Ethnic background and distribution of clinical phenotypes in patients with probable progressive supranuclear palsy.

BACKGROUND: Progressive Supranuclear Palsy (PSP) is a sporadic neurodegenerative disease without a clear geographic prevalence. Cohorts studied in the UK and India showed no higher prevalence of atypical parkinsonism in South Asian patients. We describe the ethnic and racial background of PSP patients in the Greater Toronto Area (GTA), Canada. METHODS: A prospective observational study of patients with clinically probable PSP evaluated at the dedicated Rossy PSP program. Demographic and clinical data were collected at baseline including PSP phenotype. Results were compared with the latest demographic information from the greater Toronto area. RESULTS: Of the 197 patients screened, 135 had probable PSP and resided within the GTA. The mean age at visit was 71.1 years, disease duration 4.4 years, and disease severity moderate. Compared to our catchment area, there was a higher proportion of patients with a South Asian origin and a lower proportion of patients from East and Southeastern Asia and Africa. A secondary analysis using population census data limited to individuals greater than 65 confirmed the significantly higher representation of South Asians in our clinic but found no differences for other racial and ethnic origins. CONCLUSION: Evaluation of this Toronto cohort found a greater than expected proportion of affected individuals with South Asian ethnic and racial origin. Despite limitations, our results suggest the possibility of a racial and ethnic predisposition to PSP. Further studies are needed to confirm and to address potential associated risk factors, and genome-environmental interactions.

Evaluating the Effect of Alzheimer's Disease-Related Biomarker Change in Corticobasal Syndrome and Progressive Supranuclear Palsy.

OBJECTIVES: To evaluate the effect of Alzheimer's disease (AD) -related biomarker change on clinical features, brain atrophy and functional connectivity of patients with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). METHODS: Data from patients with a clinical diagnosis of CBS, PSP, and AD and healthy controls were obtained from the 4-R-Tauopathy Neuroimaging Initiative 1 and 2, the Alzheimer's Disease Neuroimaging Initiative, and a local cohort from the Toronto Western Hospital. Patients with CBS and PSP were divided into AD-positive (CBS/PSP-AD) and AD-negative (CBS/PSP-noAD) groups based on fluid biomarkers and amyloid PET scans. Cognitive, motor, and depression scores; AD fluid biomarkers (cerebrospinal p-tau, t-tau, and amyloid-beta, and plasma ptau-217); and neuroimaging data (amyloid PET, MRI and fMRI) were collected. Clinical features, whole-brain gray matter volume and functional networks connectivity were compared across groups. RESULTS: Data were analyzed from 87 CBS/PSP-noAD and 23 CBS/PSP-AD, 18 AD, and 30 healthy controls. CBS/PSP-noAD showed worse performance in comparison to CBS/PSP-AD in the PSPRS [mean(SD): 34.8(15.8) vs 23.3(11.6)] and the UPDRS scores [mean(SD): 34.2(17.0) vs 21.8(13.3)]. CBS/PSP-AD demonstrated atrophy in AD signature areas and brainstem, while CBS/PSP-noAD patients displayed atrophy in frontal and temporal areas, globus pallidus, and brainstem compared to healthy controls. The default mode network showed greatest disconnection in CBS/PSP-AD compared with CBS/PSP-no AD and controls. The thalamic network connectivity was most affected in CBS/PSP-noAD. INTERPRETATION: AD biomarker positivity may modulate the clinical presentation of CBS/PSP, with evidence of distinctive structural and functional brain changes associated with the AD pathology/co-pathology. ANN NEUROL 2024.

Distinct involvement of the cranial and spinal nerves in progressive supranuclear palsy.

The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in the PNS are well-recognized in α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is a paucity of observations in tauopathies. To characterize the involvement of the PNS in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases [progressive supranuclear palsy (PSP), n = 15; Alzheimer's disease (AD), n = 18; chronic traumatic encephalopathy (CTE), n = 5; and corticobasal degeneration (CBD), n = 6; Pick's disease, n = 9; limbic-predominant neuronal inclusion body 4-repeat tauopathy (LNT), n = 1] using immunohistochemistry, Gallyas silver staining, biochemistry, and seeding assays. Most PSP cases revealed phosphorylated and 4-repeat tau immunoreactive tau deposits in the PNS as follows: (number of tau-positive cases/available cases) cranial nerves III: 7/8 (88%); IX/X: 10/11 (91%); and XII: 6/6 (100%); anterior spinal roots: 10/10 (100%). The tau-positive inclusions in PSP often showed structures with fibrillary (neurofibrillary tangle-like) morphology in the axon that were also recognized with Gallyas silver staining. CBD cases rarely showed fine granular non-argyrophilic tau deposits. In contrast, tau pathology in the PNS was not evident in AD, CTE and Pick's disease cases. The single LNT case also showed tau pathology in the PNS. In PSP, the severity of PNS-tau involvement correlated with that of the corresponding nuclei, although, occasionally, p-tau deposits were present in the cranial nerves but not in the related brainstem nuclei. Not surprisingly, most of the PSP cases presented with eye movement disorder and bulbar symptoms, and some cases also showed lower-motor neuron signs. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. In conclusion, prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.

