Progressive Supranuclear Palsy Subjects Research Articles

Low Clinical Sensitivity and Unexpectedly High Incidence for Neuropathologically Diagnosed Progressive Supranuclear Palsy (PSP) (S51.001)

Low Clinical Sensitivity and Unexpectedly High Incidence for Neuropathologically Diagnosed Progressive Supranuclear Palsy (PSP) (S51.001)

The utility of quantitative MRI parameters in discriminating progressive supranuclear palsy from Parkinson’s disease

ABSTRACT Objective We sought tore-evaluate the utility of all the quantitative neuroimaging parametersattributed to progressive supranuclear palsy (PSP) in discrimination betweenPSP and Parkinson’ s disease (PD) subjects in our cohort. We aimed to proposesome practical clinical remarks in this field. Methods In our retrospective study, 19 patients with‘probable’ PSP and 37 patients with PD were enrolled. The radiological measurements of PSP, describedin the previous reports, have been calculated in all subjects. The comparisonsbetween the groups were performed and the measures regarding the accuracy ofthese parameters in the differentiation of PSP from PD subjects were analyzed. Results We found that the values of magnetic resonance parkinsonism index-2 (MRPI-2), pontine-to-midbrain area (P/M) ratio, P/M 2 ratio, and 3rdV/bifrontal width ratio had high AUC values and very good discriminative powers. The analyses revealed that; for the discrimination of PSP from PD subjects, a 3rdvent/bifrontal width cut-off value of 0.30 had 42.1 % sensitivity and 97.3 % specificity; a P/M cut-off value of 6.03 had a 52.6 % sensitivity and 97.3 % specificity; and an MRPI-2 cut-off value of 7.43 had 57.9 % sensitivity and 97.3 % specificity. Remarkably, we also found that the presence of high values for both P/M and 3rdV/bifrontal ventricle rate had a positive predictive value of 100% for the diagnosis of PSP. Conclusion Our study results support the utility of previously defined neuroimaging parameters in distinguishing PSP and PD subjects. Besides, combined use of a high P/M ratio and 3rdV/bifrontal width may be practical and present strictly high evidence for the diagnosis of PSP.

Low clinical sensitivity and unexpectedly high incidence for neuropathologically diagnosed progressive supranuclear palsy.

The objective of this study was to determine the prevalence, incidence, and clinical diagnostic accuracy for neuropathologically diagnosed progressive supranuclear palsy (PSP) with data from a longitudinal clinicopathological study using Rainwater criteria to define neuropathological PSP. Of 954 autopsy cases, 101 met Rainwater criteria for the neuropathologic diagnosis of PSP. Of these, 87 were termed clinicopathological PSP as they also had either dementia or parkinsonism or both. The prevalence of clinicopathologically defined PSP subjects in the entire autopsy dataset was 9.1%, while the incidence rate was estimated at 780 per 100 000 persons per year, roughly 50-fold greater than most previous clinically determined PSP incidence estimates. A clinical diagnosis of PSP was 99.6% specific but only 9.2% sensitive based on first examination, and 99.3% specific and 20.7% sensitive based on the final clinical exam. Of the clinicopathologically defined PSP cases, 35/87 (∼40%) had no form of parkinsonism at first assessment, while this decreased to 18/83 (21.7%) at final assessment. Our study confirms a high specificity but low sensitivity for the clinical diagnosis of PSP. The low clinical sensitivity for PSP is likely primarily responsible for previous underestimates of the PSP population incidence rate.

