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Multiple system atrophy (MSA), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are the most common atypical parkinsonisms. These adult-onset and lethal neurodegenerative disorders of unknown etiology are clinically characterized by varying combinations of autonomic, levodopa-poorly responsive parkinsonsm, motor, non-motor, cerebellar syndromes, behavioral, cognitive and other neuropsychiatric disorders. Although their pathological hallmarks are different—MSA α-synucleinopathy, CBD and PSP 4-repeat (4R) tauopathies—their neuropsychiatric disturbances include anxiety, depression, agitations, attention-executive dysfunctions, less often compulsive and REM sleep behavior disorders (RBD), which may contribute to disease progression and reduced quality of life (QoL) of patients and caregivers. The present paper reviews the prevalence and type of neuropsychiatric profile in these atypical parkinsonian syndromes, their neuroimaging, and pathogenic backgrounds based on extensive literature research. MSA patients show anxiety, apathy (depression), initial RBD, attentional and executive dysfunction; PSP patients present with apathy, depression, disinhibition, and to a lesser extent, anxiety and agitation; CBD patients are featured by executive and visuospatial dysfunctions, irritability, alien limb phenomena, sleep and language disorders. Neuropsychiatric disorders in these syndromes are often similar, due to disruption of prefronto-subcortical (limbic) and striato-thalamo-cortical circuitries or default mode and attention network disorder. This supports the concept that they are brain network disorders due to complex pathogenic mechanisms related to the basic proteinopathies that are still poorly understood. Psychotic symptoms, hallucinations and delusions are rare. Neuropsychiatric changes in these disorders are often premature and anticipate motor dysfunctions; their assessment and further elucidation of their pathogenesis are warranted as a basis for early diagnosis and adequate treatment of these debilitating comorbidities.

Primary 4‐repeat tauopathies with frontotemporal lobar degeneration (FTLD) like Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration (CBD) show diverse cellular pathology in various brain regions. Besides shared characteristics of neuronal and oligodendroglial cytoplasmic inclusions of accumulated hyperphosphorylated tau protein (pTau), astrocytes in PSP and CBD contain pathognomonic pTau aggregates — hence, lending the designation tufted astrocytes (TA) or astrocytic plaques (AP), respectively. pTau toxicity is most commonly assigned to neurons, whereas the implications of astrocytic pTau for maintaining neurotransmission within the tripartite synapse of human brains is not well understood. We performed immunofluorescent synapse labeling and automated puncta quantification in the medial frontal gyrus (MFG) and striatal regions from PSP and CBD postmortem samples to capture morphometric synaptic alterations. This approach indicated general synaptic losses of both, excitatory and inhibitory bipartite synapses in the frontal cortex of PSP cases, whereas in CBD lower synapse densities were only related to astrocytic plaques. In contrast to tufted astrocytes in PSP, affected astrocytes in CBD could not preserve synaptic integrity within their spatial domains, when compared to non‐affected internal astrocytes or astrocytes in healthy controls. These findings suggest a pTau pathology‐associated role of astrocytes in maintaining connections within neuronal circuits, considered as the microscopic substrate of cognitive dysfunction in CBD. By contrasting astrocytic‐synaptic associations in both diseases, we hereby highlight astrocytic pTau as an important subject of prospective research and as a potential cellular target for therapeutic approaches in the primary tauopathies PSP and CBD. The primary tauopathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) show a diverse pattern of cellular inclusions and neuropathological characteristics. In this article, we show a differentiated analysis of synaptic loss in affected brain regions of pure 4R‐tau PSP and CBD cases. While in CBD frontal cortices synapse loss was mainly associated with the disease‐defining astrocytic plaques, a rather general synaptic depletion was apparent in PSP.

Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE‐ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)‐ℰ4 isoform. Post‐mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non‐HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies. Assessment of neuropathological findings in individuals affected by pathological expansion of CAG HTT.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are severe neurodegenerative disorders lacking disease-modifying treatments and validated biomarkers. Clinical trials face challenges due to phenotypic overlap and imperfect clinicopathological correlations. MRI-derived models have shown to accurately predict PSP and CBD pathology in a large autopsy-confirmed cohort (Illán-Gala et al., JAMA Network Open, 2022). This study examines how participant selection based on MRI models and imaging outcomes impacts sample size estimations in hypothetical clinical trials. Eighty-four participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) with baseline and longitudinal MRI data and clinical assessments were included. Diagnoses comprised Richardson syndrome (RS, 61%) and corticobasal syndrome (CBS, 30%) without Alzheimer's disease. MRI-derived models predicted PSP, CBD, or other pathologies (MRI-PSP, MRI-CBD, MRI-Other) according to baseline MRI. Cortical thickness and volume measures were derived from MRI data using Freesurfer and employed to identify an optimal MRI-signature of regions showing the highest effect size on atrophy over 12 months using linear mixed-effects models. Disease progression was also measured with PSP Rating Scale (PSPRS). Sample sizes required to detect a 30% reduction in mean change at 12 months were calculated for hypothetical clinical trials. MRI predicted PSP, CBD, and other pathologies in 46%, 26%, and 27% of participants, respectively. Among RS diagnoses, 31 (61%) were classified as MRI-PSP; among CBS, 6 (24%) were MRI-CBD. MRI-signature regions for PSP progression included midbrain, superior-temporal, and rostral-middle-frontal thickness. For CBD, key regions included midbrain and pons volumes, superior-frontal, and entorhinal thickness. In a hypothetical PSP trial, selection criteria based on clinical diagnosis required 336 participants using PSPRS as outcome, while MRI-based diagnosis with MRI-signature as outcome reduced the sample size to 121 (64% decrease). For a CBS trial, the sample size reduced from 1301 participants if inclusion was based on clinical diagnosis to 160 using MRI-based selection and outcomes. Selecting participants with increased diagnostic certainty for PSP and CBD based on baseline MRI, combined with using MRI measures as outcomes could enhance the efficiency of future phase 2 clinical trials for 4R tauopathies. We plan to replicate these results in the Davunetide trial cohort.

INTRODUCTION Primary tauopathies, including corticobasal degeneration (CBD), Pick's disease (PiD), and progressive supranuclear palsy (PSP), have aggregated tau pathology in the brain. Many other proteins are likely altered in disease; however, these have not been well characterized. METHODS We performed sarkosyl fractionation of post mortem human brain tissue to enrich soluble and insoluble proteins from CBD, PiD, and PSP cases (n = 5/group). We assessed differences in the soluble fraction, insoluble fraction, and protein solubility changes between diseases, followed by enrichment and correlation analysis. RESULTS CBD and PiD showed the greatest proteomic similarity in both the soluble and insoluble fractions, while PSP was the most divergent in comparison to other diseases. We observed critical changes in the solubility of lysosomal regulators, postsynaptic proteins, the extracellular matrix (ECM), and mitochondrial proteins. DISCUSSION We have contrasted the solubility patterns of proteins across three tauopathies for the first time. Protein solubility differences reveal divergence in disease processes. Highlights Tau isoforms are differentially soluble in primary tauopathies PSP proteomics profile was the most divergent of the tauopathies examined SORT1 is highly insoluble in CBD and aggregates to different extents in tauopathies There are shifts in solubility for key signalling pathways; ROCK1 and JAK2 Unique lysosomal proteins are more insoluble in distinct tauopathies

