as a central finding in these patients, our study evaluated [18F]-fluorodeoxyglucose (FDG) uptake patterns in patients meeting clinical and imaging criteria for FTLD, with emphasis on PPA. Fifty-one subjects underwent brain [18F]-FDG positron-emission tomography/magnetic resonance imaging (PET/MRI) as part of their routine clinical workup for dementia and neurodegenerative disease. Images were obtained using a Siemens Biograph mMR integrated 3T PET/MRI scanner. PET surface maps and fusion fluid-attenuated inversion recovery-PET images were generated utilizing MIMneuro software. Two board-certified neuroradiologists and one nuclear medicine physician blinded to patient history classified each FTLD/PPA subtype and assessed for left- versus right-side dominant hypometabolism. Qualitative and semiquantitative assessment demonstrated 18 cases of PPA, 16 behavioral variant frontotemporal dementia (bvFTD), 12 corticobasal degeneration, and 5 progressive supranuclear palsy. Among the 18 PPA subjects (11 svPPA, 5 lvPPA, and 2 agPPA), 12 (67%) demonstrated left-dominant hypometabolism and 6 (33%) right-dominant hypometabolism. While existing literature stresses left-dominant hypometabolism as a key imaging feature in the PPA subtypes, a third of our cases demonstrated right-dominant hypometabolism, suggesting that emphasis should be placed on the functionality of specific brain regions affected, rather than left versus right sidedness of hypometabolism patterns.

Tau immunotherapy is associated with glial responses in FTLD-tau

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes.

Diagnostic Utility of Measuring Cerebral Atrophy in the Behavioral Variant of Frontotemporal Dementia and Association With Clinical Deterioration

The presence of atrophy on magnetic resonance imaging can support the diagnosis of the behavioral variant of frontotemporal dementia (bvFTD), but reproducible measurements are lacking. To assess the diagnostic and prognostic utility of 6 visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index (MRPI). In this diagnostic/prognostic study, data from 235 patients with bvFTD and 225 age- and magnetic resonance imaging-matched control individuals from 3 centers were collected from December 1, 1998, to September 30, 2019. One hundred twenty-one participants with bvFTD had high confidence of frontotemporal lobar degeneration (FTLD) (bvFTD-HC), and 19 had low confidence of FTLD (bvFTD-LC). Blinded clinicians applied 6 previously validated VAS, and the MRPI was calculated with a fully automated approach. Cortical thickness and subcortical volumes were also measured for comparison. Data were analyzed from February 1 to June 30, 2020. The main outcomes of this study were bvFTD-HC or a neuropathological diagnosis of 4-repeat (4R) tauopathy and the clinical deterioration rate (assessed by longitudinal measurements of Clinical Dementia Rating Sum of Boxes). Measures of cerebral atrophy included VAS scores, the bvFTD atrophy score (sum of VAS scores in orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe, and frontal insula regions), the MRPI, and other computerized quantifications of cortical and subcortical volumes. The areas under the receiver operating characteristic curve (AUROC) were calculated for the differentiation of participants with bvFTD-HC and bvFTD-LC and controls. Linear mixed models were used to evaluate the ability of atrophy measures to estimate longitudinal clinical deterioration. Of the 460 included participants, 296 (64.3%) were men, and the mean (SD) age was 62.6 (11.4) years. The accuracy of the bvFTD atrophy score for the differentiation of bvFTD-HC from controls (AUROC, 0.930; 95% CI, 0.903-0.957) and bvFTD-HC from bvFTD-LC (AUROC, 0.880; 95% CI, 0.787-0.972) was comparable to computerized measures (AUROC, 0.973 [95% CI, 0.954-0.993] and 0.898 [95% CI, 0.834-0.962], respectively). The MRPI was increased in patients with bvFTD and underlying 4R tauopathies compared with other FTLD subtypes (14.1 [2.0] vs 11.2 [2.6] points; P < .001). Higher bvFTD atrophy scores were associated with faster clinical deterioration in bvFTD (1.86-point change in Clinical Dementia Rating Sum of Boxes score per bvFTD atrophy score increase per year; 95% CI, 0.99-2.73; P < .001). Based on these study findings, in bvFTD, VAS increased the diagnostic certainty of underlying FTLD, and the MRPI showed potential for the detection of participants with underlying 4R tauopathies. These widely available measures of atrophy can also be useful to estimate longitudinal clinical deterioration.

