Supranuclear Research Articles

Absolute quantitation of sympathetic nerve activity using [123I] metaiodobenzylguanidine SPECT-CT in neurology

Background and purposeThe ability of [123I]metaiodobenzylguanidine (MIBG) sympathetic nerve imaging with three-dimensional (3D) quantitation to clinically diagnose neurological disorders has not been evaluated. This study compared absolute heart counts calculated as mean standardized uptake values (SUVmean) using conventional planar imaging and assessed the contribution of [123I]MIBG single-photon emission computed tomography (SPECT)-CT to the diagnosis of neurological diseases.MethodsSeventy-two patients with neurological diseases were consecutively assessed using early and delayed [123I]MIBG SPECT-CT and planar imaging. Left ventricles were manually segmented in early and delayed SPECT-CT images, then the SUVmean and washout rates (WRs) were calculated. Heart-to-mediastinum ratios (HMRs) and WRs on planar images were conventionally computed. We investigated correlations between planar HMRs and SPECT-CT SUVmeans and between WRs obtained from planar and SPECT-CT images. The cutoff for SPECT-CT WRs defined by linear regression and that of normal planar WRs derived from a database were compared with neurological diagnoses of the patients. We assigned the patients to groups according to clinical diagnoses as controls (n = 6), multiple system atrophy (MSA, n = 7), progressive supranuclear palsy (PSP, n = 17), and Parkinson’s disease or dementia with Lewy bodies (PD/DLB, n = 19), then compared SPECT-CT and planar image parameters.ResultsWe found significant correlations between SPECT-CT SUVmean and planar HMR on early and delayed images (R2 = 0.69 and 0.82, p < 0.0001) and between SPECT-CT and planar WRs (R2 = 0.79, p < 0.0001). A threshold of 31% for SPECT-CT WR based on linear regression resulted in agreement between planar and SPECT-CT WR in 67 (93.1%) of 72 patients. Compared with controls, early and delayed SUVmean in patients with PSP and MSA tended more towards significance than planar HMR. This trend was similar for SPECT-CT WRs in patients with PSP.ConclusionsAbsolute heart counts and SUVmean determined using [123I]MIBG SPECT-CT correlated with findings of conventional planar images in patients with neurological diseases. Three-dimensional quantitation with [123I]MIBG SPECT-CT imaging might differentiate patients with PSP and MSA from controls.

Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p= 2.5×10-12, OR= 1.27) and APOE (rs6857; p= 1.31×10-12, OR= 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p= 2.41×10-8, OR= 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Iron deposition in subcortical nuclei of Parkinson's disease: A meta-analysis of quantitative iron-sensitive magnetic resonance imaging studies.

Iron deposition plays a crucial role in the pathophysiology of Parkinson's disease (PD), yet the distribution pattern of iron deposition in the subcortical nuclei has been inconsistent across previous studies. We aimed to assess the difference patterns of iron deposition detected by quantitative iron-sensitive magnetic resonance imaging (MRI) between patients with PD and patients with atypical parkinsonian syndromes (APSs), and between patients with PD and healthy controls (HCs). A systematic literature search was conducted on PubMed, Embase, and Web of Science databases to identify studies investigating the iron content in PD patients using the iron-sensitive MRI techniques (R2* and quantitative susceptibility mapping [QSM]), up until May 1, 2023. The quality assessment of case-control and cohort studies was performed using the Newcastle-Ottawa Scale, whereas diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Standardized mean differences and summary estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for iron content, using a random effects model. We also conducted the subgroup-analysis based on the MRI sequence and meta-regression. Seventy-seven studies with 3192 PD, 209 multiple system atrophy (MSA), 174 progressive supranuclear palsy (PSP), and 2447 HCs were included. Elevated iron content in substantia nigra (SN) pars reticulata (P <0.001) and compacta (P <0.001), SN (P <0.001), red nucleus (RN, P <0.001), globus pallidus (P <0.001), putamen (PUT, P=0.009), and thalamus (P=0.046) were found in PD patients compared with HCs. PD patients showed lower iron content in PUT (P <0.001), RN (P=0.003), SN (P=0.017), and caudate nucleus (P=0.027) than MSA patients, and lower iron content in RN (P=0.001), PUT (P <0.001), globus pallidus (P=0.004), SN (P=0.015), and caudate nucleus (P=0.001) than PSP patients. The highest diagnostic accuracy distinguishing PD from HCs was observed in SN (AUC: 0.85), and that distinguishing PD from MSA was found in PUT (AUC: 0.90). In addition, the best diagnostic performance was achieved in the RN for distinguishing PD from PSP (AUC: 0.84). Quantitative iron-sensitive MRI could quantitatively detect the iron content of subcortical nuclei in PD and APSs, while it may be insufficient to accurately diagnose PD. Future studies are needed to explore the role of multimodal MRI in the diagnosis of PD. PROSPERO; CRD42022344413.

