Publications by authors named "Tammaryn Lashley"

132 Publications

Structure-based classification of tauopathies.

Nature 2021 Oct 29;598(7880):359-363. Epub 2021 Sep 29.

MRC Laboratory of Molecular Biology, Cambridge, UK.

The ordered assembly of tau protein into filaments characterizes several neurodegenerative diseases, which are called tauopathies. It was previously reported that, by cryo-electron microscopy, the structures of tau filaments from Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration are distinct. Here we show that the structures of tau filaments from progressive supranuclear palsy (PSP) define a new three-layered fold. Moreover, the structures of tau filaments from globular glial tauopathy are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs, instead resembling the four-layered fold of corticobasal degeneration. The AGD fold is also observed in ageing-related tau astrogliopathy. Tau protofilament structures from inherited cases of mutations at positions +3 or +16 in intron 10 of MAPT (the microtubule-associated protein tau gene) are also identical to those from AGD, suggesting that relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, the structures of tau filaments from cases of familial British dementia and familial Danish dementia are the same as those from cases of Alzheimer's disease and primary age-related tauopathy. These findings suggest a hierarchical classification of tauopathies on the basis of their filament folds, which complements clinical diagnosis and neuropathology and also allows the identification of new entities-as we show for a case diagnosed as PSP, but with filament structures that are intermediate between those of globular glial tauopathy and PSP.
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http://dx.doi.org/10.1038/s41586-021-03911-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611841PMC
October 2021

The localization of amyloid precursor protein to ependymal cilia in vertebrates and its role in ciliogenesis and brain development in zebrafish.

Sci Rep 2021 Sep 27;11(1):19115. Epub 2021 Sep 27.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 41345, Gothenburg, Sweden.

Amyloid precursor protein (APP) is expressed in many tissues in human, mice and in zebrafish. In zebrafish, there are two orthologues, Appa and Appb. Interestingly, some cellular processes associated with APP overlap with cilia-mediated functions. Whereas the localization of APP to primary cilia of in vitro-cultured cells has been reported, we addressed the presence of APP in motile and in non-motile sensory cilia and its potential implication for ciliogenesis using zebrafish, mouse, and human samples. We report that Appa and Appb are expressed by ciliated cells and become localized at the membrane of cilia in the olfactory epithelium, otic vesicle and in the brain ventricles of zebrafish embryos. App in ependymal cilia persisted in adult zebrafish and was also detected in mouse and human brain. Finally, we found morphologically abnormal ependymal cilia and smaller brain ventricles in appaappb mutant zebrafish. Our findings demonstrate an evolutionary conserved localisation of APP to cilia and suggest a role of App in ciliogenesis and cilia-related functions.
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http://dx.doi.org/10.1038/s41598-021-98487-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476544PMC
September 2021

Amyloid pathology and synaptic loss in pathological aging.

J Neurochem 2021 Sep 2. Epub 2021 Sep 2.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline. Pathological aging (PA) describes patients who are amyloid-positive but cognitively unimpaired at time of death. Both AD and PA contain amyloid plaques dominated by amyloid β (Aβ) peptides. In this study, we investigated and compared synaptic protein levels, amyloid plaque load, and Aβ peptide patterns between AD and PA. Two cohorts of post-mortem brain tissue were investigated. In the first, consisting of controls, PA, AD, and familial AD (FAD) individuals, synaptic proteins extracted with tris(hydroxymethyl)aminomethane-buffered saline (TBS) were analyzed. In the second, consisting of tissue from AD and PA patients from three different regions (occipital lobe, frontal lobe, and cerebellum), a two-step extraction was performed. Five synaptic proteins were extracted using TBS, and from the remaining portion Aβ peptides were extracted using formic acid. Subsequently, immunoprecipitation with several antibodies targeting different proteins/peptides was performed for both fractions, which were subsequently analyzed by mass spectrometry. The levels of synaptic proteins were lower in AD (and FAD) compared with PA (and controls), confirming synaptic loss in AD patients. The amyloid plaque load was increased in AD compared with PA, and the relative amount of Aβ40 was higher in AD while for Aβ42 it was higher in PA. In AD loss of synaptic function was associated with increased plaque load and increased amounts of Aβ40 compared with PA cases, suggesting that synaptic function is preserved in PA cases even in the presence of Aβ.
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http://dx.doi.org/10.1111/jnc.15487DOI Listing
September 2021

Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease.

