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Alzheimer's disease (AD) brains are characterized by amyloidβ-containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles (NFT5); however, in frontotemporal dementia, the tau pathology manifests in the absence of overt amyloid-fi plaques. Therapeutic strategies so far have primarily been targeting amyloid-β, although those targeting tau are only slowly beginning to emerge. Here, we identify sodium selenate as a compound that reduces tau phosphorylation both in vitro and in vivo. Importantly, chronic oral treatment of two independent tau transgenic mouse strains with NFT pathology. P301L mutant pR5 and K3691 mutant 1(3 mice, reduces tau hyperphosphorylation and completely abrogates NFT formation. Furthermore, treatment improves contextual memory and motor performance, and prevents neurodegeneration. As hyperphosphorylation of tau precedes NFT formation, the effect of selenate on tau phosphorylation was assessed in more detail, a process regulated by both kinases and phosphatases. A major phosphatase implicated in tau dephosphorylation is the serine/threonine-specific protein phosphatase 2A (PP2A) that is educed in both levels and activity in the AD brain. We found that selenate stabilizes PP2A-tau complexes. Moreover, there was an absence of therapeutic effects in sodium selenate-treated tau transgenic mice that coexpress a dominant-negative mutant form of PP2A, suggesting a mediating role for PP2A. Taken together, sodium selenate mitigates tau pathology in several AD models, making it a promising lead compound for tau-targeted treatments of AD and related dementias. [ABSTRACT FROM AUTHOR]

Frontotemporal lobar degeneration (FTLD) is a common cause of presenile dementia characterised by behavioural and language disturbances. Pick’s disease (PiD) is a subtype of FTLD, which presents with intraneuronal inclusions consisting of hyperphosphorylated tau protein aggregates. Although Alzheimer’s disease (AD) is also characterised by tau lesions, these are both histologically and biochemically distinct from the tau aggregates found in PiD. What determines the distinct characteristics of these tau lesions is unknown. As phosphorylated, soluble tau has been suggested to be the precursor of tau aggregates, we compared both the level and phosphorylation profile of tau in tissue extracts of AD and PiD brains to determine whether the differences in the tau lesions are reflected by differences in soluble tau. Levels of soluble tau were decreased in AD but not PiD. In addition, soluble tau was phosphorylated to a greater extent in AD than in PiD and displayed a different phosphorylation profile in the two disorders. Consistently, tau kinases were activated to different degrees in AD compared with PiD. Such differences in solubility and phosphorylation may contribute, at least in part, to the formation of distinct tau deposits, but may also have implications for the clinical differences between AD and PiD. [ABSTRACT FROM AUTHOR]

Understanding the relationship between the structural and functional organization of the human brain is one of the most important goals of neuroscience. Individual variability in brain structure means that it is essential to obtain this information from the same subject. To date, this has been almost impossible. Even though noninvasive functional imaging techniques such as functional MRI (fMRI) are now commonplace, there is no complementary noninvasive structural technique. We present an in vivo method of examining the detailed neuroanatomy of any individual, which can then be correlated with that individual's own functional results. This method utilizes high-resolution structural MRI to identify distinct cortical regions based on cortical lamination structure. We demonstrate that the observed MR lamination patterns relate to myeloarchitecture through a correlation of histology with MRI. In vivo high-resolution MRI studies identify striate cortex, as well as visual area V5, in four individuals, as defined by using fMRI. The anatomical identification of a cortical area (V5/MT) outside of striate cortex is a significant advance, proving it possible to identify extra-striate cortical areas and demonstrating that in vivo structural mapping of the human cerebral cortex is possible. [ABSTRACT FROM AUTHOR]

The coronal thickness of the corpus callosum in alcoholics and age- and sex-matched controls was measured in a postmortem study. The alcoholics were found to have a significantly (p<0.001) reduced corpus callosal thickness (3.19 mm) when compared w the controls (4.02 mm). This adds weight to the previous pathological finding of reduced white matter volume in alcoholics, which presumably correlates with brain shrinkage seen on CT scans. A significant linear relationship exists between age and the corpus callosal thickness in controls and the white matter volume and corpus callosal thickness in alcoholics. [ABSTRACT FROM AUTHOR]

The article focuses on the need to understand the relationship between dementia neuropathology and age. It notes that a body of medical literature implies that the link between Alzheimer's disease (AD)-type pathology and dementia does not apply in people above 95 years of age. It examines the results of a study on the impact of age on the association between AD-type pathology and dementia which suggests that the capability to predict dementia based on neurofibrillary tangle (NFT) and neuritic plaque (NP) densities decreases among people beyond 70 years.