P.008 Spontaneous retropulsion in autopsy verified PSP

Background: Postural instability is a common symptom of progressive supranuclear palsy (PSP). Retropulsion is one form of postural instability. Spontaneous retropulsion involves loss of balance without external provocation. Others have reported on retropulsion in the clinical setting while testing for postural instability but rates of spontaneous retropulsion in the community have not been described. This study examines the prevalence of spontaneous retropulsion in PSP. Methods: A retrospective chart review examined 60 patients from the Saskatchewan Movement Disorders Program with clinical and pathology-confirmed diagnosis of PSP. We identified patients who endorsed spontaneous retropulsion. The data was analysed with univariate logistic regression. Results: The study included 43 males and 17 females. Spontaneous retropulsion was reported in 18 (30%) patients. Among the variables, only sex showed a statistical significance (p = 0.0184) with females more likely to report spontaneous retropulsion (OR = 4.25). Other variables (PSP onset age, onset age of balance impairment, gait impairment, and disease duration) were not statistically significant. Conclusions: Our data suggest that spontaneous retropulsion is common in PSP, with females being at a significantly higher risk than males. This is useful information when counselling patients on risk-avoidance behaviour to prevent falls.

Progressive Supranuclear palsy (PSP) disease progression, management, and healthcare resource utilization: a retrospective observational study in the US and Canada

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative brain disease with rapid progression and currently limited treatment options. A comprehensive understanding of disease progression, management, and healthcare resource utilization is limited, and further research is challenging due to the small population of patients. To address these challenges in conducting PSP research, individuals with PSP were recruited using a multichannel approach tailored specifically to the PSP community. We performed a retrospective observational study using data abstracted from participant medical records collected from multiple patient care centers.ResultsSeventy-two individuals with PSP were eligible for inclusion. On average, 144 medical documents per participant were collected from an average of 2.9 healthcare centers per participant, with a mean study period of 7.9 years. Among participants with a date of symptom onset documented in the medical records, the median time for the onset of the first fall was 2.0 years (IQR 3.2) before diagnosis, the median onset of unsteady gait or gait impairment was 1.2 years (IQR 1.8) before diagnosis, and the median onset of mobility problems was 0.8 years (IQR 1.8) before diagnosis. The most widely utilized healthcare resources, with at least 85% of participants using each of these resources at some point during the disease course, were medications (100%), imaging (99%), assistive devices (90%), supportive care (86%), and surgeries and procedures (85%).ConclusionsThis retrospective study adds to the current understanding of PSP symptoms, comorbidities, and healthcare resource utilization (HRU) across the disease journey. By involving individuals with PSP and their caregivers or legally authorized representatives in the research process, this study was unique in its approach to participant recruitment and enabled individuals to participate in research without the need for travel. We collected medical documents from multiple healthcare centers, allowing for broad data collection covering the entire disease journey. This approach to the collection of real-world data may be used to generate valuable insights into many aspects of disease progression and management in PSP and many other rare diseases.

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

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. 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. 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. 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.

Recent advances in stem cells therapy: efficacy, ethics, safety concerns and future directions focusing on neurodegenerative disorders- a review