Mitophagy constitutes a crucial cellular pathway in mitochondrial quality control, in which the enzymatic pair PINK1 and PRKN selectively decorates damaged mitochondria with phosphorylated-ubiquitin (pS65-Ub), facilitating their autophagic-lysosomal removal. We previously demonstrated significant accumulation of pS65-Ub labeled damaged mitochondria in Lewy body and Alzheimer's disease autopsy brain. This mitophagy alteration was strongly associated with pre-tangle tau pathology in neurons. The effects of distinct tau species on mitophagy across different cell types however remain largely unknown. We therefore expanded our analyses to primary tauopathies, exploring how specific tau forms and their aggregation influence mitophagy in selectively vulnerable brain regions and cell types. This study included 92 control and tauopathy cases with primary age-related tauopathy (PART), Pick's disease (PiD), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD). Immunohistochemistry for the mitophagy marker pS65-Ub and phospho-tau was performed in vulnerable brain regions (hippocampus for PART and PiD, primary motor cortex for PSP and CBD). A deep learning-based image identification model was used to identify and quantify distinct tau inclusions. pS65-Ub-positive cells were manually counted and grouped based on signal intensity and morphology. Immunofluorescence co-staining of pS65-Ub and phospho-tau was conducted to study their spatial relationship at single-cell level. We observed marked increases in pS65-Ub-positive cells in the hippocampus of PART and PiD cases compared to controls. Although less prominent, significant increases were also found in the primary motor cortex of PSP, whereas only minor changes were observed in CBD. Single-cell analyses revealed that the accumulation of pS65-Ub was most abundant in hippocampal neurons from PART. Cells with lower signal intensity contained mostly granular pS65-Ub deposits, while those with higher intensity harbored rather vacuolar inclusions. Across tau aggregate subtypes, pS65-Ub levels were strongly correlated and often co-resided with neurofibrillary tangles and Pick bodies. Such correlations were weaker for coiled bodies and tufted astrocytes, and absent for astrocytic plaques. Our study highlights distinct mitophagy alterations in primary tauopathies that are associated with specific tau inclusions in neurons, oligodendrocytes, and astrocytes. The observed pathological heterogeneity and complex mitophagy disruption underscores the need for future studies to elucidate pathogenic mechanisms and advance targeted therapeutics for each tauopathy.

Primary tauopathies, including corticobasal degeneration (CBD), Pick's disease (PiD) and progressive supranuclear palsy (PSP), are characterized by tau aggregation in distinct brain regions and cell types. However, alterations of other proteins associated with these diseases remain poorly understood. Sarkosyl fractionation was performed on post-mortem frontal cortex tissue from CBD, PiD and PSP cases (n = 5/group) to enrich soluble and insoluble proteins. Mass spectrometry profiled the protein abundance and solubility differences. Gene set enrichment analysis and bicorrelation was used to identify dysregulated pathways and proteins associated with tau and other disease markers. Tau isoforms exhibit disease specific solubility differences. CBD and PiD had high proteomic similarity, with only six proteins differing in solubility, whereas PSP was more distinct (78 differentially soluble proteins vs. CBD). Key solubility changes were observed in lysosomal regulators (e.g. LAMP2; log2FC=0.96, FDR= 0.04), postsynaptic proteins the extracellular matrix and mitochondrial proteins. S100B was elevated in the soluble fractions of CBD and PiD but not PSP (CBD vs PSP log2FC=0.68, PiD vs PSP log2FC=0.67) suggesting cellular distress was greater in the frontal cortex of these two tauopathies which correlates with higher tau pathology in these diseases. The scavenger receptor SORT1 was markedly more insoluble in CBD than either PiD or PSP (CBD vs PiD log2FC=0.60, CBD vs PSP log2FC=0.65), suggesting differences in lysosomal targeting of proteins such as progranulin. TBCC, a tubulin chaperone, was uniquely insoluble in PiD (CBD vs PiD log2FC=-0.93, PiD vs PSP log2FC=1.02). Bicorrelation with tau revealed 791 proteins in CBD, 3,695 in PiD and 219 in PSP (ρ<-0.7 or ρ>0.7, p-value < 0.05). Notably, MOBP, a tauopathy risk gene, correlated strongly with tau in PiD (ρ = 0.82; p-value = 0.004) but not in CBD or PSP. This study provides the first comparative analysis of protein solubility across tauopathies, revealing disease-specific proteomic signatures and divergent mechanisms. Our findings reveal key proteins and pathways linked to tau pathology, offering insights into tauopathy pathogenesis and discriminatory biomarkers.

This session examines how Alzheimer's disease (AD)-related biomarkers influence the clinical presentation, brain structure, and functional connectivity in patients with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). Although a few descriptions have associated certain clinical features to CBS and PSP with AD-neuropathological changes, those are not completely specific. AD fluid biomarker positivity is associated with distinct patterns of brain atrophy and functional disconnection detected using neuroimaging technics (MRI and fMRI), as well as differences in motor and cognitive features. Those results highlight the importance of studying the presence of AD co-pathology to understand how it may shape the clinical and neuroimaging manifestations of CBS and PSP. This session will provide insights into how biomarker-based stratification of patients can enhance diagnostic accuracy and inform personalized approaches to the management of these complex syndromes.

