Supranuclear Research Articles

Chronic Musculoskeletal Pain and Risk of Incident Parkinson's Disease: A 13-Year Longitudinal Study.

Chronic musculoskeletal pain often co-occurs with Parkinson's disease (PD); however, whether individuals with chronic pain have a higher risk of developing PD is unclear. To investigate the associations between chronic pain and incident risk of three neurodegenerative parkinsonism categories including PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). This study included 355,890 participants (mean [standard deviation] age, 56.51 [8.07] years, 48.40% male) who did not have parkinsonism at baseline from a population-based cohort. Musculoskeletal pain in the hip, neck/shoulder, back, knee, or "all over the body" was assessed. Chronic pain was defined if pain lasted ≥3 months. Participants were categorized into four groups: no chronic pain, having one or two, three or four sites, and pain "all over the body." The diagnosis of PD, MSA, and PSP used self-reports, hospital records, and death registries. Multivariable-adjusted Cox regression was performed for the analyses. Over a median follow-up of 13.0 years, 2044 participants developed PD, 77 participants developed MSA, and 126 participants developed PSP. In multivariable analyses, there was a dose-response relationship between number of chronic pain sites and incident risk of PD (hazard ratio, 1.15; 95% confidence interval, 1.07-1.23). Participants with one or two pain sites and three or four pain sites had an 11% and 49% increased risk of developing PD, respectively. There were no associations between chronic pain and MSA or PSP. Chronic musculoskeletal pain was independently associated with PD, suggesting that chronic pain could be used to identify individuals at risk of developing PD. © 2024 International Parkinson and Movement Disorder Society.

Pathological study of progressive supranuclear palsy the cases with mutations in Bassoon.

Clinical diagnosis of progressive supranuclear palsy (PSP) is difficult due to various phenotypes. Neuropathologically, PSP is defined by neuronal loss in the basal ganglia and brainstem with widespread occurrence of neurofibrillary tangles (NFTs) and accumulation of phosphorylated tau protein in neurons and glial cells in the brain. We previously identified the point mutation p.Pro3866Ala in the Bassoon (BSN) gene in a Japanese family with PSP-like syndrome. We newly detected BSN mutations in two autopsied PSP cases carrying p.Thr2542Met and p.Glu2759Gly, respectively. The case with p.Thr2542Met mutation showed neurological symptoms including behavioral abnormalities, cognitive dysfunction, and parkinsonism. Brain magnetic resonance imaging (MRI) showed atrophy of the midbrain tegmentum and hippocampus. Pathologically, moderate to severe loss of neurons with gliosis was also found in the substantia nigra, and there was an almost complete loss of neurons with gliosis in the transitional zone of the cornu ammonis (CA) 1 region to the subiculum. NFTs were observed in the globus pallidus, subthalamic nucleus, substantia nigra, and CA1. 4R tau-dominant tauopathy was detected. The case with p.Glu2759Gly mutation showed neurological symptoms, including right-dominant motor impairment, right limping gait, postural instability, and cognitive dysfunction. Brain MRI showed mild atrophy of the midbrain tegmentum and left-dominant parietal lobe atrophy. Pathologically, NFTs were detected in the globus pallidus, subthalamic nucleus, substantia nigra, thalamus, putamen, and brainstem tegmentum. Most neurons were immunopositive for four-repeat tau, whereas only a few of them harbored three-repeat tau-positive NFTs in the hippocampus. We showed the results of a pathological study of PSP cases with BSN mutations; these were two new cases. The clinical phenotypes were similar to the first case in the point of neurological symptoms. Accumulation of four-repeat tau was dominant. Further autopsies of BSN mutation cases and further elucidation of the molecular biological mechanism are desirable.

Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion.