Disentangling selective vulnerability underlying sleep disfunction in neurodegenerative diseases: differential gene expression in neuromodulatory subcortical system in Alzheimer’s disease vs. Progressive supranuclear palsy vs. controls

AbstractBackgroundSleep‐wake disturbance precedes the prodromal stage of Alzheimer’s disease (AD) and is characterized by excessive daytime sleepiness and sundowning. In contrast, hyper‐insomnia is seen in progressive supranuclear palsy (PSP), a pure 4‐repeat tauopathy. The wake‐promoting histaminergic (HA) neurons of the tuberomamillary nucleus (TMN) together with the orexinergic (OX) neurons of the lateral hypothalamic area (LHA) modulate the sleep‐wake cycle. Previously, we reported wake‐promoting nucleus (WPNs) are selectively vulnerable to AD‐tau toxicity than PSP, and neuronal loss in TMN is specific to AD. In the present study, we investigated changes in RNA expression in the TMN and LHA to understand the selective vulnerability of WPNs in AD at the molecular level.MethodLHA and TMN were dissected from serial histological sections from the postmortem brains of AD, PSP, and healthy control (HC) subjects. 50ng total RNA was extracted using RNeasy Micro Kit, and RNA integrity was accessed using Nanodrop. Cases with RIN > 5 were included for RNA sequencing. The nCounter Neuropathology panel and nSolver software (NanoString Technologies) was employed to obtain and analyze the data.ResultMolecular profiling of TMN in AD demonstrated 13 upregulated genes associated with angiogenesis, apoptosis, chromatin modification, disease‐association, and transcription factor, and 12 genes in PSP. The proto‐oncogene RELA, RNA binding protein FUS and oligodendrocyte specific NKX6‐2 genes were upregulated in AD and PSP. Further, in the LHA, we identified 17 differentially expressed genes associated with circadian rhythm, inflammatory cytokines, apoptosis, autophagy, and angiogenesis in AD over HC and 72 genes in PSP over HC. Both IL4 and CRY2 genes demonstrated downregulation in the AD and PSP.ConclusionDifferential gene expression in the WPNs revealed a significant upregulation of genes associated with pro‐inflammatory cytokines, activated microglia, apoptosis, oxidative stress, and autophagy in AD over PSP. The neuromodulatory subcortical system shows different vulnerability patterns in AD vs. PSP making it an excellent candidate to interrogate the molecular bases of vulnerability.

Postural control in Parkinsonisms during a short static sway

Neurological diseases, such as Parkinsonisms, are often associated with static postural instability. Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease classified among atypical Parkinsonisms. In the earliest stages, PSP is similar to Parkinson’s disease (PD) [1]. Static postural stability is an important contributor to the balance control framework and balance impairment can be quantified with a postural sway measure [2]. The main goal of our study was to compare postural sway changes in both PSP and PD subjects, using a standing single task of 5-6 seconds, in order to prove that a shorter sway time may be useful to distinguish Parkinsonisms. We assessed fifteen individuals with early PSP and fifteen individuals with recent diagnosis of PD (De Novo PD). Stabilometric analysis was performed for the evaluation of balance through a BTS Bioengineering system. The patient was instructed to stand on the force plate with the eyes open and measures of 5-6 seconds were taken. To find differences between the groups, univariate statistical analysis on sway data was conducted, and an alpha significance level was set to p-value < 0.05. The statistical analysis showed significant differences between De Novo PD and PSP groups for Medio- Lateral (M-L) sway (p-value=0.01), M-L range (p-value=0.023) and radius (p-value=0.026); minimum oscillation from the center of gravity and area showed a statistical trend with a p-value slightly above the 0.05 (p-value=0.056 and p-value=0.061, respectively). Several studies have demonstrated that balance dysfunction in PD is directionally dependent [2,3]. In agreement with our data, patients with atypical Parkinsonism show balance impairment on M-L direction as attested by augmented M-L sway, M-L range and radius. These results indicate that a short static sway of 5-6 seconds, could provide the clinician with a reliable and non-invasive tool to distinguish PSP from PD since the earliest stages.

