A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination.

Progressive supranuclear palsy (PSP) is an incurable neurodegenerative disease characterized by 4-repeat (0N/4R)-Tau protein accumulation in CNS neurons. We generated transgenic zebrafish expressing human 0N/4R-Tau to investigate PSP pathophysiology. Tau zebrafish replicated multiple features of PSP, including: decreased survival; hypokinesia; impaired optokinetic responses; neurodegeneration; neuroinflammation; synapse loss; and Tau hyperphosphorylation, misfolding, mislocalization, insolubility, truncation, and oligomerization. Using automated assays, we screened 147 small molecules for activity in rescuing neurological deficits in Tau zebrafish. (+)JQ1, a bromodomain inhibitor, improved hypokinesia, survival, microgliosis, and brain synapse elimination. A heterozygous brd4+/- mutant reducing expression of the bromodomain protein Brd4 similarly rescued these phenotypes. Microglial phagocytosis of synaptic material was decreased by (+)JQ1 in both Tau zebrafish and rat primary cortical cultures. Microglia in human PSP brains expressed Brd4. Our findings implicate Brd4 as a regulator of microglial synaptic elimination in tauopathy and provide an unbiased approach for identifying mechanisms and therapeutic targets in PSP.

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes.

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10-8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.

MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative movement and cognitive disorder characterized by abnormal accumulation of the microtubule-associated protein tau in the brain. Biochemically, inclusions in PSP are enriched for tau proteoforms with four microtubule-binding domain repeats (4R), an isoform that arises from alternative tau pre-mRNA splicing. While preferential aggregation and reduced degradation of 4R tau protein is thought to play a role in inclusion formation and toxicity, an alternative hypothesis is that altered expression of tau mRNA isoforms plays a causal role. This stems from the observation that PSP is associated with common variation in the tau gene (MAPT) at the 17q21.31 locus which contains low copy number repeats flanking a large recurrent genomic inversion. The complex genomic structural changes at the locus give rise to two dominant haplotypes, termed H1 and H2, that have the potential to markedly influence gene expression. Here, we explored haplotype-dependent differences in gene expression using a bulk RNA-seq dataset derived from human post-mortem brain tissue from PSP (n = 84) and controls (n = 77) using a rigorous computational pipeline, including alternative pre-mRNA splicing. We found 3579 differentially expressed genes in the temporal cortex and 10,011 in the cerebellum. We also found 7214 differential splicing events in the temporal cortex and 18,802 in the cerebellum. In the cerebellum, total tau mRNA levels and the proportion of transcripts encoding 4R tau were significantly increased in PSP compared to controls. In the temporal cortex, the proportion of reads that expressed 4R tau was increased in cases compared to controls. 4R tau mRNA levels were significantly associated with the H1 haplotype in the temporal cortex. Further, we observed a marked haplotype-dependent difference in KANSL1 expression that was strongly associated with H1 in both brain regions. These findings support the hypothesis that sporadic PSP is associated with haplotype-dependent increases in 4R tau mRNA that might play a causal role in this disorder.

Induction of tau pathology and motor dysfunction in mice by urinary exosomes from progressive supranuclear palsy patients.

BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by the presence of hyperphosphorylated and misfolded tau aggregates in neurons and glia. Recent studies have illuminated the prion-like cell-to-cell propagation of tau via exosomes. Recognizing the potential significance of excretion through urine as a crucial pathway for eliminating pathological tau from the central nervous system, this study aimed to investigate whether exosomes derived from the urine of PSP-Richardson's syndrome (PSP-RS) patients can elicit tau pathology and PSP-like symptoms in mice. METHODS: Urinary exosomes obtained from PSP-RS patients and normal controls (NCs) were stereotactically injected into the bilateral globus pallidus of mouse brains. Behavioral analyses were conducted every 3 months post-injection. After 6 months, mice were sacrificed for pathological evaluation. RESULTS: Elevated levels of phosphorylated tau and neural cell markers were observed in urinary exosomes from PSP-RS patients compared to NCs. At the 6-month mark post-injection, tau inclusions were evident in the brains of mice receiving urinary exosomes from PSP-RS patients, with widespread distribution in both injection sites and distant brain regions (cortex, hippocampus, and substantia nigra). Tau pathology manifested in neurons and astrocytes. Moreover, mice injected with urinary exosomes from PSP-RS patients exhibited impaired motor coordination and balance, mirroring PSP motor symptoms. CONCLUSION: Our findings indicate that urinary exosomes from PSP-RS patients can induce tau pathology and trigger PSP-like motor symptoms in mice. This leads to the hypothesis that exosomes may play a role in the pathogenesis of PSP.