Aims: Although the orally available brain‐penetrant copper compound CuATSM has demonstrated promising effects in SOD1‐linked mouse models, the impact of CuATSM on disease pathology in patients with amyotrophic lateral sclerosis (ALS) remains unknown. Methods: The present study set out to address this deficit by performing the first pilot comparative analysis of ALS pathology in patients that had been administered CuATSM and riluzole [N = 6 cases composed of ALS‐TDP (n = 5) and ALS‐SOD1 (n = 1)] versus riluzole only [N = 6 cases composed of ALS‐TDP (n = 4) and ALS‐SOD1 (n = 2)]. Results: Our results revealed no significant difference in neuron density or TDP‐43 burden in the motor cortex and spinal cord of patients that had received CuATSM compared with patients that had not. In patients that had received CuATSM, p62‐immunoreactive astrocytes were observed in the motor cortex and reduced Iba1 density was found in the spinal cord. However, no significant difference in measures of astrocytic activity and SOD1 immunoreactivity was found with CuATSM treatment. Discussion: These findings, in this first postmortem investigation of patients with ALS in CuATSM trials, demonstrate that in contrast to that seen in preclinical models of disease, CuATSM does not significantly alleviate neuronal pathology or astrogliosis in patients with ALS. [ABSTRACT FROM AUTHOR]

Astrocytes are a major class of glial cell in the central nervous system that have a diverse range of types and functions thought to be based on their anatomical location, morphology and cellular properties. Recent studies highlight that astrocyte dysfunction contributes to the pathogenesis of neurological conditions. However, few studies have described the pattern, distribution and density of astrocytes in the adult human cortex. This study mapped the distribution and density of astrocytes immunolabelled with a range of cytoskeletal and membrane markers in the human frontal cortex. Distinct and overlapping astrocyte populations were determined. The frontal cortex from ten normal control cases (75 ± 9 years) was immunostained with glial fibrillary acidic protein (GFAP), aldehyde dehydrogenase-1 L1 (ALDH1L1), connexin-43 (Cx43), aquaporin-4 (AQP4), and glutamate transporter 1 (GLT-1). All markers labelled populations of astrocytes in the grey and white matter, separate cortical layers, subpial and perivascular regions. All markers were informative for labelling different cellular properties and cellular compartments of astrocytes. ALDH1L1 labelled the largest population of astrocytes, and Cx43-immunopositive astrocytes were found in all cortical layers. AQP4 and GLT-1 labelled distal astrocytic process and end-feet in the same population of astrocytes (98% of GLT-1-immunopositive astrocytes contained AQP4). In contrast, GFAP, the most widely used marker, predominantly labelled astrocytes in superficial cortical layers. This study highlights the diversity of astrocytes in the human cortex, providing a reference map of the distribution of distinct and overlapping astrocyte populations which can be used for comparative purposes in various disease, inflammatory and injury states involving astrocytes. [ABSTRACT FROM AUTHOR]

Early reports of cognitive and behavioural deficits in motor neuron disease might have been overlooked initially, but the concept of a frontotemporal dementia-motor neuron disease continuum has emerged during the past decade. Frontotemporal dementia-motor neuron disease is now recognised as an important dementia syndrome, which presents substantial challenges for diagnosis and management. Frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease are characterised by overlapping patterns of TAR DNA binding protein (TDP-43) pathology, while the chromosome 9 open reading frame 72 (C9orf72) repeat expansion is common across the disease spectrum. Indeed, the C9orf72 repeat expansion provides important clues to disease pathogenesis and suggests potential therapeutic targets. Variable diagnostic criteria identify motor, cognitive, and behavioural deficits, but further refinement is needed to define the clinical syndromes encountered in frontotemporal dementia-motor neuron disease. [ABSTRACT FROM AUTHOR]