4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy.

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

Investigating differences in young- and late-onset progressive supranuclear palsy.

BACKGROUND: The impact of age of onset on the presentation of progressive supranuclear palsy phenotypes is not well studied. We hypothesized that there is difference in presentation and phenotype between young- and late-onset PSP. OBJECTIVES: Our aim was to compare phenotypes and rate of change in disability between young-onset PSP (YOPSP) and late-onset PSP (LOPSP). METHODS: Retrospective data of patients seen in the Rossy PSP Centre from March 2014 to April 2022 with clinical diagnosis of PSP as per the MDS 2017 diagnostic criteria were examined. We used cut-off age of 65 years to categorize the patients into YOPSP and LOPSP. We compared the prevalence of phenotypes, presenting symptoms, and MDS core criteria between the two groups. The severity of disease between the two groups was measured using PSP-RS. RESULTS: We found 107 patients with clinical diagnosis of PSP as per MDS criteria, a third were defined as YOPSP. PSP speech/language (SL) phenotype was more prevalent in YOPSP (18% vs 0%, p < 0.001). Aphasia was significantly higher in YOPSP (16% vs 1.4%, p = 0.03). The speech and language dysfunction (C1) core criteria were more prevalent in YOPSP (33.3% vs 12.2%, p = 0.05). Longitudinal analysis of PSP-RS showed worsening of bulbar total score at 6 months in YOPSP (t (38) = 2.87; p = 0.05). CONCLUSION: Our study revealed that YOPSP are more likely to present with a speech and language variant. Our results highlight that age of onset may predict PSP phenotypes, which holds both clinical and prognostic importance.

Disease Progression and Sphingolipids and Neurofilament Light Chain in Early Idiopathic Parkinson's Disease.

Parkinson's disease(PD) lacks a biomarker for disease progression. To analyze how cerebrospinal fluid (CSF), glucosylceramide (GlcCer), sphingomyelin (SM), or serum neurofilament light chain (NfL) associate with progression of PD in a retrospective cohort, we used linear mixed-model regressions between baseline biomarkers and change in dopamine transporter brain-imaging (DaTscan©), Montreal cognitive assesment (MoCA), or global composite outcome (GCO) score. In 191 PD patients, biomarkers were not associated with DaTscan or MoCA change over 2.1 years. Higher baseline GlcCer/SM ratio and serum-NfL nonsignificantly associated with increase in GCO score. Results do not support a role for CSF-sphingolipid/serum-NfL to predict cognitive and DaTscan progression in early-PD. Potential prediction of global clinical change warrants further study.

The Rossy Progressive Supranuclear Palsy Centre: Creation and Initial Experience.

OBJECTIVE: To describe the development and initial experience of a clinical research program in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) in Canada: The Rossy PSP Centre, to share the data acquisition tools adopted, and to report preliminary results. METHODS: Extensive demographic and longitudinal clinical information is collected every 6 months using standardized forms. Biofluids are collected for biobanking and genetic analysis, and many patients are enrolled in neuroimaging research protocols. Brain donation is an important component of the program, and standardized processing protocols have been established, including very short death to autopsy times in patients undergoing medical assistance in dying. RESULTS: Between Oct 2019 and Dec 2021, 132 patients were screened, 91 fulfilling criteria for PSP and 19 for CBS; age 71 years; 41% female; duration 5 years, age-of-onset 66 years. The most common symptoms at onset were postural instability and falls (45%), cognitive-behavioral changes (22%), and Parkinsonism (9%). The predominant clinical phenotype was Richardson syndrome (82%). Levodopa and amantadine resulted in partial and short-lasting benefit. CONCLUSIONS: The Rossy PSP Centre has been established to advance clinical and basic research in PSP and related tauopathies. The extent of the clinical data collected permits deep phenotyping of patients and allows for future clinical and basic research. Preliminary results showed expected distribution of phenotypes, demographics, and response to symptomatic treatments in our cohort. Longitudinal data will provide insight into the early diagnosis and management of PSP. Future steps include enrollment of patients in earlier stages, development of biomarkers, and fast-tracking well-characterized patients into clinical trials.