Tauopathies are neurodegenerative diseases that manifest with intracellular accumulation and aggregation of tau protein. These include Pick's disease, progressive supranuclear palsy, corticobasal degeneration and argyrophilic grain disease, where tau is believed to be the primary disease driver, as well as secondary tauopathies, such as Alzheimer's disease. There is a need to develop effective pharmacological therapies. Here we tested >1,400 clinically approved compounds using transgenic zebrafish tauopathy models. This revealed that carbonic anhydrase (CA) inhibitors protected against tau toxicity. CRISPR experiments confirmed that CA depletion mimicked the effects of these drugs. CA inhibition promoted faster clearance of human tau by promoting lysosomal exocytosis. Importantly, methazolamide, a CA inhibitor used in the clinic, also reduced total and phosphorylated tau levels, increased neuronal survival and ameliorated neurodegeneration in mouse tauopathy models at concentrations similar to those seen in people. These data underscore the feasibility of in vivo drug screens using zebrafish models and suggest serious consideration of CA inhibitors for treating tauopathies.

Proximity Elongation Assay and ELISA for the Identification of Serum Diagnostic Biomarkers in Parkinson’s Disease and Progressive Supranuclear Palsy

Clinical differentiation of progressive supranuclear palsy (PSP) from Parkinson’s disease (PD) is challenging due to overlapping phenotypes and late onset of PSP specific symptoms, highlighting the need for easily assessable biomarkers. We used proximity elongation assay (PEA) to analyze 460 proteins in serum samples from 46 PD, 30 PSP patients, and 24 healthy controls. ANCOVA was used to identify the most promising proteins and machine learning (ML) XGBoost and random forest algorithms to assess their classification performance. Promising proteins were also quantified by ELISA. Moreover, correlations between serum biomarkers and biological and clinical features were investigated. We identified five proteins (TFF3, CPB1, OPG, CNTN1, TIMP4) showing different levels between PSP and PD, which achieved good performance (AUC: 0.892) when combined by ML. On the other hand, when the three most significant biomarkers (TFF3, CPB1 and OPG) were analyzed by ELISA, there was no difference between groups. Serum levels of TFF3 positively correlated with age in all subjects’ groups, while for OPG and CPB1 such a correlation occurred in PSP patients only. Moreover, CPB1 positively correlated with disease severity in PD, while no correlations were observed in the PSP group. Overall, we identified CPB1 correlating with PD severity, which may support clinical staging of PD. In addition, our results showing discrepancy between PEA and ELISA technology suggest that caution should be used when translating proteomic findings into clinical practice.

Comprehensive mapping of synaptic vesicle protein 2A (SV2A) in health and neurodegenerative diseases: a comparative analysis with synaptophysin and ground truth for PET-imaging interpretation.

Synaptic dysfunction and loss are central to neurodegenerative diseases and correlate with cognitive decline. Synaptic Vesicle Protein 2A (SV2A) is a promising PET-imaging target for assessing synaptic density in vivo, but comprehensive mapping in the human brain is needed to validate its biomarker potential. This study used quantitative immunohistochemistry and Western blotting to map SV2A and synaptophysin (SYP) densities across six cortical regions in healthy controls and patients with early-onset Alzheimer's disease (EOAD), late-onset Alzheimer's disease (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-GRN). We identified region in SV2A density among controls and observed disease- and region-specific reductions, with the most severe in FTLD-GRN (up to 59.5%) and EOAD. EOAD showed a 49% reduction in the middle frontal gyrus (MFG), while LOAD had over 30% declines in the inferior frontal gyrus (IFG) and hippocampus (CA1). In PSP, smaller but significant reductions were noted in the hippocampal formation, with the inferior temporal gyrus (ITG) relatively unaffected. A strong positive correlation between SV2A and SYP densities confirmed SV2A's reliability as a synaptic integrity marker. This study supports the use of SV2A PET imaging for early diagnosis and monitoring of neurodegenerative diseases, providing essential data for interpreting in vivo PET results. Further research should explore SV2A as a therapeutic target and validate these findings in larger, longitudinal studies.

Combined Assessment of Function and Survival to Demonstrate the Effect of Treatment on Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease-modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect. The objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease-modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS. To simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial. The sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival. Use of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies. © 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Peripheral innate immunophenotype in neurodegenerative disease: blood-based profiles and links to survival.

The innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g., microglia), peripheral innate immune cells (e.g., blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate immune cell types across different neurodegenerative diseases remains incomplete. This study aimed to characterize peripheral innate immune profiles using flow cytometry for immunophenotyping of peripheral blood mononuclear cells in n = 148 people with Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), Lewy body dementia(LBD) as compared to n = 37 healthy controls. To compare groups, we used multivariate dissimilarity analysis and principal component analysis across 19 innate immune cell types. We identified pro-inflammatory profiles that significantly differ between patients with all-cause dementia and healthy controls, with some significant differences between patient groups. Regression analysis confirmed that time to death following the blood test correlated with the individuals' immune profile weighting, positively to TREM2+ and non-classical monocytes and negatively to classical monocytes. Taken together, these results describe transdiagnostic peripheral immune profiles and highlight the link between prognosis and the monocyte cellular subdivision and function (as measured by surface protein expression). The results suggest that blood-derived innate immune profiles can inform sub-populations of cells relevant for specific neurodegenerative diseases that are significantly linked to accelerated disease progression and worse survival outcomes across diagnoses. Blood-based innate immune profiles may contribute to enhanced precision medicine approaches in dementia, helping to identify and monitor therapeutic targets and stratify patients for candidate immunotherapies.

Efficiency of multivariate tests in trials in progressive supranuclear palsy

Measuring disease progression in clinical trials for testing novel treatments for multifaceted diseases as progressive supranuclear palsy (PSP), remains challenging. In this study we assess a range of statistical approaches to compare outcomes as measured by the items of the progressive supranuclear palsy rating scale (PSPRS). We consider several statistical approaches, including sum scores, a modified PSPRS rating scale that had been recommended by FDA in a pre-IND meeting, multivariate tests, and analysis approaches based on multiple comparisons of the individual items. In addition, we propose two novel approaches which measure disease status based on Item Response Theory models. We assess the performance of these tests under various scenarios in an extensive simulation study and illustrate their use with a re-analysis of the ABBV-8E12 clinical trial. Furthermore, we discuss the impact of the FDA-recommended scoring of item scores on the power of the statistical tests. We find that classical approaches as the PSPRS sum score demonstrate moderate to high power when treatment effects are consistent across the individual items. The tests based on Item Response Theory (IRT) models yield the highest power when the simulated data are generated from an IRT model. The multiple testing based approaches have a higher power in settings where the treatment effect is limited to certain domains or items. The study demonstrates that there is no one-size-fits-all testing procedure for evaluating treatment effects using PSPRS items; the optimal method varies based on the specific effect size patterns. The efficiency of the PSPRS sum score, while generally robust and straightforward to apply, varies depending on the specific patterns of effect sizes encountered and more powerful alternatives are available in specific settings. These findings can have important implications for the design of future clinical trials in PSP and similar multifaceted diseases.

Speech profile in different clinical PSP phenotypes: an acoustic-perceptual study.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease with pathological hallmarks and different clinical presentations. Recently, the Movement Disorder Society (MDS) promoted a new classification; specific combinations of the core clinical features identify different phenotypes, including PSP with Richardson's syndrome (PSP-RS) and PSP with predominant parkinsonism (PSP-P). Since speech disorders are very common in PSP, they were included in the MDS-PSP criteria as a supportive clinical feature in the form of hypokinetic, spastic dysarthria. However, little is known about how dysarthria presents across the different PSP variants. The aim of the present study is to evaluate the presence of differences in speech profile in a cohort of PSP-RS and PSP-P patients diagnosed according to the MDS-PSP criteria. Each patient underwent a neurological evaluation and perceptual and acoustic analysis of speech. Disease severity was rated using the Natural History and Neuroprotection in Parkinson plus syndromes-Parkinson plus scale (NNIPPS-PPS), including global score and sub-scores. Twenty-five patients (mean disease duration [standard deviation] = 3.32 [1.79]) were classified as PSP-RS, while sixteen as PSP-P (mean disease duration [standard deviation] = 3.47 [2.00]). These subgroups had homogeneous demographical and clinical characteristics, including disease severity quantified by the NNIPPS-PPS total score. Only the NNIPPS-PPS oculomotor function sub-score significantly differed, being more impaired in PSP-RS patients. No significant differences were found in all speech variables between the two groups. Speech evaluation is not a distinguishing feature of PSP subtypes in mid-stage disease.