Novel tankyrase inhibitors suppress TDP-43 aggregate formation

Transactive response DNA-binding protein of 43 kDa (TDP-43) abnormally forms aggregates in certain subtypes of frontotemporal lobar degeneration (FTLD) and in amyotrophic lateral sclerosis (ALS). The pathological forms of TDP-43 have reported to be associated with poly(ADP-ribose) (PAR), which regulates the properties of these aggregates. A recent study has indicated that tankyrase, a member of the PAR polymerase (PARP) family, regulates pathological TDP-43 formation under conditions of stress, and tankyrase inhibitors suppress TDP-43 aggregate formation and cytotoxicity. Since we reported the development of tankyrase inhibitors that are more specific than conventional inhibitors, in this study, we examined their effects on the formation of TDP-43 aggregates in cultured cells. Time-lapse imaging showed that TDP-43 aggregates appeared in the nucleus within 30 min of treatment with sodium arsenite. Several tankyrase inhibitors suppressed the formation of aggregates and decreased the levels of the tankyrase protein. Immunohistochemical studies demonstrated that tankyrase was localized to neuronal cytoplasmic inclusions in the spinal cords of patients with ALS. Moreover, the tankyrase protein levels were significantly higher in the brains of patients with FTLD than in the brains of control subjects. These findings suggest that the inhibition of tankyrase activity protects against TDP-43 toxicity. Tankyrase inhibitors may be a potential treatment to suppress the progression of TDP-43 proteinopathies.

A Clinicopathologic Study of Movement Disorders in Frontotemporal Lobar Degeneration.

Despite the considerable overlap with atypical parkinsonism, a systematic characterization of the movement disorders associated with frontotemporal lobar degeneration (FTLD) is lacking. The aim of this study is to provide a detailed description of the phenomenology and neuropathologic correlations of movement disorders in FTLD. In this cohort study, movement disorder clinical data were retrospectively collected from medical records of consecutive patients with a postmortem diagnosis of FTLD from the Queen Square Brain Bank between January 2010 and December 2018. At postmortem, neurodegenerative pathologies were systematically evaluated following consensus criteria. Degeneration of the substantia nigra was assessed as a marker of presynaptic dopaminergic parkinsonism using semiquantitative methods. A total of 55 patients (35 men [64%]) were included with median (interquartile range) age at diagnosis of 58.8 (52.6-63.9) years and a disease duration of 9.6 (6.2-12.9) years. Movement disorders were present in 19 (35%) patients without differences among disease subtypes. The most common syndromes were parkinsonism (9 patients [16%]), usually as an additional late feature, and corticobasal syndrome (CBS, 7 patients [13%]), commonly as a presenting feature. Substantia nigra degeneration was present in 37 (67%) patients although it did not show a good clinical correlation with movement disorders. Those with Pick's disease showed milder substantia nigra degeneration and better response to levodopa. Movement disorders can present in all FTLD subtypes, more commonly as a late additional feature (parkinsonism) or as a presenting symptom (CBS). The underlying pathophysiology is complex and likely to involve structures outside the presynaptic striatonigral system. © 2020 International Parkinson and Movement Disorder Society.

Aggresome formation and liquid\u2013liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43

Cytoplasmic inclusion of TAR DNA-binding protein 43 (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and a subtype of frontotemporal lobar degeneration (FTLD). Recent studies have suggested that the formation of cytoplasmic TDP-43 aggregates is dependent on a liquid–liquid phase separation (LLPS) mechanism. However, it is unclear whether TDP-43 pathology is induced through a single intracellular mechanism such as LLPS. To identify intracellular mechanisms responsible for TDP-43 aggregation, we established a TDP-43 aggregation screening system using a cultured neuronal cell line stably expressing EGFP-fused TDP-43 and a mammalian expression library of the inherited ALS/FTLD causative genes, and performed a screening. We found that microtubule-related proteins (MRPs) and RNA-binding proteins (RBPs) co-aggregated with TDP-43. MRPs and RBPs sequestered TDP-43 into the cytoplasmic aggregates through distinct mechanisms, such as microtubules and LLPS, respectively. The MRPs-induced TDP-43 aggregates were co-localized with aggresomal markers and dependent on histone deacetylase 6 (HDAC6), suggesting that aggresome formation induced the co-aggregation. However, the MRPs-induced aggregates were not affected by 1,6-hexanediol, an LLPS inhibitor. On the other hand, the RBPs-induced TDP-43 aggregates were sensitive to 1,6-hexanediol, but not dependent on microtubules or HDAC6. In sporadic ALS patients, approximately half of skein-like TDP-43 inclusions were co-localized with HDAC6, but round and granular type inclusion were not. Moreover, HDAC6-positive and HDAC6-negative inclusions were found in the same ALS patient, suggesting that the two distinct pathways are both involved in TDP-43 pathology. Our findings suggest that at least two distinct pathways (i.e., aggresome formation and LLPS) are involved in inducing the TDP-43 pathologies.