Cell-Specific Dysregulation of Iron and Oxygen Homeostasis as a Novel Pathophysiology in PSP.

OBJECTIVE: Progressive supranuclear palsy (PSP) is a 4R-tauopathy showing heterogeneous tau cytopathology commencing in the globus pallidus (GP) and the substantia nigra (SN), regions also associated with age-related iron accumulation. Abnormal iron levels have been extensively associated with tau pathology in neurodegenerative brains, however, its role in PSP pathogenesis remains yet unknown. We perform the first cell type-specific evaluation of PSP iron homeostasis and the closely related oxygen homeostasis, in relation to tau pathology in human postmortem PSP brains. METHODS: In brain regions vulnerable to PSP pathology (GP, SN, and putamen), we visualized iron deposition in tau-affected and unaffected neurons, astroglia, oligodendrocytes, and microglia, using a combination of iron staining with immunolabelling. To further explore molecular pathways underlying our observations, we examined the expression of key iron and oxygen homeostasis mRNA transcripts and proteins. RESULTS: We found astrocytes as the major cell type accumulating iron in the early affected regions of PSP, highly associated with cellular tau pathology. The same regions are affected by dysregulated expression of alpha and beta hemoglobin and neuroglobin showing contrasting patterns. We discovered changes in iron and oxygen homeostasis-related gene expression associated with aging of the brain, and identified dysregulated expression of rare neurodegeneration with brain iron accumulation (NBIA) genes associated with tau pathology to distinguish PSP from the healthy aging brain. INTERPRETATION: We present novel aspects of PSP pathophysiology highlighting an overlap with NBIA pathways. Our findings reveal potential novel targets for therapy development and have implications beyond PSP for other iron-associated neurodegenerative diseases. ANN NEUROL 2023;93:431-445.

Protracted course progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD). METHODS: Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology. RESULTS: We identified four cases with long (>10-15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele. CONCLUSIONS: We propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.

Brain structural correlates of executive and social cognition profiles in behavioral variant frontotemporal dementia and elderly bipolar disorder.

An early stage of behavioral variant frontotemporal dementia (bvFTD) often displays a mix of behavioral disturbances and personality changes hindering a differential diagnosis from elderly bipolar disorder (BD), making this process a big challenge. However, no studies have compared these pathologies from neuropsychological and neuroanatomical perspectives. The aim of the present study was to compare the executive functions (EF) and social cognition profiles as well as the structural neuroimaging of bvFTD and elderly patients with BD. First, we compared the executive and social cognition performances of 16 bvFTD patients, 13 BD patients and 22 healthy controls. Second, we compared grey matter volumes in both groups of patients and controls using voxel-based morphometry. Lastly, we examined the brain regions where atrophy might be associated with specific impairments in bvFTD and BD patients. Compared to controls, bvFTD patients showed deficits in working memory, abstraction capacity, inhibitory control, cognitive flexibility, verbal fluency and theory of mind (ToM). Patients with BD showed lower performance than controls in terms of abstraction capacity and verbal inhibitory control. In bvFTD patients, atrophy of frontal, temporal and insular cortices was related to EF deficits. Atrophy of the amygdala, the hippocampus, the parahippocampal gyrus, the putamen, the insula, the precuneus, the right temporo-parietal junction and superior temporal pole was associated to ToM impairments. No significant associations between atrophy and EF performance were observed in BD patients. BvFTD patients showed greater EF and ToM deficits than BD patients. Moreover, compared to BD, bvFTD patients exhibited a significant decrease in GM volume in frontal, temporal and parietal regions. Our results provide the first comparison of EF, social cognition and neuroanatomical profiles of bvFTD and elderly BD patients. These findings shed light on differential diagnosis of these disorders and may have important clinical implications.

Altered neural signatures of interoception in multiple sclerosis.