Idiopathic normal pressure hydrocephalus-like MRI features in patients with progressive supranuclear palsy: a comparative case-control study

ABSTRACT Background The occurrence of neurodegenerative disease in patients with normal pressure hydrocephalus (NPH) is emphasized in recent reports. Based on this common co-occurrence, some of the hydrocephalic disorders appearing in late adulthood have been hypothesized to result from initially unapparent parenchymal abnormalities of neurodegenerative origin. Among these diseases, progressive supranuclear palsy (PSP) has been specifically remarked on. We aimed to comparatively investigate the neuroimaging clues of iNPH in our PSP subjects. Methods Eighteen patients with a clinical diagnosis of PSP, 44 with Parkinson’s disease (PD), and 44 healthy control (HC) individuals were enrolled. The disproportionately enlarged subarachnoid space hydrocephalus (DESH) score, the Evans’ index (EI), and the callosal angle (CA) were measured on the conventional magnetic resonance imaging (MRI). The comparative analyses were performed using IBM SPSS Statistics 26. Results We found that dilated Sylvian fissures score (p = 0.016) and focal sulcal dilatation score (p = 0.037) were higher in the PSP group in comparison to HC whereas the CA score was higher in PSP subjects in comparison to both PD patients and HC (p = 0.000). Remarkably, the DESH score was also found to be higher in the PSP group in comparison to the age-matched HC group (p = 0.024). Conclusions We found that the NPH-like MRI features were more common in PSP subjects in comparison to PD subjects and age-matched HC. These results may provide critical contributions to the literature regarding the overlap between PSP and NPH.

The Overlap in Neuroimaging Findings Between Idiopathic Normal Pressure Hydrocephalus and Progressive Supranuclear Palsy.

The neuroimaging findings of brain stem atrophy resembling progressive supranuclear palsy (PSP) radiology are common in idiopathic normal pressure hydrocephalus (iNPH) subjects. Besides, recent studies report the existence of iNPH-like MRI findings in PSP subjects. We aimed to comparatively investigate the neuroimaging indices of iNPH and PSP in our patient groups in a detailed methodology. Ultimately, 19 probable PSP patients and 18 patients with a definite diagnosis of iNPH were enrolled. The subjects were recruited retrospectively from those who had been admitted between 2017 and 2021 to the Movement Disorders Polyclinic and the Neurosurgery Clinic of the Diskapi Yildirim Beyazit Training and Education Hospital. MRI-based DESH score, Evans index, and the callosal angle (CA) have been calculated in all the individuals. Besides, quantitative MRI parameters of PSP were evaluated in every subject. Statistical analyses were performed using IBM SPSS Statistics 26. The comparative analyses regarding the radiological parameters of PSP did not reveal any difference between patient groups. On the other hand, the comparisons of the neuroimaging parameters of iNPH, yielded differences in the CA, CA score, and the total DESH score. However, the ROC curve analyses did not reveal a discriminative power at a value of "very good" or "excellent" in any of the indices. We found that the neuroimaging features of iNPH and PSP highly overlapped between these patient groups. These results may provide indirect evidence regarding the coexistence of PSP and iNPH pathophysiology that has been deliberated in several recent reports.

Hypothalamic melanin‐concentrating hormone neurons, key sleep cycle modulators, degenerate early in Alzheimer’s disease