Neurodegeneration refers to the gradual loss of neurons and extensive changes occur in glial cells like tau inclusions in astrocytes and oligodendrocytes, α-synuclein inclusions in oligodendrocytes and SOD1 aggregates in astrocytes along with deterioration in the motor, cognition, learning, and behaviour. Common neurodegenerative disorders are Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease (HD), Spinocerebellar Ataxia (SCAs), and Supranuclear palsy are some common one. There is a lack of effective treatment for neurodegenerative diseases, and scientists are putting their efforts into developing therapies against them. Stem cell therapy has emerged as a hope for neurodegenerative disorders since it is not only the damaged neurons that might be replaced, but other neuromodulators and neuroprotectors are secreted. Stem cell terminal differentiation before implantation ensures the implantation of correct cells and molecular markers like carbonic anhydrase II, CNPase (2′,3′-cyclic nucleotide 3′-phosphohydrolase), myelin basic protein (MBP), and myelin oligodendrocyte glycoprotein ​(MOG) elucidate the differentiation. Secretion of various growth factors like epidermal growth factor (EGF), keratinocyte growth factor (KGF), vascular endothelial growth factor-α (VEGF-α), transforming growth factor (TGF) and macrophage inflammatory protein (MIP) supports cell survival, cell proliferation, blood vessel formation, axon regeneration, and neuroglial functional connection formation at the site of degeneration. Adverse effects of stem cell therapy, like teratogenicity and differentiation in different cells other than the desired one under the influence of microenvironment, are a few key concerns. Post-transplantation improved synaptic plasticity, apoptosis inhibition, and reduction in tau-phosphorylation and Amyloid beta (Aβ) production has been observed in Alzheimer’s patients.A large number of experimental, preclinical, and clinical studies have been conducted, and encouraging results have been obtained. The present review exhaustively discusses various kinds of stem cells, their usage in treating neurodegenerative disorders, limitations and challenges, and ethical issues related to stem cell therapy.

Pharmacotherapies for the Treatment of Progressive Supranuclear Palsy: A Narrative Review.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder resulting from the deposition of misfolded and neurotoxic forms of tau protein in specific areas of the midbrain, basal ganglia, and cortex. It is one of the most representative forms of tauopathy. PSP presents in several different phenotypic variations and is often accompanied by the development of concurrent neurodegenerative disorders. PSP is universally fatal, and effective disease-modifying therapies for PSP have not yet been identified. Several tau-targeting treatment modalities, including vaccines, monoclonal antibodies, and microtubule-stabilizing agents, have been investigated and have had no efficacy. The need to treat PSP and other tauopathies is critical, and many clinical trials investigating tau-targeted treatments are underway. In this review, the PubMed database was queried to collect information about preclinical and clinical research on PSP treatment. Additionally, the US National Library of Medicine's ClinicalTrials.gov website was queried to identify past and ongoing clinical trials relevant to PSP treatment. This narrative review summarizes our findings regarding these reports, which include potential disease-modifying drug trials, modifiable risk factor management, and symptom treatments.

Low-intensity vestibular noise stimulation improves postural symptoms in progressive supranuclear palsy

BackgroundPostural imbalance and falls are an early disabling symptom in patients with progressive supranuclear palsy (PSP) of multifactorial origin that may involve abnormal vestibulospinal reflexes. Low-intensity noisy galvanic vestibular stimulation (nGVS) is a non-invasive treatment to normalize deficient vestibular function and attenuate imbalance in Parkinson’s disease. The presumed therapeutic mode of nGVS is stochastic resonance (SR), a mechanism by which weak sensory noise stimulation can enhance sensory information processing.ObjectiveTo examine potential treatment effects of nGVS on postural instability in 16 patients with PSP with a clinically probable and [18F]PI-2620 tau-PET-positive PSP.MethodsEffects of nGVS of varying intensity (0–0.7 mA) on body sway were examined, while patients were standing with eyes closed on a posturographic force plate. We assumed a bell-shaped response curve with maximal sway reductions at intermediate nGVS intensities to be indicative of SR. An established SR-curve model was fitted on individual patient outcomes and three experienced human raters had to judge whether responses to nGVS were consistent with the exhibition of SR.ResultsWe found nGVS-induced reductions of body sway compatible with SR in 9 patients (56%) with optimal improvements of 31 ± 10%. In eight patients (50%), nGVS-induced sway reductions exceeded the minimal clinically important difference (improvement: 34 ± 5%), indicative of strong SR.ConclusionnGVS yielded clinically relevant reductions in body sway compatible with the exhibition of SR in vestibular sensorimotor pathways in at least half of the assessed patients. Non-invasive vestibular noise stimulation may be thus a well-tolerated treatment strategy to ameliorate postural symptoms in PSP.