Episodic memory is relatively preserved in semantic dementia, despite hippocampal atrophy. Tan et al. investigate structural degeneration in key components of the Papez memory circuit, and suggest that preservation of crucial relays (hippocampus→mammillary bodies and posterior cingulate→hippocampus) underlies the conservation of episodic memory observed in most patients with semantic dementia.Despite accruing evidence for relative preservation of episodic memory in the semantic variant of primary progressive aphasia (previously semantic dementia), the neural basis for this remains unclear, particularly in light of their well-established hippocampal involvement. We recently investigated the Papez network of memory structures across pathological subtypes of behavioural variant frontotemporal dementia and demonstrated severe degeneration of all relay nodes, with the anterior thalamus in particular emerging as crucial for intact episodic memory. The present study investigated the status of key components of Papez circuit (hippocampus, mammillary bodies, anterior thalamus, cingulate cortex) and anterior temporal cortex using volumetric and quantitative cell counting methods in pathologically-confirmed cases with semantic variant of primary progressive aphasia (n = 8; 61–83 years; three males), behavioural variant frontotemporal dementia with TDP pathology (n = 9; 53–82 years; six males) and healthy controls (n = 8, 50–86 years; four males). Behavioural variant frontotemporal dementia cases with TDP pathology were selected because of the association between the semantic variant of primary progressive aphasia and TDP pathology. Our findings revealed that the semantic variant of primary progressive aphasia and behavioural variant frontotemporal dementia show similar degrees of anterior thalamic atrophy. The mammillary bodies and hippocampal body and tail were preserved in the semantic variant of primary progressive aphasia but were significantly atrophic in behavioural variant frontotemporal dementia. Importantly, atrophy in the anterior thalamus and mild progressive atrophy in the body of the hippocampus emerged as the main memory circuit regions correlated with increasing dementia severity in the semantic variant of primary progressive aphasia. Quantitation of neuronal populations in the cingulate cortices confirmed the selective loss of anterior cingulate von Economo neurons in behavioural variant frontotemporal dementia. We also show that by end-stage these neurons selectively degenerate in the semantic variant of primary progressive aphasia with preservation of neurons in the posterior cingulate cortex. Overall, our findings demonstrate for the first time, severe atrophy, although not necessarily neuronal loss, across all relay nodes of Papez circuit with the exception of the mammillary bodies and hippocampal body and tail in the semantic variant of primary progressive aphasia. Despite the longer disease course in the semantic variant of primary progressive aphasia compared with behavioural variant frontotemporal dementia, we suggest here that the neural preservation of crucial memory relays (hippocampal→mammillary bodies and posterior cingulate→hippocampus) likely reflects the conservation of specific episodic memory components observed in most patients with semantic variant of primary progressive aphasia. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia refers to a group of neurodegenerative disorders characterized by behaviour and language alterations and focal brain atrophy. Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by loss of motor neurons resulting in muscle wasting and paralysis. Frontotemporal dementia and amyotrophic lateral sclerosis are considered to exist on a disease spectrum given substantial overlap of genetic and molecular signatures. The predominant genetic abnormality in both frontotemporal dementia and amyotrophic lateral sclerosis is an expanded hexanucleotide repeat sequence in the C9orf72 gene. In terms of brain pathology, abnormal aggregates of TAR-DNA-binding protein-43 are predominantly present in frontotemporal dementia and amyotrophic lateral sclerosis patients. Currently, sensitive and specific diagnostic and disease surveillance biomarkers are lacking for both diseases. This has impeded the capacity to monitor disease progression during life and the development of targeted drug therapies for the two diseases. The purpose of this review is to examine the status of current biofluid biomarker discovery and development in frontotemporal dementia and amyotrophic lateral sclerosis. The major pathogenic proteins implicated in different frontotemporal dementia and amyotrophic lateral sclerosis molecular subtypes and proteins associated with neurodegeneration and the immune system will be discussed. Furthermore, the use of mass spectrometry-based proteomics as an emerging tool to identify new biomarkers in frontotemporal dementia and amyotrophic lateral sclerosis will be summarized. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3θ levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3θ, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3θ for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already symptomatic at the time of treatment. Our study identified 14-3-3θ as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy. [Display omitted] • 14-3-3θ interacts preferentially with pathogenic TDP-43 • Increased neuronal levels of the cytoplasmic 14-3-3θ promote TDP-43 pathology • Degron-mediated reduction of pathogenic TDP-43 improved ALS/FTD models TDP-43 forms neuronal deposits in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) due to unknown causes. Ke et al. identified the TDP-43 interactor 14-3-3θ, which promotes TDP-43 deposition. They devised a treatment harnessing 14-3-3θ's affinity for TDP-43, mitigating deficits and neurodegeneration in ALS/FTD models with implications for future therapy. [ABSTRACT FROM AUTHOR]