A Practical Approach to Differentiate the Frontotemporal Tauopathy Subtypes.

This study proposes a practical approach, using the minimum number of brain regions and stains, to consolidate previously published neuropathological criteria into one operationalized schema to differentiate subtypes of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau). This approach uses the superior frontal and precentral cortices and hippocampus stained for phosphorylated-tau, p62 and modified Bielschowsky silver, and the midbrain stained only for modified Bielschowsky silver. Accuracy of interrater reliability was determined by 10 raters in 24 FTLD-tau cases (Pick disease = 4, corticobasal degeneration = 9, progressive supranuclear palsy = 5, globular glial tauopathy = 6) including 4 with a mutation in MAPT collected with consent by Sydney Brain Bank. All brain regions and stains assessed proved informative for accurate pathological subtyping, and many neuropathological features were identified as common across the FTLD-tau subtypes. By identifying subtype-specific neuropathological features in the sections selected, 10 independent observers assigned the cases to a FTLD-tau subtype with almost perfect agreement between raters, emphasizing the requirement for the assessment of subtype-specific features for the accurate subtyping of FTLD-tau. This study consolidates current consensus diagnostic criteria for classifying FTLD-tau subtypes with an efficient, simple and accurate approach that can be implemented in future clinicopathological studies.

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

BackgroundMicroglial dysfunction is implicated in frontotemporal lobar degeneration (FTLD). Although studies have reported excessive microglial activation or senescence (dystrophy) in Alzheimer’s disease (AD), few have explored this in FTLD. We examined regional patterns of microglial burden, activation and dystrophy in sporadic and genetic FTLD, sporadic AD and controls.MethodsImmunohistochemistry was performed in frontal and temporal grey and white matter from 50 pathologically confirmed FTLD cases (31 sporadic, 19 genetic: 20 FTLD-tau, 26 FTLD-TDP, four FTLD-FUS), five AD cases and five controls, using markers to detect phagocytic (CD68-positive) and antigen-presenting (CR3/43-positive) microglia, and microglia in general (Iba1-positive). Microglial burden and activation (morphology) were assessed quantitatively for each microglial phenotype. Iba1-positive microglia were assessed semi-quantitatively for dystrophy severity and qualitatively for rod-shaped and hypertrophic morphology. Microglia were compared in each region between FTLD, AD and controls, and between different pathological subtypes of FTLD, including its main subtypes (FTLD-tau, FTLD-TDP, FTLD-FUS), and subtypes of FTLD-tau, FTLD-TDP and genetic FTLD. Microglia were also compared between grey and white matter within each lobe for each group.ResultsThere was a higher burden of phagocytic and antigen-presenting microglia in FTLD and AD cases than controls, but activation was often not increased. Burden was generally higher in white matter than grey matter, but activation was greater in grey matter. However, microglia varied regionally according to FTLD subtype and disease mechanism. Dystrophy was more severe in FTLD and AD than controls, and more severe in white than grey matter, but this also varied regionally and was particularly extensive in FTLD due to progranulin (GRN) mutations. Presence of rod-shaped and hypertrophic microglia also varied by FTLD subtype.ConclusionsThis study demonstrates regionally variable microglial involvement in FTLD and links this to underlying disease mechanisms. This supports investigation of microglial dysfunction in disease models and consideration of anti-senescence therapies in clinical trials.