Assessment of [18F]PI-2620 Tau-PET Quantification via Non-Invasive Automatized Image Derived Input Function

Purpose[18F]PI-2620 positron emission tomography (PET) detects misfolded tau in progressive supranuclear palsy (PSP) and Alzheimer’s disease (AD). We questioned the feasibility and value of absolute [18F]PI-2620 PET quantification for assessing tau by regional distribution volumes (VT). Here, arterial input functions (AIF) represent the gold standard, but cannot be applied in routine clinical practice, whereas image-derived input functions (IDIF) represent a non-invasive alternative. We aimed to validate IDIF against AIF and we evaluated the potential to discriminate patients with PSP and AD from healthy controls by non-invasive quantification of [18F] PET.MethodsIn the first part of the study, we validated AIF derived from radial artery whole blood against IDIF by investigating 20 subjects (ten controls and ten patients). IDIF were generated by manual extraction of the carotid artery using the average and the five highest (max5) voxel intensity values and by automated extraction of the carotid artery using the average and the maximum voxel intensity value. In the second part of the study, IDIF quantification using the IDIF with the closest match to the AIF was transferred to group comparison of a large independent cohort of 40 subjects (15 healthy controls, 15 PSP patients and 10 AD patients). We compared VT and VT ratios, both calculated by Logan plots, with distribution volume (DV) ratios using simplified reference tissue modelling and standardized uptake value (SUV) ratios.ResultsAIF and IDIF showed highly correlated input curves for all applied IDIF extraction methods (0.78 < r < 0.83, all p < 0.0001; area under the curves (AUC): 0.73 < r ≤ 0.82, all p ≤ 0.0003). Regarding the VT values, correlations were mainly found between those generated by the AIF and by the IDIF methods using the maximum voxel intensity values. Lowest relative differences (RD) were observed by applying the manual method using the five highest voxel intensity values (max5) (AIF vs. IDIF manual, avg: RD = -82%; AIF vs. IDIF automated, avg: RD = -86%; AIF vs. IDIF manual, max5: RD = -6%; AIF vs. IDIF automated, max: RD = -26%). Regional VT values revealed considerable variance at group level, which was strongly reduced upon scaling by the inferior cerebellum. The resulting VT ratio values were adequate to detect group differences between patients with PSP or AD and healthy controls (HC) (PSP target region (globus pallidus): HC vs. PSP vs. AD: 1.18 vs. 1.32 vs. 1.16; AD target region (Braak region I): HC vs. PSP vs. AD: 1.00 vs. 1.00 vs. 1.22). VT ratios and DV ratios outperformed SUV ratios and VT in detecting differences between PSP and healthy controls, whereas all quantification approaches performed similarly in comparing AD and healthy controls.ConclusionBlood-free IDIF is a promising approach for quantification of [18F]PI-2620 PET, serving as correlating surrogate for invasive continuous arterial blood sampling. Regional [18F]PI-2620 VT show large variance, in contrast to regional [18F]PI-2620 VT ratios scaled with the inferior cerebellum, which are appropriate for discriminating PSP, AD and healthy controls. DV ratios obtained by simplified reference tissue modeling are similarly suitable for this purpose.

Proteomic changes in the human cerebrovasculature in Alzheimer's disease and related tauopathies linked to peripheral biomarkers in plasma and cerebrospinal fluid.

Cerebrovascular dysfunction is a pathological hallmark of Alzheimer's disease (AD). Nevertheless, detecting cerebrovascular changes within bulk tissues has limited our ability to characterize proteomic alterations from less abundant cell types. We conducted quantitative proteomics on bulk brain tissues and isolated cerebrovasculature from the same individuals, encompassing control (N=28), progressive supranuclear palsy (PSP) (N=18), and AD (N=21) cases. Protein co-expression network analysis identified unique cerebrovascular modules significantly correlated with amyloid plaques, cerebrovascular amyloid angiopathy (CAA), and/or tau pathology. The protein products within AD genetic risk loci were concentrated within cerebrovascular modules. The overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with cerebrovascular network highlighted a significant increase of matrisome proteins, SMOC1 and SMOC2, in CSF, plasma, and brain. These findings enhance our understanding of cerebrovascular deficits in AD, shedding light on potential biomarkers associated with CAA and vascular dysfunction in neurodegenerative diseases.