Neuronal loss and gliosis were observed in most regions examined, and were most prominent in the superior frontal, inferior temporal and anterior cingulate cortices, caudate nucleus, amygdala, substantia nigra and locus coeruleus. The formalin-fixed brain (1175 g) revealed frontotemporal atrophy, white matter loss, lateral ventricle dilatation and flattening of the caudate nucleus. The fourth, a patient with sporadic GGT Type I with widespread TDP-43 neuronal and oligodendroglial pathology, which had similar regional distribution as tau pathology [[6]]. Two additional GGT patients (Type III) with mutations in I MAPT i are held by Sydney Brain Bank [[3]] and coexisting TDP-43 pathology consistent with LATE stage 2 was found in one with a P301L mutation. [Extracted from the article]

Tau pathology in Alzheimer's disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The 'early' AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that are considered to be on the same disease spectrum because of overlapping genetic, pathological and clinical traits. Changes in serum proteins in FTD and ALS are poorly understood, and currently no definitive biomarkers exist for diagnosing or monitoring disease progression for either disease. Here we applied quantitative discovery proteomics to analyze protein changes in FTD (N = 72) and ALS (N = 28) patient serum compared to controls (N = 22). Twenty three proteins were significantly altered in FTD compared to controls (increased—APOL1, C3, CTSH, EIF5A, MYH2, S100A8, SUSD5, WDR1; decreased—C1S, C7, CILP2, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, IGHV1, ITIH2, PROS1, SHBG, UMOD, VASN) and 14 proteins were significantly altered in ALS compared to controls (increased—APOL1, CKM, CTSH, IGHG1, IGKC, MYH2; decreased—C7, COMP, CRTAC1, EFEMP1, FBLN1, GSN, HSPG2, SHBG). There was substantial overlap in the proteins that were altered in FTD and ALS. These results were validated using western blotting. Gene ontology tools were used to assess functional pathways potentially dysregulated in the two diseases, and calcium ion binding and innate immunity pathways were altered in both diseases. When put together, these results suggest significant overlap in pathophysiological peripheral changes in FTD and ALS. This study represents the first proteomics side-by-side comparison of serum changes in FTD and ALS, providing new insights into under-recognized perturbed pathways and an avenue for biomarker development for FTD and ALS. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders with different pathological signatures, genetic variability and complex disease mechanisms, for which no effective treatments exist. Despite advances in understanding the underlying pathology of FTD, sensitive and specific fluid biomarkers for this disease are lacking. As in other types of dementia, mounting evidence suggests that neuroinflammation is involved in the progression of FTD, including cortical inflammation, microglial activation, astrogliosis and differential expression of inflammation-related proteins in the periphery. Furthermore, an overlap between FTD and autoimmune disease has been identified. The most substantial evidence, however, comes from genetic studies, and several FTD-related genes are also implicated in neuroinflammation. This Review discusses specific evidence of neuroinflammatory mechanisms in FTD and describes how advances in our understanding of these mechanisms, in FTD as well as in other neurodegenerative diseases, might facilitate the development and implementation of diagnostic tools and disease-modifying treatments for FTD. [ABSTRACT FROM AUTHOR]