Astrocyte tau deposition in progressive supranuclear palsy is associated with dysregulation of MAPT transcription.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by 4R tau deposition in neurons as well as in astrocytes and oligodendrocytes. While astrocytic tau deposits are rarely observed in normal aging (so-called aging-related tau astrogliopathy, ARTAG) and Alzheimer's disease (AD), astrocytic tau in the form of tufted astrocytes is a pathognomonic hallmark of PSP. Classical biochemical experiments emphasized tau synthesis in neurons in the central nervous system, suggesting that astrocytic tau inclusions might be derived from uptake of extracellular neuronal-derived tau. However, recent single-nucleus RNAseq experiments highlight the fact that MAPT, the gene encoding tau, is also expressed by astrocytes, albeit in lower amounts. We, therefore, revisited the question of whether astrocyte-driven expression of tau might contribute to astrocytic tau aggregates in PSP by performing fluorescent in situ hybridization/immunohistochemical co-localization in human postmortem brain specimens from individuals with PSP and AD with ARTAG as well as normal controls. We find that, in PSP but not in AD, tau-immunoreactive astrocytes have higher levels of MAPT mRNA compared to astrocytes that do not have tau aggregates. These results suggest that astrocytic responses in PSP are unique to this tauopathy and support the possibility that fundamental changes in PSP astrocyte-endogenous mRNA biology contribute to increased synthesis of tau protein and underlies the formation of the astrocytic tau deposits characteristic of PSP.

Transcriptional expression patterns of the cortical morphometric similarity network in progressive supranuclear palsy.

BACKGROUND: It has been demonstrated that progressive supranuclear palsy (PSP) correlates with structural abnormalities in several distinct regions of the brain. However, whether there are changes in the morphological similarity network (MSN) and the relationship between changes in brain structure and gene expression remain largely unknown. METHODS: We used two independent cohorts (discovery dataset: PSP: 51, healthy controls (HC): 82; replication dataset: PSP: 53, HC: 55) for MSN analysis and comparing the longitudinal changes in the MSN of PSP. Then, we applied partial least squares regression to determine the relationships between changes in MSN and spatial transcriptional features and identified specific genes associated with MSN differences in PSP. We further investigated the biological processes enriched in PSP-associated genes and the cellular characteristics of these genes, and finally, we performed an exploratory analysis of the relationship between MSN changes and neurotransmitter receptors. RESULTS: We found that the MSN in PSP patients was mainly decreased in the frontal and temporal cortex but increased in the occipital cortical region. This difference is replicable. In longitudinal studies, MSN differences are mainly manifested in the frontal and parietal regions. Furthermore, the expression pattern associated with MSN changes in PSP involves genes implicated in astrocytes and excitatory and inhibitory neurons and is functionally enriched in neuron-specific biological processes related to synaptic signaling. Finally, we found that the changes in MSN were mainly negatively correlated with the levels of serotonin, norepinephrine, and opioid receptors. CONCLUSIONS: These results have enhanced our understanding of the microscale genetic and cellular mechanisms responsible for large-scale morphological abnormalities in PSP patients, suggesting potential targets for future therapeutic trials.

Systematic review of phenotypes in McLeod syndrome and case report of a progressive supranuclear palsy in a female carrier.

INTRODUCTION: We present a systematic review of phenotypes of McLeod syndrome (MLS) and a case of a 73-year-old female carrier of the genetic alteration leading to MLS with the typical progressive supranuclear palsy (PSP) phenotype. METHODS: To facilitate clinical reasoning and enable targeted diagnosis, we conducted a systematic review of the papers describing symptomatic cases of confirmed McLeod syndrome. This review follows the PRISMA 2020 statement: an updated guideline for reporting systematic reviews (Page et al in Syst Rev 10(1):89, 2021). RESULTS: The average onset of MLS was at 40.2 years of age with chorea (46%), seizures and psychiatric changes (each 13%). Very common are weakened Kell antigen (100%), changes in muscle biopsy (100%), genetic alterations in XK (100%), elevated creatine kinase (97%), acanthocytes (96%), MRI changes (95%), chorea (84%) and hyporeflexia (82%). CONCLUSION: This review of 65 males and 11 females gives a concise overview of clinical phenotypes in MLS, reinforcing our view that this female patient had PSP independent of MLS carrier status. This report highlights the pitfalls of anchoring in medical decision-making, particularly the possible diagnostic bias of a known genetic carrier status of a very rare disease.