Brain Pathol 2021 Jul 28:e13009. Epub 2021 Jul 28.

The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre-codon 200 (n = 10), PSEN1 post-codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid-beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub-group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post-codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post-codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD.
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http://dx.doi.org/10.1111/bpa.13009DOI Listing
July 2021

Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease.

Acta Neuropathol 2021 10 28;142(4):689-706. Epub 2021 Jul 28.

Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.

Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here, we compared antemortem PiB PET with follow-up postmortem estimation of amyloid-β burden using stereologic methods to estimate the relative area fraction of diffuse and cored/compact amyloid-β plaques across 16 brain regions in 15 individuals with ADAD and 14 individuals with LOAD. In ADAD, we found that PiB PET correlated with diffuse plaques in the frontal, parietal, temporal, and striatal regions commonly used to summarize amyloid-β burden in PiB PET, and correlated with both diffuse and cored/compact plaques in the occipital lobe and parahippocampal gyrus. In LOAD, we found that PiB PET correlated with both diffuse and cored/compact plaques in the anterior cingulate, frontal lobe (middle frontal gyrus), and parietal lobe, and showed additional correlations with diffuse plaque in the amygdala and occipital lobe, and with cored/compact plaque in the temporal lobe. Thus, commonly used PiB PET summary regions predominantly reflect diffuse plaque burden in ADAD and a mixture of diffuse and cored/compact plaque burden in LOAD. In direct comparisons of ADAD and LOAD, postmortem stereology identified much greater mean amyloid-β plaque burdens in ADAD versus LOAD across almost all brain regions studied. However, standard PiB PET did not recapitulate these stereologic findings, likely due to non-trivial amyloid-β plaque burdens in ADAD within the cerebellum and brainstem-commonly used reference regions in PiB PET. Our findings suggest that PiB PET summary regions correlate with amyloid-β plaque burden in both ADAD and LOAD; however, they might not be reliable in direct comparisons of regional amyloid-β plaque burden between the two forms of AD.
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http://dx.doi.org/10.1007/s00401-021-02342-yDOI Listing
October 2021

Association of clusterin with the BRI2-derived amyloid molecules ABri and ADan.

Neurobiol Dis 2021 10 21;158:105452. Epub 2021 Jul 21.

Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

Familial British and Danish dementias (FBD and FDD) share striking neuropathological similarities with Alzheimer's disease (AD), including intraneuronal neurofibrillary tangles as well as parenchymal and vascular amyloid deposits. Multiple amyloid associated proteins with still controversial role in amyloidogenesis colocalize with the structurally different amyloid peptides ABri in FBD, ADan in FDD, and Aβ in AD. Genetic variants and plasma levels of one of these associated proteins, clusterin, have been identified as risk factors for AD. Clusterin is known to bind soluble Aβ in biological fluids, facilitate its brain clearance, and prevent its aggregation. The current work identifies clusterin as the major ABri- and ADan-binding protein and provides insight into the biochemical mechanisms leading to the association of clusterin with ABri and ADan deposits. Mirroring findings in AD, the studies corroborate clusterin co-localization with cerebral parenchymal and vascular amyloid deposits in both disorders. Ligand affinity chromatography with downstream Western blot and amino acid sequence analyses unequivocally identified clusterin as the major ABri- and ADan-binding plasma protein. ELISA highlighted a specific saturable binding of clusterin to ABri and ADan with low nanomolar Kd values within the same range as those previously demonstrated for the clusterin-Aβ interaction. Consistent with its chaperone activity, thioflavin T binding assays clearly showed a modulatory effect of clusterin on ABri and ADan aggregation/fibrillization properties. Our findings, together with the known multifunctional activity of clusterin and its modulatory activity on the complex cellular pathways leading to oxidative stress, mitochondrial dysfunction, and the induction of cell death mechanisms - all known pathogenic features of these protein folding disorders - suggests the likelihood of a more complex role and a translational potential for the apolipoprotein in the amelioration/prevention of these pathogenic mechanisms.
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http://dx.doi.org/10.1016/j.nbd.2021.105452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440498PMC
October 2021

HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing.

Acta Neuropathol 2021 10 18;142(4):609-627. Epub 2021 Jul 18.

The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.