Background: Chronic alcohol use disorders (AUD) are associated with white matter (WM) degeneration with altered myelin integrity. Matrix assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) enables high throughput analysis of myelin lipid biochemical histopathology to help characterize disease mechanisms.Purpose: This study utilized MALDI-IMS to investigate frontal lobe WM myelin lipid abnormalities in AUD.Methods: Standardized cores of formalin-fixed WM from Brodmann Area 4 (BA4) and BA8/9 of 20 postmortem AUD and 19 control adult human brains were embedded in carboxymethyl-cellulose, cryo-sectioned (8 μm), thaw-mounted onto indium tin oxide (ITO) -coated glass slides, and sublimed with 2,5-dihydroxybenzxoic acid (DHB) matrix. Lipids were imaged by MALDI-time of flight in the negative ionization mode. Data were visualized with FlexImaging software v4.0 and analyzed with ClinProTools v3.0.Results: Principal component analysis (PCA) and data bar plots of MALDI-IMS data differentiated AUD from control WM. The dominant effect of AUD was to broadly reduce expression of sphingolipids (sulfatides and ceramides) and phospholipids. Data bar plots demonstrated overall similar responses to AUD in BA4 and BA8/9. However, differential regional effects of AUD on WM lipid profiles were manifested by non-overlapping expression or discordant responses to AUD for a subset of lipid ions.Conclusions: Human AUD is associated with substantial inhibition of frontal lobe WM lipid expression with regional variability in these effects. MALDI-IMS can be used to characterize the nature of AUD-associated lipid biochemical abnormalities for correlation with lifetime exposures and WM degeneration, altered gene expression, and responses to abstinence or treatment. [ABSTRACT FROM AUTHOR]

Correction to: I Scientific Reports i https://doi.org/10.1038/s41598-021-83872-z, published online 01 March 2021 The original version of this Article contained an error in the Data availability section, where the link to the raw data in the Sequence Read Archive (NCBI-SRA) was incorrect. All summary data generated in this study are included in this published article (and supplementary information files). [Extracted from the article]

Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients. [ABSTRACT FROM AUTHOR]

Primary progressive aphasia (PPA) comprises a heterogeneous group of neurodegenerative conditions that can be classified in three cliniconeuroanatomic syndromes. Limited information exists, however, about patterns of neuropathologic spreading and microscopic changes underpinning each syndrome. We performed an analysis of a longitudinal in vivo cohort and a postmortem PPA cohort to investigate neurodegeneration over time and to quantify microscopic changes in key language brain areas. The longitudinal analyses demonstrated distinctive patterns of topological extension of brain atrophy. Although semantic variant (sv-PPA) showed an eccentric pattern, nonfluent and/or agrammatic (nfv-PPA) and logopenic (lv-PPA) variants showed additional multifocal extension. The quantitative pathology showed that sv-PPA had neuronal loss and thinning in BA 38, whereas nfv-PPA showed thinning in BA 44/45 and evidence of microscopic involvement in BA 40/22. Although lv-PPA showed neuronal loss focused on BA 40/22, imaging results demonstrated widespread left-sided brain atrophy. These analyses provide an account of the pathologic process whereby each variant has stereotypical patterns of brain atrophy extension, which is largely determined by the specific pathologic type. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of new clinical diagnostic criteria for frontotemporal dementia (FTD) syndromes, including primary progressive aphasias (PPA), on prior clinical diagnosis and to explore clinicopathological correlations. Methods: 178 consecutive neuropathologically ascertained cases initially diagnosed with a FTD syndrome were collected through specialist programmes: the Cambridge Brain Bank, UK, and Sydney Brain Bank, Australia. 135 cases were reclassified using the revised diagnostic criteria into behavioural variant (bvFTD), semantic variant PPA (sv-PPA), non-fluent/agrammatic variant PPA (nfv-PPA) and logopenic variant PPA (lv-PPA). Pathological diagnoses included FTLD-tau, FTLDTDP, FTLD-FUS, FTLD-UPS, FLTD-ni and Alzheimer's disease (AD). Statistical analyses included X² tests, analyses of variance and discriminant statistics. Results: Comparison of the original and revised diagnosis revealed no change in 90% of bvFTD and sv- PPA cases. By contrast, 51% of nfv-PPA cases were reclassified as lv-PPA, with apraxia of speech and sentence repetition assisting in differentiation. Previous patterns of pathology were confirmed, although more AD cases occurred in FTD syndromes (10% bvFTD, ~ 1 5 % sv-PPA and ~ 3 0 % nfv-PPA) than expected. AD was the dominant pathology (77%) of lv-PPA. Discriminant analyses revealed that object agnosia, phonological errors and neuropsychiatric features differentiated AD from FTLD. Conclusions: This study provides pathological validation that the new criteria assist with separating PPA cases with AD pathology into the new lv-PPA syndrome and found that a number of diagnostic clinical features (disinhibition, food preferences and naming) did not assist in discriminating the different FTD syndromes. [ABSTRACT FROM AUTHOR]