Identification of metabolic progression and subtypes in progressive supranuclear palsy by PET molecular imaging.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with diverse clinical presentations that are linked to tau pathology. Recently, Subtype and Stage Inference (SuStaIn) algorithm, an innovative data-driven method, has been developed to model both the spatial-temporal progression and subtypes of disease. This study explores PSP progression using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging and the SuStaIn algorithm to identify PSP metabolic progression subtypes and understand disease mechanisms. The study included 72 PSP patients and 70 controls, with an additional 24 PSP patients enrolled as a test set, undergoing FDG-PET, dopamine transporter (DAT) PET, and neuropsychological assessments. The SuStaIn algorithm was employed to analyze the FDG-PET data, identifying progression subtypes and sequences. Two PSP subtypes were identified: the cortical subtype with early prefrontal hypometabolism and the brainstem subtype with initial midbrain alterations. The cortical subtype displayed greater cognitive impairment and DAT reduction than the brainstem subtype. The test set demonstrates the robustness and reproducibility of the findings. Pathway analysis indicated that disruptions in dopaminergic cortico-basal ganglia pathways are crucial for elucidating the mechanisms of cognitive and behavioral impairment in PSP, leading to the two metabolic progression subtypes. This study identified two spatiotemporal progression subtypes of PSP based on FDG-PET imaging, revealing significant differences in metabolic patterns, striatal dopaminergic uptake, and clinical profiles, particularly cognitive impairments. The findings highlight the crucial role of dopaminergic cortico-basal ganglia pathways in PSP pathophysiology, especially in the cortical subtype, providing insights into PSP heterogeneity and potential avenues for personalized treatments.

Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy.

Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Although metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed. We analyzed 342 postmortem brain samples from the Mayo Clinic Brain Bank and examined 658 metabolites in the cerebellar cortex and the temporal cortex between the two tauopathies. Our findings indicate that both diseases display oxidative stress associated with lipid metabolism, mitochondrial dysfunction linked to lysine metabolism, and an indication of tau-induced polyamine stress response. However, specific to AD, we detected glutathione-related neuroinflammation, deregulations of enzymes tied to purines, and cognitive deficits associated with vitamin B. Our findings underscore vast alterations in the brain's metabolome, illuminating shared neurodegenerative pathways and disease-specific traits in AD and PSP. First high-throughput metabolic comparison of Alzheimer's diesease (AD) versus progressive supranuclear palsy (PSP) in brain tissue. Cerebellar cortex (CER) shows substantial AD-related metabolic changes, despite limited proteinopathy. AD impacts both CER and temporal cortex (TCX); PSP's changes are primarily in CER. AD and PSP share metabolic alterations despite major pathological differences.

Essential tremor with tau pathology features seeds indistinguishable in conformation from Alzheimer's disease and primary age-related tauopathy.

Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disease that, in some cases, is associated with cognitive impairment and tau accumulation. Consequently, we explored the tau assembly conformation in ET patients with tau pathology using cytometry-based tau biosensor assays. These assays quantify tau prion seeding activity present in brain homogenates based on conversion of intracellular tau-fluorescent protein fusions from a soluble to an aggregated state. Prions exhibit seeding barriers, whereby a specific assembly structure cannot serve as a template for a native monomer if the amino acids are not compatible. We recently exploited the tau prion species barrier to define tauopathies by systematically substituting alanine (Ala) in the tau monomer and measuring its incorporation into seeded aggregates within biosensor cells. The Ala scan precisely classified the conformation of tau seeds from diverse tauopathies. We next studied 18 ET patient brains with tau pathology. Only one case had concurrent high amyloid-β plaque pathology consistent with Alzheimer's disease (AD). We detected robust tau seeding activity in 9 (50%) of the patients. This predominantly localized to the temporal pole and temporal cortex. We examined 8 ET cases with the Ala scan and determined that the amino acid requirements for tau monomer incorporation into aggregates seeded from these ET brain homogenates were identical to those of AD and primary age-related tauopathy (PART), and completely distinct from other tauopathies such as corticobasal degeneration, chronic traumatic encephalopathy, and progressive supranuclear palsy. Based on these studies, tau assembly cores in a pathologically confined subset of ET cases with high tau pathology are identical to AD and PART. This could facilitate more precise diagnosis and therapy for ET patients with cognitive impairment.