AbstractBackgroundSleep disorders represent one of the leading causes of life impairment and a major therapeutic challenge in patients with Alzheimer’s disease (AD) and tauopathies. However, the disease specific neurobiological basis of these sleep disturbances remains mostly elusive. Melanin‐concentrating hormone (MCH) neurons are a conserved neuronal population in the lateral and posterior hypothalamus with critical sleep/wake and metabolic control functions in animals, but largely underexplored in humans. Here, we used unbiased stereology to examine the involvement of MCH neurons in Alzheimer’s disease (AD) as a 3R‐tauopathy, and progressive supranuclear palsy (PSP) as a 4R‐tauopathy featuring hyperinsomnia.MethodWe used unbiased stereology to quantify total and MCH‐positive neuronal numbers and tau burden in the region of interest (ROI) of 5 AD and 6 PSP brains (for detailed demographics see Table 1). Data were analyzed using Wilcoxon signed rank and Mann‐Whitney U tests.ResultBoth AD and PSP subjects show significant neuronal tau‐burden in the ROI. There was no statistically significant difference in the absolute number of MCH‐neurons and non‐MCH‐neurons (Figure 1), or proportion of MCH neurons in the total neuronal population between AD (26.5%) and PSP (24.9%). Whereas there was no difference in the proportion of tau+ non‐MCH neurons between AD and PSP, the proportion of tau+ MCH‐neurons was significantly higher in AD relative to PSP (p=0.0043) (Figure 2). Contrary to AD, where MCH and non‐MCH neurons had similar tau‐burden (18.8% and 17.1%, respectively), in PSP there was a significantly lower involvement of MCH‐neurons (4.9%) in comparison to the total neuronal population (19.9%, p=0.0313) (Figure 2). In the PSP group there was a positive correlation between Braak stages and the proportion of tau+ MCH neurons (p=0.023), but not total tau+ neurons.ConclusionOur preliminary data show a trend for lower neuronal numbers in AD and in PSP, lower neuronal numbers correlated with higher Braak stages. Together, it suggest an early vulnerability of MHC to AD and a moderate vulnerability to PSP. We are analyzing further cases to increase the power of analysis. Different involvement of MCH‐neurons in AD and PSP may reflect the specific patterns of sleep disorders in those tauopathies.

Increased Noradrenaline as an Additional Cerebrospinal Fluid Biomarker in PSP-Like Parkinsonism.

Academic centers utilize sequential clinical and neuroimaging assessments, including morphometric ratios, to obtain an unequivocal diagnosis of the non-synucleinopathic forms of Parkinsonism, such as progressive supranuclear palsy (PSP), however, a 1–2 year follow-up is required. The on-going long-lasting trials using anti-tau antibodies for PSP patients might therefore be biased by the incorrect enrollment of Parkinson’s disease (PD) patients manifesting early axial signs. This perspective study aimed at achieving two major goals: first, to summarize the established biomarker candidates found in cerebrospinal fluid (CSF) in probable PSP patients, including low p-tau and altered neurofilaments. Second, we share our recent data, from CSF samples of well-selected PSP subjects, attributable to both main variants (and revisited in light of MDS criteria), who were followed for 1 year before and 2 years after lumbar puncture. We found a significantly high level of noradrenaline (NE) in these patients, similar to controls, when compared to PD patients. In contrast, CSF samples, in PD, showed a significant reduction in CSF NE and its major metabolite, which confirmed that PD is a multi-system disease involving several endogenous pathways. The NE axis impairments were prominent in PSP featuring worse NPI. It might represent a counterpart to the early and peculiar psycho-pathological profiles that are observed in tauopathies. In conclusion, we highlight that CSF biomarkers, which are easy to collect, can provide rapid insights as diagnostic tools. Early alterations in endogenous NE machinery in atypical Parkinsonism may represent a specific risk trait in forms characterized by a worse prognosis.

Mitochondrial tRNA methylation in Alzheimer\u2019s disease and progressive supranuclear palsy

BackgroundMethylation of mitochondrial tRNAs (mt-tRNA) at the 9th position (“p9 site”) is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression.MethodsMitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman’s rho. Fisher’s Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation.ResultsVariable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related.ConclusionWith mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.