Heterogeneous nuclear ribonucleoproteins (HnRNPs) are a group of ubiquitously expressed RNA-binding proteins implicated in the regulation of all aspects of nucleic acid metabolism. HnRNP K is a member of this highly versatile hnRNP family. Pathological redistribution of hnRNP K to the cytoplasm has been linked to the pathogenesis of several malignancies but, until now, has been underexplored in the context of neurodegenerative disease. Here we show hnRNP K mislocalisation in pyramidal neurons of the frontal cortex to be a novel neuropathological feature that is associated with both frontotemporal lobar degeneration and ageing. HnRNP K mislocalisation is mutually exclusive to TDP-43 and tau pathological inclusions in neurons and was not observed to colocalise with mitochondrial, autophagosomal or stress granule markers. De-repression of cryptic exons in RNA targets following TDP-43 nuclear depletion is an emerging mechanism of potential neurotoxicity in frontotemporal lobar degeneration and the mechanistically overlapping disorder amyotrophic lateral sclerosis. We silenced hnRNP K in neuronal cells to identify the transcriptomic consequences of hnRNP K nuclear depletion. Intriguingly, by performing RNA-seq analysis we find that depletion of hnRNP K induces 101 novel cryptic exon events. We validated cryptic exon inclusion in an SH-SY5Y hnRNP K knockdown and in FTLD brain exhibiting hnRNP K nuclear depletion. We, therefore, present evidence for hnRNP K mislocalisation to be associated with FTLD and for this to induce widespread changes in splicing.
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http://dx.doi.org/10.1007/s00401-021-02340-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423707PMC
October 2021

Discriminatory ability of next-generation tau PET tracers for Alzheimer's disease.

Brain 2021 Sep;144(8):2284-2290

Department of Imaging, Centre for Radiopharmaceutical Chemistry, University College London, London WC1E 6BS, UK.

A next generation of tau PET tracers for the imaging of Alzheimer's disease and other dementias has recently been developed. Whilst the new compounds have now entered clinical studies, there is limited information available to assess their suitability for clinical applications. Head-to-head comparisons are urgently needed to understand differences in the radiotracer binding profiles. We characterized the binding of the tau tracers PI2620, RO948, MK6240 and JNJ067 in human post-mortem brain tissue from a cohort of 25 dementia cases and age-matched controls using quantitative phosphorimaging with tritium-labelled radiotracers in conjunction with phospho-tau specific immunohistochemistry. The four radiotracers depicted tau inclusions composed of paired helical filaments with high specificity, both in cases with Alzheimer's disease and in primary tauopathy cases with concomitant Alzheimer's disease pathology. In contrast, cortical binding to primary tauopathy in cases without paired helical filament tau was found to be within the range of age-matched controls. Off-target binding to monoamine oxidase B has been overcome, as demonstrated by heterologous blocking studies in basal ganglia tissue. The high variability of cortical tracer binding within the Alzheimer's disease group followed the same pattern with each tracer, suggesting that all compounds are suited to differentiate Alzheimer's disease from other dementias.
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http://dx.doi.org/10.1093/brain/awab120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453387PMC
September 2021

A novel presenilin 1 duplication mutation (Ile168dup) causing Alzheimer's disease associated with myoclonus, seizures and pyramidal features.

Neurobiol Aging 2021 07 5;103:137.e1-137.e5. Epub 2021 Feb 5.

Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK. Electronic address:

Mutations in the Presenilin 1 (PSEN1) gene are the most common cause of autosomal dominant familial Alzheimer's disease. We report the clinical, imaging and postmortem findings of kindred carrying a novel duplication mutation (Ile168dup) in the PSEN1 gene. We interpret the pathogenicity of this novel variant and discuss the additional neurological features (pyramidal dysfunction, myoclonus and seizures) that accompanied cognitive decline. This report broadens the clinical phenotype of PSEN1 insertion mutations while also highlighting the importance of considering duplication, insertion and deletion mutations in cases of young onset dementia.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.032DOI Listing
July 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Neuroligin-1 in brain and CSF of neurodegenerative disorders: investigation for synaptic biomarkers.

Acta Neuropathol Commun 2021 02 1;9(1):19. Epub 2021 Feb 1.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy At University of Gothenburg, Mölndal, Sweden.