Corticobasal syndrome (CBS) corresponds to a clinical phenotype with heterogeneous neuropathology, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), and synucleinopathies such as Lewy Body Disease (LBD), in rare cases. Previous reports of CBS-LBD describe patients with diffuse LBD, a younger age of onset and occasionally lacking core features like REM sleep Behavior Disorder (RBD). We present a young patient with CBS who had a rapid progression and was found to have a high burden of limbic LBD and high AD co-pathology at autopsy. A 58-year-old right-handed woman consulted for progressively worsening apraxia, writing, and visuospatial difficulties over the year prior to presentation. She had minimal short-term memory loss initially, did not have RBD nor visual hallucinations and remained independent in activities of daily living. She scored 20/30 on the Montreal Cognitive Assessment, with difficulties in visuospatial and executive tasks. The neurological exam showed predominant apraxia, asymmetric parkinsonism and sensory neglect, all left-sided. The brain MRI confirmed striking asymmetric atrophy affecting the right parieto-temporal lobes. Cerebrospinal fluid (CSF) demonstrated decreased Abeta 42/tau index and elevated total and phosphorylated tau. Her condition progressed quickly over the next year, and she passed away four years after diagnosis. Brain autopsy showed asymmetric moderate-severe cortical atrophy with abundant phospho-synuclein positive Lewy bodies extending to the temporal but not frontal/parietal cortices, consistent with limbic (transitional) LBD and high Alzheimer's disease co-pathology (A3, B3, C3). There was severe Lewy body pathology in the hippocampal CA2 subfield, prominent phospho-tau in the substantia nigra, severe neuron loss in the locus coeruleus, and severe gliosis in the motor cortex. AD and LBD commonly occur together, but the frequency of AD and LBD as a cause of CBS is unknown. Here, we add to the literature of co-pathology in CBS and consider that early age and rapid progression could suggest dual pathology and potential synergistic effects. CSF testing limited to AD biomarkers will miss this dual pathology. Thus, CSF α-synuclein seeding amplification may help identify patients with dual AD-LBD pathology and assist prognostication.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by upper and lower motor neuron signs. There are, however, cases where upper motor neurons (UMNs) are predominantly affected, leading to clinical presentations of UMN‐dominant ALS or primary lateral sclerosis. Furthermore, cases exhibiting an UMN‐predominant pattern of motor neuron disease (MND) presenting with corticobasal syndrome (CBS) have been sparsely reported. This study aims to clarify the clinicopathological features of patients with UMN‐predominant MND. We reviewed 24 patients with UMN‐predominant MND with TDP‐43 pathology in the presence or absence of frontotemporal lobar degeneration. Additionally, we reviewed the medical records of patients with pathologically‐confirmed corticobasal degeneration (CBD) who received a final clinical diagnosis of CBS (n = 10) and patients with pathologically‐confirmed progressive supranuclear palsy (PSP) who received a final clinical diagnosis of PSP syndrome (n = 10). Of 24 UMN‐predominant MND patients, 20 had a clinical diagnosis of an atypical parkinsonian disorder, including CBS (n = 11) and PSP syndrome (n = 8). Only two patients had antemortem diagnoses of motor neuron disease. UMN‐predominant MND patients with CBS less frequently exhibited apraxia than those with CBD, and they were less likely to meet clinical criteria for possible or probable CBS. Similarly, UMN‐predominant MND patients with PSP syndrome less often met clinical criteria for probable PSP than PSP patients with PSP syndrome. Our findings suggest that UMN‐predominant MND can mimic atypical parkinsonism, and should be considered in the differential diagnosis of CBS and PSP syndrome, in particular when criteria are not met. Heatmap and hierarchical clustering based on neuronal loss in 24 UMN‐predominant MND cases. Two distinct clusters are identified by hierarchical clustering based on neuronal loss. The heatmap reflects the severity of neuronal loss, and a color scale is given at the right. Missing data are shown in gray. Patients are represented with columns, and the study ID of each patient is provided. The main clinical features and diagnoses of each case are shown.