Corpus callosum damage in PSP and unsteady PD patients: A multimodal MRI study.

INTRODUCTION: Postural instability (PI) is a common disabling symptom in Parkinson's disease (PD) patients, but the brain alterations underlying this sign are not fully understood yet. This study aimed to investigate the association between PI and callosal damage in PD and progressive supranuclear palsy (PSP) patients, using multimodal MR imaging. METHODS: One-hundred and two PD patients stratified according to the presence/absence of PI (PD-steady N=58; PD-unsteady N=44), 69 PSP patients, and 38 healthy controls (HC) underwent structural and diffusion 3T brain MRI. Thickness, fractional anisotropy (FA) and mean diffusivity (MD) were calculated over 50 equidistant points covering the whole midsagittal profile of the corpus callosum (CC) and compared among groups. Associations between imaging metrics and postural instability score were investigated using linear regression. RESULTS: Both PSP and PD-unsteady patient groups showed CC involvement in comparison with HC, while no difference was found between PD-steady patients and controls. The CC damage was more severe and widespread in PSP than in PD patients. The CC genu was the regions most damaged in PD-unsteady patients compared with PD-steady patients, showing significant microstructural alterations of MD and FA metrics. Linear regression analysis pointed at the MD in the CC genu as the main contributor to PI among the considered MRI metrics. CONCLUSION: This study identified callosal microstructural alterations associated with PI in unsteady PD and PSP patients, which provide new insights on PI pathophysiology and might serve as imaging biomarkers for assessing postural instability progression and treatment response.

Progressive Supranuclear Palsy: Subcortical Tau Depositions Are Associated with Cortical Perfusion in Frontal and Limbic Regions.

 In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer [18F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion.

In a study of 32 patients with progressive supranuclear palsy (PSP), we used a molecular imaging tracer called [18F]PI-2620 to measure two things: the presence of a protein called tau in deep brain areas (specifically, the globus pallidus internus and dentate nucleus) and the function of the brain's cortex by assessing blood flow (perfusion). We found that higher amounts of tau in these deep brain areas were associated with reduced blood flow in the limbic cortex, which is involved in emotion regulation. Also, the frontal areas of the brain showed reduced blood flow related to tau in these deep brain regions. However, this connection was statistically significant only for the dentate nucleus. This study suggests that the buildup of tau protein in deeper brain areas can disrupt function in parts of the brain's cortex, highlighting the damaging role of tau in PSP.

DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson's disease, and progressive supranuclear palsy: a cross-comparative investigation.

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by neuronal loss and gliosis, with oligodendroglial cytoplasmic inclusions (GCIs) containing α-synuclein being the primary pathological hallmark. Clinical presentations of MSA overlap with other parkinsonian disorders, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), posing challenges in early diagnosis. Numerous studies have reported alterations in DNA methylation in neurodegenerative diseases, with candidate loci being identified in various parkinsonian disorders including MSA, PD, and PSP. Although MSA and PSP present with substantial white matter pathology, alterations in white matter have also been reported in PD. However, studies comparing the DNA methylation architectures of white matter in these diseases are lacking. We therefore aimed to investigate genome-wide DNA methylation patterns in the frontal lobe white matter of individuals with MSA (n = 17), PD (n = 17), and PSP (n = 16) along with controls (n = 15) using the Illumina EPIC array, to identify shared and disease-specific DNA methylation alterations. Genome-wide DNA methylation profiling of frontal lobe white matter in the three parkinsonian disorders revealed substantial commonalities in DNA methylation alterations in MSA, PD, and PSP. We further used weighted gene correlation network analysis to identify disease-associated co-methylation signatures and identified dysregulation in processes relating to Wnt signaling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport to be shared between these parkinsonian disorders. Our overall analysis points toward more similarities in DNA methylation patterns between MSA and PD, both synucleinopathies, compared to that between MSA and PD with PSP, which is a tauopathy. Our results also highlight several shared DNA methylation changes and pathways indicative of converging molecular mechanisms in the white matter contributing toward neurodegeneration in all three parkinsonian disorders.