Synaptic pathology is a central event in Alzheimer's disease (AD) and other neurodegenerative conditions, and investigation of synaptic proteins can provide valuable tools to follow synaptic dysfunction and loss in these diseases. Neuroligin-1 (Nlgn1) is a postsynaptic cell adhesion protein, important for synapse stabilization and formation. Nlgn1 has been connected to cognitive disorders, and specifically to AD, as target of the synaptotoxic effect of amyloid-β (Aβ) oligomers and Aβ fibrils. To address changes in Nlgn1 expression in human brain, brain regions in different neurological disorders were examined by Western blot and mass spectrometry. Brain specimens from AD (n = 23), progressive supranuclear palsy (PSP, n = 11), corticobasal degeneration (CBD, n = 10), and Pick's disease (PiD, n = 9) were included. Additionally, cerebrospinal fluid (CSF) samples of AD patients (n = 43) and non-demented controls (n = 42) were analysed. We found decreased levels of Nlgn1 in temporal and parietal cortex (~ 50-60% reductions) in AD brains compared with controls. In frontal grey matter the reduction was not seen for AD patients; however, in the same region, marked reduction was found for PiD (~ 77%), CBD (~ 66%) and to a lesser extent for PSP (~ 43%), which could clearly separate these tauopathies from controls. The Nlgn1 level was reduced in CSF from AD patients compared to controls, but with considerable overlap. The dramatic reduction of Nlgn1 seen in the brain extracts of tauopathies warrants further investigation regarding the potential use of Nlgn1 as a biomarker for these neurodegenerative diseases.
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http://dx.doi.org/10.1186/s40478-021-01119-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852195PMC
February 2021

The association of circulating amylin with β-amyloid in familial Alzheimer's disease.

Alzheimers Dement (N Y) 2021 20;7(1):e12130. Epub 2021 Jan 20.

Department of Pharmacology and Nutritional Sciences University of Kentucky Lexington Kentucky USA.

Introduction: This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD).

Methods: Evidence of amylin-AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats.

Results: Amylin-Aβ cross-seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aβ concentrations. AD risk and amylin gene are not correlated. Suppressed amylin secretion protected APP/PS1 rats against AD-associated effects. In contrast, hypersecretion or intravenous injection of human amylin in APP/PS1 rats exacerbated AD-like pathology through disruption of CSF-brain Aβ exchange and amylin-Aβ cross-seeding.

Discussion: These findings strengthened the hypothesis of circulating amylin-AD interaction and suggest that modulation of blood amylin levels may alter Aβ-related pathology/symptoms.
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http://dx.doi.org/10.1002/trc2.12130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816817PMC
January 2021

Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis.

Cell Rep 2021 01;34(2):108615

Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. Electronic address:

Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer's disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease.
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http://dx.doi.org/10.1016/j.celrep.2020.108615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809623PMC
January 2021

MOBP and HIP1 in multiple system atrophy: New α-synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis.

Neuropathol Appl Neurobiol 2021 08 19;47(5):640-652. Epub 2021 Jan 19.

Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.

Aims: Multiple system atrophy (MSA) is a fatal neurodegenerative disease. Similar to Parkinson's disease (PD), MSA is an α-synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α-synuclein (SNCA) in oligodendrocytes. We previously identified consistent changes in myelin-associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation.

Methods: We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays.

Results: We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington's disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with SNCA.

Conclusions: This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA.
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http://dx.doi.org/10.1111/nan.12688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219819PMC
August 2021

Molecular forms of neurogranin in cerebrospinal fluid.

J Neurochem 2021 05 17;157(3):816-833. Epub 2020 Dec 17.

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Neurogranin (Ng) is a 78 amino acid neuronal protein and a biomarker candidate for Alzheimer's disease (AD). Ng has been suggested to bind to calmodulin and phosphatidic acid via its centrally located IQ domain. Ng is cleaved within this functionally important domain, yielding the majority of fragments identified in cerebrospinal fluid (CSF), suggesting that cleavage of Ng may be a mechanism to regulate its function. Up to now, Ng has been shown to be present in CSF as both C-terminal fragments as well as full-length protein. To obtain an overview of the different molecular forms of Ng present in CSF, we show by size exclusion chromatography (SEC), immunoblotting, immunoprecipitation, and MS that Ng is present in CSF as several molecular forms. Besides monomeric full-length Ng, also higher molecular weight forms of Ng, and C-terminal- and previously not identified N-terminal fragments were observed. We found by immunodepletion that C-terminal peptides contribute on average to ~50% of the total-Ng ELISA signal in CSF samples. There were no differences in the overall C-terminal fragment/total-Ng ratios between samples from AD and control groups. In addition, we found that monomeric Ng and its C-terminal fragments bind to heparin via a heparin-binding motif, which might be of relevance for their export mechanism from neurons. Taken together, this study highlights the presence of several molecular forms of Ng in CSF, comprising monomeric full-length Ng, and N- and C-terminal truncations of Ng, as well as larger forms of still unknown composition.
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http://dx.doi.org/10.1111/jnc.15252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378242PMC
May 2021

Soluble and insoluble dipeptide repeat protein measurements in C9orf72-frontotemporal dementia brains show regional differential solubility and correlation of poly-GR with clinical severity.