Is there a spinal tap responder in progressive supranuclear palsy? The first prospective study.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease, and sometimes shows idiopathic normal pressure hydrocephalus (iNPH)-like presentations. We aimed to evaluate spinal tap responsiveness in patients with PSP, including the effect of sham spinal tap. Eleven patients with PSP, ten with probable/definite iNPH, and eight control patients were prospectively enrolled. All participants underwent sham spinal tap and spinal tap procedures. Gait was evaluated using wearable inertial sensors. We defined "tap responders" as individuals with a 10% or more improvement from baseline in any of the gait parameters (timed up-and-go test total time, stride length, and velocity during straight walking under single-task and cognitive dual-task conditions). We compared the ratio of responders in patients with PSP to patients with iNPH and controls. The ratio of tap responders and the ratio of sham tap responders in patients with PSP were significantly higher than those in control patients, and not different from those in patients with iNPH. PSP patients with iNPH-like MRI features tended to respond to the spinal tap compared to those without such imaging features. Notably, one patient with PSP, who responded to the spinal tap beyond the effect of sham spinal tap, was treated by the shunt operation. This is the first prospective study to demonstrate tap and shunt responsiveness in patients with PSP while highlighting the placebo effects of the spinal tap in patients with PSP or iNPH. Our findings suggest that some PSP patients have impaired cerebrospinal fluid circulation, contributing to a distinct component of the clinical spectrum.

Converging peripheral blood microRNA profiles in Parkinson's disease and progressive supranuclear palsy.

MicroRNAs act via targeted suppression of messenger RNA translation in the DNA-RNA-protein axis. The dysregulation of microRNA(s) reflects the epigenetic changes affecting the cellular processes in multiple disorders. To understand the complex effect of dysregulated microRNAs linked to neurodegeneration, we performed a cross-sectional microRNA expression analysis in idiopathic Parkinson's disease (n = 367), progressive supranuclear palsy (n = 35) and healthy controls (n = 416) from the Luxembourg Parkinson's Study, followed by prediction modelling, enriched pathway analysis and target simulation of dysregulated microRNAs using probabilistic Boolean modelling. Forty-six microRNAs were identified to be dysregulated in Parkinson's disease versus controls and 16 in progressive supranuclear palsy versus controls with 4 overlapping significantly dysregulated microRNAs between the comparisons. Predictive power of microRNA subsets (including up to 100 microRNAs) was modest for differentiating Parkinson's disease or progressive supranuclear palsy from controls (maximal cross-validated area under the receiver operating characteristic curve 0.76 and 0.86, respectively) and low for progressive supranuclear palsy versus Parkinson's disease (maximal cross-validated area under the receiver operating characteristic curve 0.63). The enriched pathway analysis revealed natural killer cell pathway to be dysregulated in both, Parkinson's disease and progressive supranuclear palsy versus controls, indicating that the immune system might play an important role in both diseases. Probabilistic Boolean modelling of pathway dynamics affected by dysregulated microRNAs in Parkinson's disease and progressive supranuclear palsy revealed partially overlapping dysregulation in activity of the transcription factor EB, endoplasmic reticulum stress signalling, calcium signalling pathway, dopaminergic transcription and peroxisome proliferator-activated receptor gamma coactivator-1α activity, though involving different mechanisms. These findings indicated a partially convergent (sub)cellular end-point dysfunction at multiple levels in Parkinson's disease and progressive supranuclear palsy, but with distinctive underlying molecular mechanisms.

Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19

The majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble α-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) also frequently experience hyposmia. We previously postulated that microglial activation as well as α-synuclein and tau misprocessing can occur during host responses following microbial encounters. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19 + patients (n = 22), individuals with Lewy body disease (e.g., PD; dementia with Lewy bodies (n = 6)), Alzheimer disease (AD; n = 3), and other neurodegenerative disorders (e.g., progressive supranuclear palsy (n = 2); multisystem atrophy (n = 1)). Further, we included neurologically healthy controls (n = 9), and added subjects with an inflammation-rich brain disorder as neurological controls (NCO; n = 7). When probing for microglial and histiocytic reactivity in the anterior olfactory nuclei (AON) by anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, microglial signals on average were not significantly altered in COVID19 + patients relative to healthy controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-α-synuclein and phospho-tau signals were detected in the AON of tauopathy- and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes in the rostral, intracranial portion of the olfactory circuitry -when present- reflected neurodegenerative processes seen elsewhere in the brain. In general, microglial reactivity correlated best with the degree of Alzheimer’s-linked tauopathy and declined with progression of age in COVID19 + patients.

“¿Cómo qué, cómo qué? cómo qué?” Single-language echolalia in a bilingual female with progressive supranuclear palsy: a case report

ABSTRACT The case study explores bilingualism and neurodegenerative disorders, specifically progressive supranuclear palsy (PSP) with speech and language disorder (PSP-SL). It features a 78-year-old Mexican American woman who exhibits echolalia only in response to Spanish. This selective impairment suggests unevenly affected language control mechanisms despite her proficiency in both languages. Cognitive function is evaluated with neuropsychological tests; she's diagnosed with PSP-SL, depression, and anxiety. Echolalia in response to one language implies complex phonological retrieval mechanisms. Such observations prompt further inquiry into bilingual language control and processing mechanisms. The case supports evidence that bilingualism may attenuate neurodegeneration effects, suggesting better inhibitory control over disinhibited speech through enhanced executive functioning benefits.