Reproducible metabolic topographies associated with multiple system atrophy: Network and regional analyses in Chinese and American patient cohorts

PurposeMultiple system atrophy (MSA) is an atypical parkinsonian syndrome and often difficult to discriminate clinically from progressive supranuclear palsy (PSP) and Parkinson's disease (PD) in early stages. Although a characteristic metabolic brain network has been reported for MSA, it is unknown whether this network can provide a clinically useful biomarker in different centers. This study was aimed to identify and cross-validate MSA-related brain network and assess its ability for differential diagnosis and clinical correlations in Chinese and American patient cohorts. MethodsWe included 18F-FDG PET scans retrospectively from 128 clinically diagnosed parkinsonian patients (34 MSA, 34 PSP and 60 PD) and 40 normal subjects in China and in the USA. Using PET images from 20 moderate-stage MSA patients of parkinsonian subtype and 20 normal subjects in both centers, we reproduced MSA-related pattern (MSAPRP) of spatial covariance and estimated its reliability. MSAPRP scores were evaluated in assessing differential diagnosis among moderate- and early-stage MSA, PSP or PD patients and clinical correlations with disease severity. Regional metabolic differences were detected using statistical parameter mapping analysis. MSA-related network and regional topographies of metabolic abnormality were cross-validated between the Chinese and American cohorts. ResultsWe generated a highly reliable MSAPRP characterized by decreased loading in inferior frontal cortex, striatum and cerebellum, and increased loading in sensorimotor, parietal and occipital cortices. MSAPRP scores discriminated between normal, MSA, PSP and PD subjects and correlated with standardized ratings of clinical stages and motor symptoms in MSA. High similarities in MSAPRPs, network scores and corresponding maps of metabolic abnormality were observed between two different cohorts. ConclusionWe have demonstrated reproducible metabolic topographies associated with MSA at both network and regional levels in two independent patient cohorts. Moreover, MSAPRP scores are sensitive for evaluating disease discrimination and clinical correlates. This study supports differential diagnosis of MSA regardless of different patient populations, PET scanners and imaging protocols.

\u201cFeasibility and utility of a simple computerized test for measuring saccade latency in progressive supranuclear palsy- a proof-of-concept study\u201d

BackgroundReliable detection of slowed vertical saccades may help discriminate progressive supranuclear palsy (PSP) from the subset of Parkinson’s disease patients who lack tremor (akinetic-rigid or PD-postural instability and gait disorder PIGD subtype), and from age-related oculomotor changes. We investigated the feasibility of a camera-less computerized behavioral saccade latency paradigm previously validated in PD to discriminate probable PSP-Richardson syndrome (PSP-RS) from PD-PIGD and age-matched controls.MethodsIn this proof-of-concept case-control study, reflexive saccade latencies were measured in 5 subjects with probable PSP-RS, 5 subjects with PD-PIGD subtype, and 5 age-matched controls using the behavioral paradigm. The battery was repeated approximately one month later. All subjects were examined off levodopa by a movement disorders neurologist and by an ophthalmologist, who also performed a dilated eye exam.ResultsVertical prosaccade latencies were longer in the PSP group (median = 903 ms) relative to PD (median = 268 ms) and control groups (median = 235 ms), with no overlap between groups (100% accuracy). PSP subjects also had larger vertical-horizontal discrepancies than comparison groups. Test-retest reliability for the behavioral saccade measures was good (interclass correlation coefficient = 0.948; 95% confidence interval [0.856, 0.982]), and the measures strongly correlated with clinical ratings.ConclusionsComputerized behavioral measurement of reflexive saccade latency is feasible in PSP, and potentially discriminates probable PSP-RS from the PD-PIGD subtype. Findings from this proof-of-concept study support utility of the approach for obtaining objective saccade metrics in clinical evaluations and for tracking change in future, larger trials of moderately advanced PSP. Future studies should also examine the behavioral paradigm in earlier presentations of PSP and other subtypes of PSP.