Acta Neuropathol Commun 2020 11 9;8(1):184. Epub 2020 Nov 9.

UK Dementia Research Institute at UCL, Cruciform Building, Gower Street, London, WC1E 6BT, UK.

A C9orf72 repeat expansion is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. One of the suggested pathomechanisms is toxicity from dipeptide repeat proteins (DPRs), which are generated via unconventional translation of sense and antisense repeat transcripts with poly-GA, poly-GP and poly-GR being the most abundant dipeptide proteins. Animal and cellular studies highlight a neurotoxic role of poly-GR and poly-PR and to a lesser degree of poly-GA. Human post-mortem studies in contrast have been much less clear on a potential role of DPR toxicity but have largely focused on immunohistochemical methods to detect aggregated DPR inclusions. This study uses protein fractionation and sensitive immunoassays to quantify not only insoluble but also soluble poly-GA, poly-GP and poly-GR concentrations in brain homogenates of FTD patients with C9orf72 mutation across four brain regions. We show that soluble DPRs are less abundant in clinically affected areas (i.e. frontal and temporal cortices). In contrast, the cerebellum not only shows the largest DPR load but also the highest relative DPR solubility. Finally, poly-GR levels and poly-GP solubility correlate with clinical severity. These findings provide the first cross-comparison of soluble and insoluble forms of all sense DPRs and shed light on the distribution and role of soluble DPRs in the etiopathogenesis of human C9orf72-FTD.
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http://dx.doi.org/10.1186/s40478-020-01036-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650212PMC
November 2020

A Clinicopathologic Study of Movement Disorders in Frontotemporal Lobar Degeneration.

Mov Disord 2021 03 6;36(3):632-641. Epub 2020 Nov 6.

Department of Clinical and Movement Neurosciences, Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, United Kingdom.

Background: Despite the considerable overlap with atypical parkinsonism, a systematic characterization of the movement disorders associated with frontotemporal lobar degeneration (FTLD) is lacking.

Objective: The aim of this study is to provide a detailed description of the phenomenology and neuropathologic correlations of movement disorders in FTLD.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1002/mds.28356DOI Listing
March 2021

The age-dependent associations of white matter hyperintensities and neurofilament light in early- and late-stage Alzheimer's disease.

Neurobiol Aging 2021 01 19;97:10-17. Epub 2020 Sep 19.

Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.

Neurofilament light (NFL) is an emerging marker of axonal degeneration. This study investigated the relationship between white matter hyperintensities (WMHs) and plasma NFL in a large elderly cohort with, and without, cognitive impairment. We used the Alzheimer's Disease Neuroimaging Initiative and included 163 controls, 103 participants with a significant memory concern, 279 with early mild cognitive impairment (EMCI), 152 with late mild cognitive impairment (LMCI), and 130 with Alzheimer's disease, with 3T MRI and plasma NFL data. Multiple linear regression models examined the relationship between WMHs and NFL, with and without age adjustment. We used smoking status, history of hypertension, history of diabetes, and BMI as additional covariates to examine the effect of vascular risk. We found increases of between 20% and 41% in WMH volume per 1SD increase in NFL in significant memory concern, early mild cognitive impairment, late mild cognitive impairment, and Alzheimer's disease groups (p < 0.02). Marked attenuation of the positive associations between WMHs and NFL were seen after age adjustment, suggesting that a significant proportion of the association between NFL and WMHs is age-related. No effect of vascular risk was observed. These results are supportive of a link between WMH and axonal degeneration in early to late disease stages, in an age-dependent, but vascular risk-independent manner.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.008DOI Listing
January 2021

Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases.

Mol Neurobiol 2021 Feb 30;58(2):631-646. Epub 2020 Sep 30.

The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Disorders, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.