Combinations of physical and cognitive training for subcortical neurodegenerative diseases with physical, cognitive and behavioral symptoms: a systematic review.

The onset of the symptoms of subcortical NDs is due to a unique part of the brain which strengthens the idea of reciprocal influence of physical activity and cognitive training in improving clinical symptoms. Consequently, protocols combining the two stimulations are becoming increasingly popular in NDs. Our threefold aim was to (A) describe the different combinations of physical and cognitive training used to alleviate the motor and cognitive symptoms of patients with subcortical neurodegenerative disorders, (B) compare the effects of these different combinations (sequential, dual tasking, synergical) on symptoms, and (C) recommend approaches for further studies. We conducted literature searches of PubMed, BASE and ACM, to carry out a systematic review of randomized controlled trials and controlled trials of combined physical and cognitive training among patients with Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia, spinocerebellar ataxia, Friedreich's ataxia, and progressive supranuclear palsy. Physical, neuropsychological, behavioral outcomes were considered. The Cochrane risk-of-bias tool was used to verify the critical appraisal. Twenty-one studies focused on Parkinson's disease with 940 participants were included. Despites promising benefits on cognitive and physical function, our results revealed discrepant findings for research on combined training. Inconsistencies were linked to the choice of tests, the functions that were targeted, disease progression, and trainings. There was a dearth of follow-up data. Differences between combined training are unclear, particularly regarding the role of cognitive load. Future studies should focus on comparing the feasibility, tolerability, and effectiveness of different combinations of motor-cognitive training.

Multi-Class Detection of Neurodegenerative Diseases from EEG Signals Using Lightweight LSTM Neural Networks.

Neurodegenerative diseases severely impact the life of millions of patients worldwide, and their occurrence is more and more increasing proportionally to longer life expectancy. Electroencephalography has become an important diagnostic tool for these diseases, due to its relatively simple procedure, but it requires analyzing a large number of data, often carrying a small fraction of informative content. For this reason, machine learning tools have gained a considerable relevance as an aid to classify potential signs of a specific disease, especially in its early stages, when treatments can be more effective. In this work, long short-term memory-based neural networks with different numbers of units were properly designed and trained after accurate data pre-processing, in order to perform a multi-class detection. To this end, a custom dataset of EEG recordings from subjects affected by five neurodegenerative diseases (Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, progressive supranuclear palsy, and vascular dementia) was acquired. Experimental results show that an accuracy up to 98% was achieved with data belonging to different classes of disease, up to six including the control group, while not requiring particularly heavy computational resources.

Triple Crown: A Single Autopsy Case with Alzheimer’s Disease, Parkinson’s Disease, and Progressive Supranuclear Palsy

Abstract Introduction/Objective Neurodegenerative diseases such as Alzheimer’s Disease(AD), Idiopathic Parkinson’s disease (PD), and Progressive Supranuclear Palsy (PSP), manifest with progressive cognitive and motor deterioration. While each condition traditionally presents distinct clinical features, overlapping symptoms among them make antemortem clinical diagnose less accurate. Concomitant proteinopathies are frequent among neurodegenerative diseases. Here, we report a single autopsy case demonstrating the simultaneous presence of PSP, PD and AD. Methods/Case Report A 70- year- old male, with dementia and a familial history of progressive supranuclear palsy in his brother, underwent autopsy due to concern for progressive supranuclear palsy. The histopathological examination revealed the presence of “ C” age- related plaque score providing definite diagnosis of Alzheimer’s disease. Immunohistochemistry studies on brain sections revealed the presence of Tau positive globose tangles and neurites indicating progressive supranuclear palsy. Furthermore, alpha-synuclein positivity was observed for Lewy bodies and Lewy neurites, confirming idiopathic Parkinson’s disease. Results (if a Case Study enter NA) NA Conclusion While coexisting neurodegenerative diseases with different proteinopathies have been well documented, this case represents the first report providing pathological confirmation of the simultaneous presence of Alzheimer’s Disease, Parkinson’s Disease, and progressive supranuclear palsy in a single patient. These unique findings underscore the complexity of neurodegenerative processes and highlights the importance of comprehensive diagnostic evaluation in patients presenting with overlapping clinical symptoms. These findings hold significant potential to contribute further in the field.