Abstract: Semantic dementia (SD) is a syndrome of progressive impairment in semantic memory. Fifty-eight brain regions were measured in seven post mortem SD cases, ten normal controls and two disease controls (diagnosis frontotemporal dementia and motor neuron disease, FTD–MND). Manual segmentation of the whole brain has not previously been undertaken in a series of SD cases, either post mortem or during life. Widespread volume loss relative to controls was found in SD, with anterior temporal lobe regions bearing the brunt (>60% atrophy of temporopolar and perirhinal cortices bilaterally). Comparison of regional volumes in SD and FTD–MND found greater atrophy in SD only in temporopolar and perirhinal volumes. The sole region showing atrophy relative to controls in FTD–MND but not SD was motor cortex. Posterior temporal and frontal regions were not consistently affected and no significant asymmetry of atrophy was found. In summary, whole-brain regional evaluation in SD, in comparison with normal controls and FTD–MND, found anterior temporal atrophy encompassing the perirhinal cortex with relative sparing of adjacent posterior temporal regions. [Copyright &y& Elsevier]

Behavioral variant frontotemporal dementia (bvFTD) is a younger onset form of neurodegeneration initiated in the frontal and/or temporal lobes with a slow clinical onset but rapid progression. bvFTD is highly complex biologically with different pathological signatures and genetic variants that can exhibit a spectrum of overlapping clinical manifestations. Although the role of innate immunity has been extensively investigated in bvFTD, the involvement of adaptive immunity in bvFTD pathogenesis is poorly understood. We analyzed blood serum proteomics to identify proteins that are associated with autoimmune disease in bvFTD. Eleven proteins (increased: ATP5B, CALML5, COLEC11, FCGBP, PLEK, PLXND1; decreased: APOB, ATP8B1, FAM20C, LOXL3, TIMD4) were significantly altered in bvFTD with autoimmune disease compared to those without autoimmune disease. The majority of these proteins were enriched for glycoprotein-associated proteins and pathways, suggesting that the glycome is targeted in bvFTD with autoimmune disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bright, Katzeff, Hodges, Piguet, Kril, Halliday and Kim.)