Heterogenous nuclear ribonucleoproteins (hnRNPs) are a complex and functionally diverse family of RNA binding proteins with multifarious roles. They are involved, directly or indirectly, in alternative splicing, transcriptional and translational regulation, stress granule formation, cell cycle regulation, and axonal transport. It is unsurprising, given their heavy involvement in maintaining functional integrity of the cell, that their dysfunction has neurological implications. However, compared to their more established roles in cancer, the evidence of hnRNP implication in neurological diseases is still in its infancy. This review aims to consolidate the evidences for hnRNP involvement in neurological diseases, with a focus on spinal muscular atrophy (SMA), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), congenital myasthenic syndrome (CMS), and fragile X-associated tremor/ataxia syndrome (FXTAS). Understanding more about hnRNP involvement in neurological diseases can further elucidate the pathomechanisms involved in these diseases and perhaps guide future therapeutic advances.
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http://dx.doi.org/10.1007/s12035-020-02137-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843550PMC
February 2021

Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice.

Proc Natl Acad Sci U S A 2020 09 8;117(38):23925-23931. Epub 2020 Sep 8.

German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany;

Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging.
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http://dx.doi.org/10.1073/pnas.2011133117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519322PMC
September 2020

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

J Clin Invest 2020 11;130(11):6080-6092

Center for Genomics of Neurodegenerative Disease, and.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.
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http://dx.doi.org/10.1172/JCI139741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598060PMC
November 2020

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration.

J Neuroinflammation 2020 Aug 10;17(1):234. Epub 2020 Aug 10.

Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK.

Background: Microglial 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.

Methods: Immunohistochemistry 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.

Results: There 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.

Conclusions: This 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.
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http://dx.doi.org/10.1186/s12974-020-01907-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418403PMC
August 2020

Neuronal intranuclear inclusion disease is genetically heterogeneous.

Ann Clin Transl Neurol 2020 09 10;7(9):1716-1725. Epub 2020 Aug 10.

Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico-based screening using whole-genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.
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http://dx.doi.org/10.1002/acn3.51151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480908PMC
September 2020

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis.

Acta Neuropathol 2020 11 3;140(5):599-623. Epub 2020 Aug 3.

The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.

Dysregulated RNA metabolism is emerging as a crucially important mechanism underpinning the pathogenesis of frontotemporal dementia (FTD) and the clinically, genetically and pathologically overlapping disorder of amyotrophic lateral sclerosis (ALS). Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins with diverse, multi-functional roles across all aspects of mRNA processing. The role of these proteins in neurodegeneration is far from understood. Here, we review some of the unifying mechanisms by which hnRNPs have been directly or indirectly linked with FTD/ALS pathogenesis, including their incorporation into pathological inclusions and their best-known roles in pre-mRNA splicing regulation. We also discuss the broader functionalities of hnRNPs including their roles in cryptic exon repression, stress granule assembly and in co-ordinating the DNA damage response, which are all emerging pathogenic themes in both diseases. We then present an integrated model that depicts how a broad-ranging network of pathogenic events can arise from declining levels of functional hnRNPs that are inadequately compensated for by autoregulatory means. Finally, we provide a comprehensive overview of the most functionally relevant cellular roles, in the context of FTD/ALS pathogenesis, for hnRNPs A1-U.
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http://dx.doi.org/10.1007/s00401-020-02203-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547044PMC
November 2020

Relevance of biomarkers across different neurodegenerative diseases.

Alzheimers Res Ther 2020 05 13;12(1):56. Epub 2020 May 13.

Dementia Research Centre, University College London Institute of Neurology, London, UK.

Background: The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field.

Purpose Of Review: Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.
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http://dx.doi.org/10.1186/s13195-020-00601-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222479PMC
May 2020

CSF amyloid is a consistent predictor of white matter hyperintensities across the disease course from aging to Alzheimer's disease.

Neurobiol Aging 2020 07 17;91:5-14. Epub 2020 Mar 17.

Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.

This study investigated the relationship between white matter hyperintensities (WMH) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Subjects included 180 controls, 107 individuals with a significant memory concern, 320 individuals with early mild cognitive impairment, 171 individuals with late mild cognitive impairment, and 151 individuals with AD, with 3T MRI and CSF Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) data. Multiple linear regression models assessed the relationship between WMH and CSF Aβ1-42, t-tau, and p-tau. Directionally, a higher WMH burden was associated with lower CSF Aβ1-42 within each diagnostic group, with no evidence for a difference in the slope of the association across diagnostic groups (p = 0.4). Pooling all participants, this association was statistically significant after adjustment for t-tau, p-tau, age, diagnostic group, and APOE-ε4 status (p < 0.001). Age was the strongest predictor of WMH (partial R~16%) compared with CSF Aβ1-42 (partial R~5%). There was no evidence for an association with WMH and either t-tau or p-tau. These data are supportive of a link between amyloid burden and presumed vascular pathology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.03.008DOI Listing
July 2020

Investigation of pathology, expression and proteomic profiles in human TREM2 variant postmortem brains with and without Alzheimer's disease.