The olfactory bulb proteotype differs across frontotemporal dementia spectrum

Mild olfactory dysfunction has been observed in frontotemporal dementias (FTD). However, the underlying molecular mechanisms associated to this deficit are poorly understood. We applied quantitative proteomics to analyze pathological effects on the olfactory bulb (OB) from progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration (FTLD-TDP43) subjects respect to elderly non-FTD group. Our data revealed: i) a mitochondrial and calcium homeostasis impairment in PSP and ii) a disruption of protein synthesis and vesicle trafficking in FTLD-TDP43. Although differential OB proteomes clearly differ between both FTD phenotypes, functional analyses pointed out an imbalance in survival signaling in both pathologies. A common alteration of olfactory mitogen-activated protein kinases (MAPKs), calcium/calmodulin dependent protein kinase II (CAMKII), and protein kinase C (PKC) signaling pathways was observed in PSP and FTLD subjects. In contrast, a specific shut off in mitogen-activated protein kinase kinase 4 (SEK1/MKK4)/stress-activated protein kinase (SAPK) axis was exclusively observed in PSP, whereas a specific phosphoinositide-dependent protein kinase 1 (PDK1) inactivation was observed in FTLD-TDP43. In summary, our data contribute to a better understanding of the molecular mechanisms that are modulated in PSP and FTLD-TDP43 at olfactory level, highlighting cross-disease similarities and differences in the regulation of survival pathways across FTD spectrum. SignificanceThis work reflects differential olfactory molecular disarrangements in PSP and FTLD-TDP43, two clinically similar FTD disorders, but with different neuropathological signature. Besides FTDs present mild olfactory dysfunction, our data provide basic information for understanding the implication of the OB in the pathophysiology of FTDs.

Multimodal MRI evaluation of parkinsonian limbic pathologies

Previous multimodal magnetic resonance imaging (MRI) studies of parkinsonian syndromes have focused primarily on motor-related basal ganglia structures. The present study investigated MRI changes in nonmotor-related limbic structures in 35 Parkinson's disease, 16 multiple system atrophy parkinsonian subtype, 17 progressive supranuclear palsy, and 37 control subjects. Mean diffusivity (MD), fractional anisotropy, transverse relaxation rate (R2*), quantitative susceptibility mapping, and volume measurements were obtained from the amygdala, hippocampus, and nucleus accumbens (NAc) to examine differences between groups and to test for associations with clinical scores. Compared with controls, Parkinson's disease subjects had lower NAc volume; multiple system atrophy parkinsonian subtype subjects had higher NAc transverse relaxation rate; and progressive supranuclear palsy subjects had higher amygdala and hippocampus MD and lower hippocampus fractional anisotropy (p's ≤ 0.008). Among parkinsonian subjects, amygdala and hippocampus MD associated positively with Unified Parkinson's Disease Rating Scale nonmotor and activities of daily living scores (p's ≤ 0.005). Together, these findings support the inclusion of limbic structures in future MRI studies of parkinsonian syndromes.

MRI evaluation of progressive supranuclear palsy: differentiation from Parkinson’s disease and multiple system atrophy

ABSTRACTObjectives: To evaluate the magnetic resonance imaging (MRI)-derived parameters in differentiation of patients with progressive supranuclear palsy (PSP) from patients with Parkinson’s disease (PD), multiple system atrophy (MSA), and control subjects was aimed.Methods: Thirty-three patients [mean age, 65.21 ± 4.75 years; PSP (n = 9), MSA (n = 8), PD (n = 6), and control subjects (n = 10)] who have undergone cranial MRI were included in this retrospective study. MRI-derived parameters including areas of midbrain and pons, midbrain area-to-pons area (M/P) ratio, widths of middle cerebellar peduncle (MCP) and superior cerebellar peduncle (SCP), MCP/SCP ratio, magnetic resonance parkinsonism index (MRPI), cerebral interpeduncular angle, and length of midbrain tegmentum were compared in patients with PSP, PD, MSA, and control subjects through the analysis of variance and Kruskal–Wallis tests with Bonferroni correction and Mann–Whitney U test.Results: The length of midbrain tegmentum, midbrain area, SCP, and M/P ratio were found to be lower, while cerebral interpeduncular angle and MRPI were higher in patients with PSP. Pons area, MCP width, and MCP/SCP ratio were found to be lower in patients with MSA. For PSP, cerebral interpeduncular angle has a sensitivity of 100% and specifity of 90%, and MRPI had a sensitivity of 88.9% and specifity of 100% for PSP.Discussion: Several MRI-derived parameters can be used in differentiation of patients with PSP from patients with PD, MSA and control subjects. The cerebral interpeduncular angle and MRPI, which demonstrated higher values in patients with PSP, were more significant for PSP than the other parameters.