Multiple sclerosis (MS) patients present several alterations related to sensing of bodily signals. However, no specific neurocognitive impairment has yet been proposed as a core deficit underlying such symptoms. We aimed to determine whether MS patients present changes in interoception-that is, the monitoring of autonomic bodily information-a process that might be related to various bodily dysfunctions. We performed two studies in 34 relapsing-remitting, early-stage MS patients and 46 controls matched for gender, age, and education. In Study 1, we evaluated the heartbeat-evoked potential (HEP), a cortical signature of interoception, via a 128-channel EEG system during a heartbeat detection task including an exteroceptive and an interoceptive condition. Then, we obtained whole-brain MRI recordings. In Study 2, participants underwent fMRI recordings during two resting-state conditions: mind wandering and interoception. In Study 1, controls exhibited greater HEP modulation during the interoceptive condition than the exteroceptive one, but no systematic differences between conditions emerged in MS patients. Patients presented atrophy in the left insula, the posterior part of the right insula, and the right anterior cingulate cortex, with abnormal associations between neurophysiological and neuroanatomical patterns. In Study 2, controls showed higher functional connectivity and degree for the interoceptive state compared with mind wandering; however, this pattern was absent in patients, who nonetheless presented greater connectivity and degree than controls during mind wandering. MS patients were characterized by atypical multimodal brain signatures of interoception. This finding opens a new agenda to examine the role of inner-signal monitoring in the body symptomatology of MS.

Posterior cortical atrophy: a single case cognitive and radiological follow-up.

Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by initial predominant visuoperceptual deficits followed by a progressive decline in other cognitive functions. This syndrome has not been as thoroughly described as other dementias, particularly from a neuropsychological evolution perspective with only a few studies describing the evolution of its cognitive progression. In this investigation we review the literature on this rare condition and we perform a 7-year neuropsychological and neuroradiological follow-up of a 64-year-old man with PCA. The subject's deficits initially appeared in his visuoperceptual skills with later affectation appearing in language and other cognitive functions, this being coherent with the patient's parieto-temporal atrophy evolution.

Convergence of interoception, emotion, and social cognition: A twofold fMRI meta-analysis and lesion approach.

Guided by indirect evidence, recent approaches propose a tripartite crosstalk among interoceptive signaling, emotional regulation, and low-level social cognition. Here we examined the neurocognitive convergence of such domains. First, we performed three meta-analyses of functional magnetic resonance imaging studies to identify which areas are consistently coactivated by these three systems. Multi-level Kernel Density Analysis (MKDA) revealed major overlaps in the right anterior insular and frontotemporal regions (viz., the orbitofrontal and inferior frontal gyri, the amygdala, and mid temporal lobe/subcortical structures). Second, we explored such domains in patients with fronto-insulo-temporal damage. Relative to controls, the patients showed behavioral impairments of interoception, emotional processing, and social cognition, with preservation of other cognitive functions. Convergent results from both studies offer direct support for a model of insular-frontotemporal regions integrating interoception, emotion, and social cognition.

Brain Network Organization and Social Executive Performance in Frontotemporal Dementia.

OBJECTIVES: Behavioral variant frontotemporal dementia (bvFTD) is characterized by early atrophy in the frontotemporoinsular regions. These regions overlap with networks that are engaged in social cognition-executive functions, two hallmarks deficits of bvFTD. We examine (i) whether Network Centrality (a graph theory metric that measures how important a node is in a brain network) in the frontotemporoinsular network is disrupted in bvFTD, and (ii) the level of involvement of this network in social-executive performance. METHODS: Patients with probable bvFTD, healthy controls, and frontoinsular stroke patients underwent functional MRI resting-state recordings and completed social-executive behavioral measures. RESULTS: Relative to the controls and the stroke group, the bvFTD patients presented decreased Network Centrality. In addition, this measure was associated with social cognition and executive functions. To test the specificity of these results for the Network Centrality of the frontotemporoinsular network, we assessed the main areas from six resting-state networks. No group differences or behavioral associations were found in these networks. Finally, Network Centrality and behavior distinguished bvFTD patients from the other groups with a high classification rate. CONCLUSIONS: bvFTD selectively affects Network Centrality in the frontotemporoinsular network, which is associated with high-level social and executive profile.

A Lesion-Proof Brain? Multidimensional Sensorimotor, Cognitive, and Socio-Affective Preservation Despite Extensive Damage in a Stroke Patient.