Clinicopathologic and Neuroimaging Correlations of Nonverbal Oral Apraxia in Patients With Neurodegenerative Disease.

BACKGROUND AND OBJECTIVES: Nonverbal oral apraxia (NVOA) is the inability to plan, sequence, and execute voluntary oromotor movements in the absence of weakness. In the context of neurodegenerative disease, it remains unclear whether it is linked to a specific underlying pathologic, clinical, or neuroimaging finding. Thus, we aimed to assess the clinicopathologic and neuroimaging associations of NVOA. METHODS: We conducted a retrospective study of autopsy-confirmed patients previously assessed through an NVOA evaluation tool with a previously published cutpoint to screen for NVOA. We compared demographic and clinical characteristics and postmortem pathology between those who developed NVOA and those who did not. We also compared clinicopathologic characteristics in mild vs greater than mild NVOA and early vs late-emerging NVOA. SPM12 was used to assess patterns of gray matter loss in NVOA vs non-NVOA with age and sex included as covariates. RESULTS: A total of 104 patients (median age at symptom onset 63 years, 43% female) were included in the study. 63 (60.6%) developed NVOA. NVOA appeared at a median of 4.3 years from symptom onset. 29% developed NVOA within the first 3 years. Primary progressive apraxia of speech and the nonfluent variant of primary progressive aphasia were the most common baseline diagnoses in the NVOA group while progressive supranuclear palsy (PSP) syndrome and logopenic progressive aphasia (LPA) were the most common in patients without NVOA. Atrophy of the left lateral and medial posterior frontal cortex was related to NVOA. The most common pathologies associated with NVOA were PSP (36.5%) and corticobasal degeneration (CBD) (33.3%). In patients without NVOA, PSP (26.8%) and other pathologies (26.8%) were the most frequent. 11% of patients with NVOA had persistently mild NVOA and were more likely to have baseline diagnoses of LPA, PSP syndrome, or semantic dementia. The most frequent pathologies in this group were Alzheimer disease and PSP. The pathologic associations of greater than mild NVOA were CBD and PSP. DISCUSSION: NVOA is present in several clinical syndromes. It is most associated with PSP and CBD. NVOA is a manifestation of left lateral and medial posterior frontal cortex damage rather than a particular pathology.

Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials.

BACKGROUND: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. OBJECTIVE: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. METHODS: Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. RESULTS: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. CONCLUSIONS: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies.

Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aß-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

Proteomic networks of gray and white matter reveal tissue-specific changes in human tauopathy.

OBJECTIVE: To define tauopathy-associated changes in the human gray and white matter proteome. METHOD: We applied tandem mass tagged labeling and mass spectrometry, consensus, and ratio weighted gene correlation network analysis (WGCNA) to gray and white matter sampled from postmortem human dorsolateral prefrontal cortex. The sampled tissues included control as well as Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal degeneration with tau pathology, and chronic traumatic encephalopathy. RESULTS: Only eight proteins were unique to gray matter while six were unique to white matter. Comparison of the gray and white matter proteome revealed an enrichment of microglial proteins in the white matter. Consensus WGCNA sorted over 6700 protein isoforms into 46 consensus modules across the gray and white matter proteomic networks. Consensus network modules demonstrated unique and shared disease-associated microglial and endothelial protein changes. Ratio WGCNA sorted over 6500 protein ratios (white:gray) into 33 modules. Modules associated with mitochondrial proteins and processes demonstrated higher white:gray ratios in diseased tissues relative to control, driven by mitochondrial protein downregulation in gray and upregulation in white. INTERPRETATION: The dataset is a valuable resource for understanding proteomic changes in human tauopathy gray and white matter. The identification of unique and shared disease-associated changes across gray and white matter emphasizes the utility of examining both tissue types. Future studies of microglial, endothelial, and mitochondrial changes in white matter may provide novel insights into tauopathy-associated changes in human brain.

In Vivo Assessment of Astrocyte Reactivity in Patients with Progressive Supranuclear Palsy.

OBJECTIVE: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. METHODS: We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. RESULTS: The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. INTERPRETATION: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024;96:247-261.

Neuropathologic Validation and Diagnostic Accuracy of Presynaptic Dopaminergic Imaging in the Diagnosis of Parkinsonism.