Importance: Globular glial tauopathies (GGTs), as defined by a consensus study in 2013, belong to the group of frontotemporal lobar degenerations and expand the spectrum of glial-predominant neurodegenerative diseases. Three neuropathological subtypes of GGT (types I-III) are characterized by phosphorylated tau-immunopositive inclusions that are predominantly in oligodendroglia and/or astroglia in the frontal, temporal, and/or precentral cortices. Type II is largely restricted to the corticospinal system. The low incidence of GGT (<10% of cases of frontotemporal lobar degeneration with tau pathology), together with its unusual combination of neuronal and nonneuronal pathology, has hindered identification and accurate diagnosis. This review collated clinical, demographic, neuropathological, and genetic data from 88 published GGT cases identified on PubMed to examine the association between GGT and frontotemporal dementia and associated disorders., Observations: Among 88 patients with GGT (46 female [52.3%]; mean [SD] age at disease onset, 65 [11] years), 44 patients (50.0%) had idiopathic disease, and 21 patients (23.9%) had a variation in the microtubule-associated protein tau (MAPT) gene. Those with idiopathic GGT compared with those with a variation in MAPT had a mean (SD) age at symptom onset of 70 (8) years vs 54 (9) years and a mean (SD) disease duration of 7 (3) years vs 6 (3) years, respectively. A similar sex distribution was observed among patients with GGT; however, female patients were typically 6 years older at symptom onset than male patients (mean [SD] age, 68 [11] years vs 62 [11] years, respectively). Disease duration was similar in both sexes (mean [SD], 6 [3] years for women and 6 [4] years for men). The most common predominant clinical features were primary progressive aphasia (22 patients [25.0%]), behavioral-variant frontotemporal dementia (20 patients [22.7%]), upper motor neuron signs (11 patients [12.5%]), memory impairment (7 patients [8.0%]), and Richardson syndrome (7 patients [8.0%]). Although some demographic differences between GGT subtypes were identified, the predictive value of the clinical presentation was low, calling into question the need for neuropathological subtyping. Further neuropathological studies are needed to clarify whether GGT type II should be interpreted as atypical progressive supranuclear palsy or a separate entity. Few cases (7 patients [8.0%]) had coexisting proteinopathies., Conclusions and Relevance: This review of the published data suggests an association between regional distribution of glial tau pathology and neuronal degeneration. Targeting glial tau accumulation or sustaining their neuron-supportive function might require different therapeutic or neuroprotective strategies and more accurate preclinical models to explore disease mechanisms and track progression. Emerging data support the important role of glia in the pathogenesis of neurodegenerative disorders, highlighting the need to raise awareness of GGT in clinical and research settings.

The frontotemporal tauopathies all deposit abnormal tau protein aggregates, but often of only certain isoforms and in distinguishing pathologies of five main types (neuronal Pick bodies, neurofibrillary tangles, astrocytic plaques, tufted astrocytes, globular glial inclusions and argyrophilic grains). In those with isoform specific tau aggregates glial pathologies are substantial, even though there is limited evidence that these cells normally produce tau protein. This review will assess the differentiating features and clinicopathological correlations of the frontotemporal tauopathies, the genetic predisposition for these different pathologies, their neuroanatomical selectivity, current observations on how they spread through the brain, and any potential contributing cellular and molecular changes. The findings show that diverse clinical phenotypes relate most to the brain region degenerating rather than the type of pathology involved, that different regions on the MAPT gene and novel risk genes are associated with specific tau pathologies, that the 4-repeat glial tauopathies do not follow individual patterns of spreading as identified for neuronal pathologies, and that genetic and pathological data indicate that neuroinflammatory mechanisms are involved. Each pathological frontotemporal tauopathy subtype with their distinct pathological features differ substantially in the cell type affected, morphology, biochemical and anatomical distribution of inclusions, a fundamental concept central to future success in understanding the disease mechanisms required for developing therapeutic interventions. Tau directed therapies targeting genetic mechanisms, tau aggregation and pathological spread are being trialled, although biomarkers that differentiate these diseases are required. Suggested areas of future research to address the regional and cellular vulnerabilities in frontotemporal tauopathies are discussed.

Objective: To investigate the prevalence of clinically relevant multiple system atrophy (MSA) and Lewy body disease (LBD) pathologies in a large frontotemporal lobar degeneration (FTLD) cohort to determine if concomitant pathologies underlie the heterogeneity of clinical features., Methods: All prospectively followed FTLD-tau and FTLD-TDP cases held by the Sydney Brain Bank (n = 126) were screened for coexisting MSA and LBD (Braak ≥ stage IV) pathology. Relevant clinical (including family history) and genetic associations were determined., Results: MSA pathology was not identified in this series. Of the FTLD cohort, 9 cases had coexisting LBD ≥ Braak stage IV and were associated with different FTLD subtypes including Pick disease (n = 2), corticobasal degeneration (n = 2), progressive supranuclear palsy (n = 2), and TDP type A (n = 3). All FTLD-TDP cases with coexisting LBD had mutations in progranulin (n = 2) or an abnormal repeat expansion in C9orf72 (n = 1). All FTLD-tau cases with coexisting LBD were sporadic. The H1H1 MAPT haplotype was found in all cases that could be genotyped (n = 6 of 9). Seven cases presented with a predominant dementia disorder, 3 of which developed parkinsonism. Two cases presented with a movement disorder and developed dementia in their disease course. The age at symptom onset (62 ± 11 years) and disease duration (8 ± 5 years) in FTLD cases with coexisting LBD did not differ from pure FTLD or pure LBD cases in the brain bank., Conclusion: Coexisting LBD in FTLD comprises a small proportion of cases but has implications for clinical and neuropathologic diagnoses and the identification of biomarkers., (© 2019 American Academy of Neurology.)