In this study, we report an unusual case of mutidimensional sensorimotor, cognitive, and socio-affective preservation in an adult with extensive, acquired bilateral brain damage. At age 43, patient CG sustained a cerebral hemorrhage and a few months later, she suffered a second (ischemic) stroke. As a result, she exhibited extensive damage of the right hemisphere (including frontal, temporal, parietal, and occipital regions), left Sylvian and striatal areas, bilateral portions of the insula and the amygdala, and the splenium. However, against all probability, she was unimpaired across a host of cognitive domains, including executive functions, attention, memory, language, sensory perception (e.g., taste recognition and intensity discrimination), emotional processing (e.g., experiencing of positive and negative emotions), and social cognition skills (prosody recognition, theory of mind, facial emotion recognition, and emotional evaluation). Her functional integrity was further confirmed through neurological examination and contextualized observation of her performance in real-life tasks. In sum, CG's case resists straightforward classifications, as the extent and distribution of her lesions would typically produce pervasive, multidimensional deficits. We discuss the rarity of this patient against the backdrop of other reports of atypical cognitive preservation, expound the limitations of several potential accounts, and highlight the challenges that the case poses for current theories of brain organization and resilience.

Heart evoked potential triggers brain responses to natural affective scenes: A preliminary study.

The relationship between ongoing brain interoceptive signals and emotional processes has been addressed only indirectly through external stimulus-locked measures. In this study, an internal body trigger (heart evoked potential, HEP) was used to measure ongoing internally triggered signals during emotional states. We employed high-density electroencephalography (hd-EEG), source reconstruction analysis, and behavioral measures to assess healthy participants watching emotion-inducing video-clips (positive, negative, and neutral emotions). Results showed emotional modulation of the HEP at specific source-space nodes of the fronto-insulo-temporal networks related to affective-cognitive integration. This study is the first to assess the direct convergence among continuous triggers of viscerosensory cortical markers and emotion through dynamic stimuli presentation.

Disentangling interoception: insights from focal strokes affecting the perception of external and internal milieus.

Interoception is the moment-to-moment sensing of the physiological condition of the body. The multimodal sources of interoception can be classified into two different streams of afferents: an internal pathway of signals arising from core structures (i.e., heart, blood vessels, and bronchi) and an external pathway of body-mapped sensations (i.e., chemosensation and pain) arising from peripersonal space. This study examines differential processing along these streams within the insular cortex (IC) and their subcortical tracts connecting frontotemporal networks. Two rare patients presenting focal lesions of the IC (insular lesion, IL) or its subcortical tracts (subcortical lesion, SL) were tested. Internally generated interoceptive streams were assessed through a heartbeat detection (HBD) task, while those externally triggered were tapped via taste, smell, and pain recognition tasks. A differential pattern was observed. The IC patient showed impaired internal signal processing while the SL patient exhibited external perception deficits. Such selective deficits remained even when comparing each patient with a group of healthy controls and a group of brain-damaged patients. These outcomes suggest the existence of distinguishable interoceptive streams. Results are discussed in relation with neuroanatomical substrates, involving a fronto-insulo-temporal network for interoceptive and cognitive contextual integration.

The roles of interoceptive sensitivity and metacognitive interoception in panic.

BACKGROUND: Interoception refers to the ability to sense body signals. Two interoceptive dimensions have been recently proposed: (a) interoceptive sensitivity (IS) -objective accuracy in detecting internal bodily sensations (e.g., heartbeat, breathing)-; and (b) metacognitive interoception (MI) -explicit beliefs and worries about one's own interoceptive sensitivity and internal sensations. Current models of panic assume a possible influence of interoception on the development of panic attacks. Hypervigilance to body symptoms is one of the most characteristic manifestations of panic disorders. Some explanations propose that patients have abnormal IS, whereas other accounts suggest that misinterpretations or catastrophic beliefs play a pivotal role in the development of their psychopathology. Our goal was to evaluate these theoretical proposals by examining whether patients differed from controls in IS, MI, or both. Twenty-one anxiety disorders patients with panic attacks and 13 healthy controls completed a behavioral measure of IS motor heartbeat detection (HBD) and two questionnaires measuring MI. FINDINGS: Patients did not differ from controls in IS. However, significant differences were found in MI measures. Patients presented increased worries in their beliefs about somatic sensations compared to controls. These results reflect a discrepancy between direct body sensing (IS) and reflexive thoughts about body states (MI). CONCLUSION: Our findings support the idea that hypervigilance to body symptoms is not necessarily a bottom-up dispositional tendency (where patients are hypersensitive about bodily signals), but rather a metacognitive process related to threatening beliefs about body/somatic sensations.