Characterisation of tau in the human and rodent enteric nervous system under physiological conditions and in tauopathy

Tau is normally a highly soluble phosphoprotein found predominantly in neurons. Six different isoforms of tau are expressed in the adult human CNS. Under pathological conditions, phosphorylated tau aggregates are a defining feature of neurodegenerative disorders called tauopathies. Recent findings have suggested a potential role of the gut-brain axis in CNS homeostasis, and therefore we set out to examine the isoform profile and phosphorylation state of tau in the enteric nervous system (ENS) under physiological conditions and in tauopathies. Surgical specimens of human colon from controls, Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) patients were analyzed by Western Blot and immunohistochemistry using a panel of anti-tau antibodies. We found that adult human ENS primarily expresses two tau isoforms, localized in the cell bodies and neuronal processes. We did not observe any difference in the enteric tau isoform profile and phosphorylation state between PSP, PD and control subjects. The htau mouse model of tauopathy also expressed two main isoforms of human tau in the ENS, and there were no apparent differences in ENS tau localization or phosphorylation between wild-type and htau mice. Tau in both human and mouse ENS was found to be phosphorylated but poorly susceptible to dephosphorylation with lambda phosphatase. To investigate ENS tau phosphorylation further, primary cultures from rat enteric neurons, which express four isoforms of tau, were pharmacologically manipulated to show that ENS tau phosphorylation state can be regulated, at least in vitro. Our study is the first to characterize tau in the rodent and human ENS. As a whole, our findings provide a basis to unravel the functions of tau in the ENS and to further investigate the possibility of pathological changes in enteric neuropathies and tauopathies.

Reproducible network and regional topographies of abnormal glucose metabolism associated with progressive supranuclear palsy: Multivariate and univariate analyses in American and Chinese patient cohorts.

Progressive supranuclear palsy (PSP) is a rare movement disorder and often difficult to distinguish clinically from Parkinson's disease (PD) and multiple system atrophy (MSA) in early phases. In this study, we report reproducible disease-related topographies of brain network and regional glucose metabolism associated with PSP in clinically-confirmed independent cohorts of PSP, MSA, and PD patients and healthy controls in the USA and China. Using 18 F-FDG PET images from PSP and healthy subjects, we applied spatial covariance analysis with bootstrapping to identify a PSP-related pattern (PSPRP) and estimate its reliability, and evaluated the ability of network scores for differential diagnosis. We also detected regional metabolic differences using statistical parametric mapping analysis. We produced a highly reliable PSPRP characterized by relative metabolic decreases in the middle prefrontal cortex/cingulate, ventrolateral prefrontal cortex, striatum, thalamus and midbrain, covarying with relative metabolic increases in the hippocampus, insula and parieto-temporal regions. PSPRP network scores correlated positively with PSP duration and accurately discriminated between healthy, PSP, MSA and PD groups in two separate cohorts of parkinsonian patients at both early and advanced stages. Moreover, PSP patients shared many overlapping areas with abnormal metabolism in the same cortical and subcortical regions as in the PSPRP. With rigorous cross-validation, this study demonstrated highly comparable and reproducible PSP-related metabolic topographies at network and regional levels across different patient populations and PET scanners. Metabolic brain network activity may serve as a reliable and objective marker of PSP, although cross-validation applying recent diagnostic criteria and classification is warranted.