Objective: To assess the incidence, heritability, and neuropathology of primary progressive aphasia (PPA) with amyotrophic lateral sclerosis (ALS) in a large Australian cohort., Methods: A total of 130 patients with a primary nonfluent variant of PPA (nfvPPA) or semantic variant of PPA (svPPA) were assessed for concomitant ALS and a strong family history of neurodegenerative diseases (Goldman score ≤3). Neuropathologic examination was carried out in 28% (n = 36) of these PPA and PPA-ALS cases that had come to autopsy., Results: ALS was identified in 18% of patients with nfvPPA and 5% of patients with svPPA. PPA-ALS but not PPA was found to have a strong family history. At autopsy, frontotemporal lobar degeneration (FTLD)-TDP was identified in 100% of nfvPPA-ALS cases, 100% of svPPA-ALS cases, 24% of nfvPPA cases, and 78% of svPPA cases. Clinicopathologic assessments revealed a significant association between a strong family history and underlying FTLD-TDP pathology. Pathogenic mutations in known frontotemporal dementia (FTD)/ALS genes were identified in 100% of these familial PPA cases but only 50% of familial PPA-ALS cases, suggesting the involvement of novel genetic variants in this underacknowledged phenotype., Conclusion: The present study identified ALS in 12% of a large cohort of patients with nfvPPA and svPPA, which is comparable to the 10%-15% reported in FTD overall, indicating that a third of patients with FTD-ALS will have a predominant language profile. These findings highlight the importance of assessing for ALS in PPA, particularly since this is the only PPA phenotype in which a perfect clinicopathologic association has been reported in to date., (© 2019 American Academy of Neurology.)

Introduction: Exploring the degree of heritability in a large cohort of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau) and determining if different FTLD-tau subtypes are associated with stronger heritability will provide important insight into disease pathogenesis., Methods: Using modified Goldman pedigree classifications, heritability was examined in pathologically proven FTLD-tau cases with dementia at any time (n = 124) from the Sydney-Cambridge collection., Results: Thirteen percent of the FTLD-tau cohort have a suggested autosomal dominant pattern of inheritance, 25% have some family history, and 62% apparently sporadic. MAPT mutations were found in 9% of cases. Globular glial tauopathy was associated with the strongest heritability with 40% having a suggested autosomal dominant pattern of inheritance followed by corticobasal degeneration (19%), Pick's disease (8%), and progressive supranuclear palsy (6%)., Discussion: Similar to clinical frontotemporal dementia syndromes, heritability varies between pathological subtypes. Further identification of a genetic link in cases with strong heritability await discovery.

Background: Subcortical small vessel disease and vascular risk factors are associated with motor and cognitive impairment. In this study we examined the relationship between these factors and the severity of motor impairment and dementia in pathologically-confirmed Parkinson's disease (PD)., Methods: The extent and severity of small vessel disease (SVD) was assessed pathologically in 77 patients with PD. The severity of motor impairment was determined using a cumulative index derived from longitudinal measures of Hoehn and Yahr score. The presence of dementia was scored using the Clinical Dementia Rating. The presence or absence of vascular risk factors and stroke were also recorded. Interactions were assessed using stepwise multiple regression analyses., Results: Significant correlations were demonstrated between perivascular pallor in the globus pallidus interna and the Hoehn and Yahr stage and between increasing Braak PD stage, the number of vascular risk factors and dementia. Among the vascular risk factors, hypertension was the only variable to independently correlate with dementia. SVD pathology did not correlate with dementia in our cohort., Conclusions: This study demonstrates an association between SVD and motor impairment, and between vascular risk factors, particularly hypertension, and dementia in PD and highlights the need to manage vascular co-morbidities in PD patients., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)