BACKGROUND AND OBJECTIVES: Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism. METHODS: Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism. RESULTS: All of 47 patients with PD, 41 of 42 with MSA, 68 of 73 with PSP, and 6 of 10 with CBD (sensitivity 100%, 97.6%, 93.2%, and 60%, respectively) had abnormal presynaptic dopaminergic imaging. Eight of 17 patients with presumed postsynaptic parkinsonism had abnormal scans (specificity 52.9%). DISCUSSION: DAT imaging has very high sensitivity and negative predictive value for the diagnosis of presynaptic dopaminergic parkinsonism, particularly for PD. However, patients with CBD, and to a lesser extent PSP (of various phenotypes) and MSA (with predominant ataxia), can show normal DAT imaging. A range of other neurodegenerative disorders may have abnormal DAT scans with low specificity in the differential diagnosis of parkinsonism. DAT imaging is a useful diagnostic tool in the differential diagnosis of parkinsonism, although clinicians should be aware of its diagnostic properties and limitations. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DAT imaging does not accurately distinguish between presynaptic dopaminergic parkinsonism and non-presynaptic dopaminergic parkinsonism.

Clinical Utility of Tectal Plate Measurements on Magnetic Resonance Imaging in Progressive Supranuclear Palsy.

BACKGROUND: Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), observed in PSP-Richardson's syndrome (PSP-RS) and to a lesser extent PSP-parkinsonism (PSP-P). OBJECTIVE: Our aim was to critically evaluate the utility of manual magnetic resonance imaging measurements of the midbrain tectal plate as a diagnostic biomarker in PSP. METHODS: Length of the tectal plate and width of the superior and inferior colliculi were measured in 40 PSP (20 PSP-RS and 20 PSP-P) patients and compared with 20 Parkinson's disease and 20 healthy control subjects. RESULTS: Tectal plate length was reduced in both PSP groups compared with Parkinson's disease and control subjects and was most abnormal in PSP-RS followed by PSP-P. Reduced tectal plate length was associated with worse PSP Rating Scale scores. CONCLUSIONS: Simple manual measurements of tectal plate length show utility as a diagnostic biomarker in PSP, particularly for PSP-RS.

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.

Clinical and neuroimaging characteristics of primary lateral sclerosis with overlapping features of progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a neurodegenerative disorder that primarily affects the central motor system. In rare cases, clinical features of PLS may overlap with those of progressive supranuclear palsy (PSP). We investigate neuroimaging features that can help distinguish PLS with overlapping features of PSP (PLS-PSP) from PSP. METHODS: Six patients with PLS-PSP were enrolled between 2019 and 2023. We compared their clinical and neuroimaging characteristics with 18 PSP-Richardson syndrome (PSP-RS) patients and 20 healthy controls. Magnetic resonance imaging, 18F-flortaucipir positron emission tomography (PET), quantitative susceptibility mapping, and diffusion tensor imaging tractography (DTI) were performed to evaluate eight brain regions of interest. Area under the receiver operating characteristic curve (AUROC) was calculated. RESULTS: Five of the six PLS-PSP patients (83.3%) were male. Median age at symptom onset was 61.5 (52.5-63) years, and all had mixed features of PLS and PSP. Volumes of the pallidum, caudate, midbrain, and cerebellar dentate were smaller in PSP-RS than PLS-PSP, providing good discrimination (AUROC = 0.75 for all). The susceptibilities in pallidum, midbrain, and cerebellar dentate were greater in PSP-RS compared to PLS-PSP, providing excellent discrimination (AUROC ≥ 0.90 for all). On DTI, fractional anisotropy (FA) in the posterior limb of the internal capsule from the corticospinal tract was lower in PLS-PSP compared to PSP-RS (AUROC = 0.86), but FA in the superior cerebellar peduncle was lower in PSP-RS (AUROC = 0.95). Pallidum flortaucipir PET uptake was greater in PSP-RS compared to PLS-PSP (AUROC = 0.74). CONCLUSIONS: Regional brain volume, tractography, and magnetic susceptibility, but not tau-PET, are useful in distinguishing PLS-PSP from PSP.

Clinical and Pathological Features of FTDP-17 with MAPT p.K298_H299insQ Mutation.

BACKGROUND: MAPT is a causative gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), a hereditary degenerative disease with various clinical manifestations, including progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease, and frontotemporal dementia. OBJECTIVES: To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease. METHODS: Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3. RESULTS: We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3. CONCLUSIONS: This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson's disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.