Target-enriched sequencing of chromosome 17q21.31 in sporadic tauopathies reveals no candidate variants

The main genetic risk factors for progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are located at chromosome 17q21.31. The identification of risk H1 subhaplotypes suggests that disease-specific variants can be identified by resequencing the 17q21.31 region (1.4 Mb) in carriers of risk H1 subhaplotypes. We hypothesized that PSP/CBD H1 subhaplotype carriers could have undergone a mutational event absent among unaffected carriers leading to the disease risk. We performed this strategy in definite PSP subjects, definite CBD subjects, and healthy controls and tried to replicate the findings in a larger PSP/CBD case-control series. In the resequencing process, 40 candidate variants were identified, but an association between PSP and rs76970862 was replicated only using an unadjusted model. Gene expression association analysis of this variant suggested no potential functional effect. Although our results failed to identify disease-associated variants, it is still possible that the risk of PSP/CBD at chromosome 17 is driven by rare variants, even in PSP/CBD H1 cases or variants located outside the capture regions.

Neck Vibration Proprioceptive Postural Response Intact in Progressive Supranuclear Palsy unlike Idiopathic Parkinson's Disease.

Progressive supranuclear palsy (PSP) and late-stage idiopathic Parkinson’s disease (IPD) are neurodegenerative movement disorders resulting in different postural instability and falling symptoms. IPD falls occur usually forward in late stage, whereas PSP falls happen in early stages, mostly backward, unprovoked, and with high morbidity. Postural responses to sensory anteroposterior tilt illusion by bilateral dorsal neck vibration were probed in both groups versus healthy controls on a static recording posture platform. Three distinct anteroposterior body mass excursion peaks (P1–P3) were observed. 18 IPD subjects exhibited well-known excessive response amplitudes, whereas 21 PSP subjects’ responses remained unaltered to 22 control subjects. Neither IPD nor PSP showed response latency deficits, despite brainstem degeneration especially in PSP. The observed response patterns suggest that PSP brainstem pathology might spare the involved proprioceptive pathways and implies viability of neck vibration for possible biofeedback and augmentation therapy in PSP postural instability.

Pittsburgh Compound B and AV-1451 positron emission tomography assessment of molecular pathologies of Alzheimer's disease in progressive supranuclear palsy

IntroductionLittle is known about Alzheimer's disease molecular proteins, beta-amyloid and paired helical filament (PHF) tau, in progressive supranuclear palsy (PSP). Recent techniques have been developed to allow for investigations of these proteins in PSP. We determined the frequency of beta-amyloid deposition in PSP, and whether beta-amyloid deposition in PSP is associated with PHF-tau deposition pattern, or clinical features. MethodsThirty probable PSP participants underwent MRI, [18F]AV-1451 PET and Pittsburgh compound B (PiB) PET. Apolipoprotein (APOE) genotyping was also performed. A global PiB standard-uptake value ratio (SUVR) was calculated. AV-1451 SUVRs were calculated for a set of Alzheimer's disease (AD)-related regions and a set of PSP-related regions. Voxel-level analyses were conducted to assess for differences in AV-1451 uptake patterns and MRI atrophy between PiB(+) and PiB(−) cases compared to 60 normal PiB(−) controls. Statistical testing for correlations and associations between variables of interest were also performed. ResultsTwelve subjects (40%) showed beta-amyloid deposition. Higher PiB SUVR correlated with older age but not with AV-1451 SUVR in the AD- or PSP-related regions. Higher AV-1451 SUVR in AD-related regions was associated with higher AV-1451 SUVR in PSP-related regions. We found little evidence for beta-amyloid related differences in clinical metrics, proportion of APOE e4 carriers, pattern of AV-1451 uptake, or pattern of atrophy. ConclusionBeta-amyloid deposition occurs in a relatively high proportion of PSP subjects. Unlike in Alzheimer's disease, however, there is little evidence that beta-amyloid, and PHF-tau, play a significant role in neurodegeneration in PSP.