Comparison of Prodromal Symptoms of Patients with Behavioral Variant Frontotemporal Dementia and Alzheimer Disease

Introduction: Behavioral variant frontotemporal dementia (bvFTD) is the most common clinical subtype of frontotemporal lobar degeneration. bvFTD is often characterized by changes in behavior and personality, frequently leading to psychiatric misdiagnoses. On the other hand, substantial clinical overlap with other neurodegenerative diseases, such as Alzheimer disease (AD), further complicates the diagnostics. Objective: Our aim was to identify the main differences in early symptoms of bvFTD and AD in the prodromal stages of the diseases. In addition, patients with bvFTD were analyzed separately according to whether they carry the C9orf72repeat expansion or not. Methods: Patient records of bvFTD (n = 75) and AD (n = 83) patients were analyzed retrospectively for memory and neuropsychiatric symptoms, sleeping disorders, and somatic complaints before the setting of the accurate diagnosis. Results: A total of 84% of bvFTD patients (n = 63) and 98.8% of AD patients (n = 82) reported subjective memory disturbances in the prodromal phases of the disease. bvFTD patients presented significantly more often with sleeping disorders, headache, inexplicable collapses, transient loss of consciousness, somatization, delusions, and hallucinations, suicidality, changes in oral behaviors, and urinary problems. In addition, poor financial judgement was frequently detected in patients with prodromal bvFTD. Aberrant sensations in the nose and throat without any physical explanation, regarded as somatizations, emerged only in bvFTD patients with the C9orf72 repeat expansion. Conclusions: Subjective reporting of impaired episodic memory is a poor indicator in differentiating bvFTD from AD. Sleeping disturbances, delusions, hallucinations, and unexplained somatic complaints in a patient with cognitive disturbances should prompt the clinicians to consider bvFTD as a possible diagnostic option behind these symptoms. The spectrum of symptoms in the prodromal stages of bvFTD may be more diverse than the latest criteria suggest.

Coping and Supporting Patients and Families of Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) is a comprehensive term encompassing a group of clinically overlapping but heterogeneous conditions with selective frontal and temporal lobar neurodegeneration. Among the three clinical subtypes of FTLD, behavioral variant frontotemporal dementia (bvFTD) and semantic dementia (SD) were specified as "designated intractable diseases" by the Japanese Ministry of Health, Labor and Welfare in 2015. Under this designation system, relatively young patient with bvFTD or SD of certain severities can receive partial financial support from the Japanese local government. Here we introduce financial and social support for FTLD, including utilization of the designated intractable disease system and other support available in Japan. In addition, we describe the methods for coping and care of prominent symptoms in FTLD. Lastly, we address the current status of a nationwide Japanese FTLD study cohort named FTLD-J.

Pick's disease: clinicopathologic characterization of 21 cases.

Pick's disease (PiD) is a unique subtype of frontotemporal lobar degeneration characterized pathologically by aggregates of 3-Repeat tau. Few studies have examined the clinical variability and disease progression in PiD. We describe the clinical features, neuropsychological profiles and coexistent pathologies in 21 cases of autopsy-confirmed PiD. This study was a retrospective analysis of patients with Pick's disease evaluated at Mayo Clinic, Rochester or Jacksonville (1995-2018), and identified through an existing database. Twenty-one cases with sufficient clinical data were identified. Behavioral variant FTD (bvFTD; 12/21) was the most common phenotype, followed by primary progressive aphasia (PPA; 7/21), corticobasal syndrome (CBS; 1/21) and amnestic dementia (1/21). Median age at disease onset was 54years, with PPA cases (median = 52years) presenting earlier than bvFTD (median = 59). Median disease duration (onset-death) overall was 10years and did not differ significantly between bvFTD (median = 9.5years) and PPA (median = 13). Age at death was not significantly different in PPA (median = 66) compared to bvFTD (median = 68.5). A third of the cases (n = 7/21) demonstrated pure PiD pathology, while the remainder showed co-existent other pathologies including Alzheimer's type (n = 6), cerebral amyloid angiopathy (n = 3), combined Alzheimer's and amyloid angiopathy (n = 4), and Lewy body disease (n = 1). Our study shows that bvFTD and PPA are the most common clinical phenotypes associated with PiD, although rare presentations such as CBS were also seen. Coexisting non-Pick's pathology was also present in many cases. Our study highlights the clinical and pathologic heterogeneity in PiD.