Brain Pathol 2020 07 29;30(4):794-810. Epub 2020 Apr 29.

The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.

Triggering receptor expressed on myeloid cells 2 TREM2 was identified as a risk factor for late onset Alzheimer's disease (AD). Here we compared TREM2 cases with a variant (TREM2 ) and cases without a TREM2 variant (TREM2 ), considering pathological burden, inflammatory response and altered canonical pathways and biochemical functions between the cohorts. We hypothesised that TREM2 cases would have a loss of function, indicating an altered inflammatory profile compared to TREM2 cases. Immunohistochemistry was performed using antibodies against Aβ, tau and microglia markers in TREM2 cases, with and without AD, which were compared to sporadic TREM2 AD, familial AD and neurologically normal control cases. Aβ and tau load were measured along with the composition of Aβ plaques, in addition to microglial load and circularity. Expression and proteomic profiles were determined from the frontal cortex of selected cases. TREM2 control cases had no Aβ or tau deposition. No differences in the amount of Aβ or tau, or the composition of Aβ plaques were observed between TREM2 and TREM2 SAD cases. There were no differences in microglial load observed between disease groups. However, the TREM2 SAD cases showed more amoeboid microglia than the TREM2 SAD cases, although no differences in the spatial relationship of microglia and Aβ plaques were identified. Visualisation of the canonical pathways and biological functions showed differences between the disease groups and the normal controls, clearly showing a number of pathways upregulated in TREM2 SAD, TREM2 SAD and FAD groups whilst, the TREM2 controls cases showed a downregulation of the majority of the represented pathways. These findings suggest that the TREM2 control group, although carrying the TREM2 variant, have no pathological hallmarks of AD, have altered microglial and expression profiles compared to the TREM2 SAD cases. This indicates that other unknown factors may initiate the onset of AD, with TREM2 influencing the microglial involvement in disease pathogenesis.
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http://dx.doi.org/10.1111/bpa.12842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018003PMC
July 2020

In vivo staging of frontotemporal lobar degeneration TDP-43 type C pathology.

Alzheimers Res Ther 2020 03 27;12(1):34. Epub 2020 Mar 27.

Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, 8-11 Queen Square, London, WC1N 3BG, UK.

Background: TDP-43 type C is one of the pathological forms of frontotemporal lobar degeneration (FTLD) and mainly associated clinically with the semantic variant of primary progressive aphasia (svPPA). We aimed to define in vivo the sequential pattern of neuroanatomical involvement in a cohort of patients with FTLD-TDP type C pathology.

Methods: We extracted the volumes of a set of cortical and subcortical regions from MRI scans of 19 patients with post mortem confirmed TDP-43 type C pathology (all with left hemisphere-predominant atrophy at baseline). In the initial development phase, we used w-scores computed from 81 cognitively normal controls to define a set of sequential stages of neuroanatomical involvement within the FTLD-TDP type C cohort where a w-score of < - 1.65 was considered abnormal. In a subsequent validation phase, we used 31 follow-up scans from 14 of the 19 patients in the same cohort to confirm the staging model.

Results: Four sequential stages were identified in the initial development phase. Stage 1 was defined by atrophy in the left amygdala, medial temporal cortex, temporal pole, lateral temporal cortex and right medial temporal cortex; Stage 2 by atrophy in the left supratemporal cortex; Stage 3 by atrophy in the right anterior insula; and Stage 4 by atrophy in the right accumbens. In the validation phase, calculation of w-scores in the longitudinal scans confirmed the staging system, with all patients either staying in the same stage or progressing to a later stage at follow-up.

Conclusion: In vivo imaging is able to detect distinct stages of neuroanatomical involvement in FTLD-TDP type C pathology. Using an imaging-derived staging system allows a more refined stratification of patients with svPPA during life.
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http://dx.doi.org/10.1186/s13195-020-00600-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102433PMC
March 2020
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