THE EFFECTIVENESS OF PROGRESSIVE RESISTANCE TRAINING IN MANAGING PROGRESSIVE SUPRANUCLEAR PALSY: A CASE STUDY

SETTING The Centre for STRONG Medicine is an outpatient multidisciplinary geriatric service at Concord Hospital, Sydney. An 82-year-old male with a primary diagnosis of Progressive Supranuclear Palsy (PSP) with cardiac and metabolic comorbidities was referred in March 2023. PSP is a rare neurological disorder that affects gait, balance, vision, and cognition. The participant mobilised with a rollator and had previously sustained vertebral and wrist fractures secondary to falls. MANAGEMENT Management was to use progressive resistance training (PRT) to combat mobility decline, prevent falls and provide education to encourage independent exercise. Initial assessment determined current health status using Falls Self Efficacy Scale (FSE-I) and Fried Frailty Phenotype (FFP) questionnaires, and measured function and strength using maximal gait speed, five times sit-to-stand (5xSTS) and one repetition maximum (1RM), respectively. FSE-I determined a high fear of falling and FFP determined frail classification. Outcomes informed the PRT exercise prescription targeting the major muscle groups for 2-3 sets of 7-9 repetitions at 70-85% 1RM progressed gradually and preformed twice weekly in a supervised group. Education regarding breathing, exercise tempo, rest, progression, and risk mitigation were provided. All outcomes were reassessed after 12-weeks of training. RESULTS Attendance was 100% (23 sessions) with improvement in all outcomes. Functional improvements included 0.25metres/second increase in maximal gait speed, 2.5 second reduction in 5xSTS, and safe mobilisation without a rollator. Strength improvements included 101% increase in 1RM leg press, 100% increase in 1RM triceps extension and 72% increase in 1RM seated row. Frailty status improved to pre-frail and fear of falling reduced. Self-reported improvements included increased steadiness and confidence exercising unsupervised. DISCUSSION Although PSP is progressive, PRT resulted in meaningful benefits in strength and function that improved daily task performance and confidence. Further research is needed to investigate the effects of PRT on PSP management in a larger cohort.

Impaired sequence manipulation in non-demented patients with progressive supranuclear palsy.

Sequential working memory is the ability to maintain and manipulate sequential information at a second time scale. Patients with progressive supranuclear palsy (PSP) or Parkinson's disease (PD) perform poorly in tests that require the flexible arrangement of thoughts or actions. This study investigated whether sequential working memory is differently impaired in patients with PSP versus PD. Twenty-nine patients with PSP Richardson's syndrome (PSP-RS), 36 patients with PD, and 36 healthy controls (HC) completed 3 well-established neuropsychological tests, including digit span forward (DST-F), digit span backward (DST-B), and adaptive digit ordering tests (DOT-A). The DST-F required maintaining digit sequences, and the DST-B and DOT-A required maintaining and manipulating digit sequences. The PSP-RS group scored lower than the PD and HC groups in the DST-B and DOT-A but not in the DST-F, indicating that the ability to manipulate sequences was impaired, but the maintenance ability was preserved in PSP-RS patients. Moreover, in PSP-RS, the DST-B score negatively correlated with the severity of motor symptoms. The actual levodopa dose positively correlated with the DST-B ordering cost (DST-F score vs. DST-B score). The PSP patients who took a greater dose of levodopa tended to have higher DST-B ordering cost. There was no effect of levodopa on DST-B or DOT-A in PD. These results suggested that the ability to manipulate sequence was already reduced in patients with PSP-RS and was worse than in patients with PD.

Effects of physiotherapy and home-based training in parkinsonian syndromes: protocol for a randomised controlled trial (MobilityAPP)

IntroductionGait and mobility impairment are pivotal signs of parkinsonism, and they are particularly severe in atypical parkinsonian disorders including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A pilot...

Faster, More Practical, but Still Accurate: Deep Learning for Diagnosis of Progressive Supranuclear Palsy.

Faster, More Practical, but Still Accurate: Deep Learning for Diagnosis of Progressive Supranuclear Palsy.