Comparative Study of GPT-4Vision and Convolutional Neural Networks in Histopathological Image Analysis

Abstract Introduction/Objective Recent advancements in artificial intelligence (AI), particularly with Large Language Models like ChatGPT-4Vision (GPT-4V), have expanded the potential for automated interpretation of medical images. This study evaluates the diagnostic accuracy of GPT-4V in histopathological analysis of neurodegenerative diseases and compares its performance with traditional Convolutional Neural Networks (CNNs). Methods/Case Report We utilized 1515 histopathological images, including hematoxylin and eosin (H&E) staining and tau immunohistochemistry, from patients with various neurodegenerative diseases, such as Alzheimer’s disease, progressive supranuclear palsy, and corticobasal degeneration. GPT-4V’s performance was assessed through multi- step prompts to assess how textual context influences the image interpretation. In the quantitative analysis, the diagnostic accuracy of GPT-4V and the CNN-based model YOLOv8 was assessed for classifying three tau lesions—astrocytic plaques, neuritic plaques, and tufted astrocytes. The analysis used both zero-shot and few-shot learning methods, where GPT-4V and YOLOv8 were evaluated on their ability to distinguish these lesions using ten hold-out test images and 490 training images per lesion. Results (if a Case Study enter NA) GPT-4V accurately recognized Lewy bodies in all cases, but it showed limited accuracy in identifying neurofibrillary tangles (20%) and Pick bodies (0%) on H&E slides. Notably, GPT-4V often suggested Alzheimer’s disease as a potential diagnosis, relying more on contextual clues, such as the prevalence of certain diseases, rather than direct image analysis. In the tau immunohistochemical analysis, GPT-4V’s diagnoses were strongly influenced by additional information about staining and brain region. However, few-shot learning markedly improved GPT-4V’s diagnostic capabilities from 40% accuracy with zero-shot learning to 90% with few-shot learning, reaching best accuracy with 20-shot learning. This performance compared favorably against YOLOv8, which also achieved 90% accuracy but required 100-shot learning. Conclusion While GPT-4V faces challenges in independently interpreting histopathological images, few-shot learning significantly improves its accuracy. This approach is particularly promising for neuropathology, where acquiring extensive labeled datasets is challenging. The findings highlight the need for ongoing refinement of AI applications in pathology, emphasizing balanced integration of textual and visual data to optimize diagnostic efficacy and reliability.

Apraxia phenotypes and frontotemporal lobar degeneration.

Apraxia has been identified in all clinical forms of frontotemporal lobar degeneration (FTLD). The characteristics of apraxia symptoms and their underlying cognitive/motor basis are not fully understood. This study investigated apraxia in pathological subtypes of FTLD. The study constituted a retrospective review of 115 pathologically confirmed cases of FTLD from a single cognitive neurology centre. Patients in whom apraxia had been documented as a notable clinical characteristic were identified. Apraxia features, demographic, cognitive, neurological, and imaging findings were recorded. Eighteen patients were identified: 12 with FTLD-tau pathology (7 corticobasal degeneration (CBD), four Pick type and one progressive supranuclear palsy (PSP)) and six with FTLD-TDP pathology, all type A and four linked to progranulin gene mutations. Apraxia as a dominant presenting feature was typically associated with tau pathologies, whereas it emerged in the context of aphasia in TDP pathology. Apraxia typically predominated in one body part (face or limb) in tau but not TDP pathology. Relatively preserved activities in daily life were associated with TDP. Apraxia of speech was associated with tau pathology. Pick-type pathology was linked to symmetrical atrophy and late development of limb rigidity. Apraxia in FTLD subtypes has variable characteristics. Apraxia associated with CBD pathology conformed to criteria for probable corticobasal syndrome (CBS), whereas apraxia with Pick-type pathology did not. Apraxia in patients with TDP-A pathology was interpreted as one manifestation of their generalised communication disorder. Apraxia in FTLD may have distinct cognitive and motor substrates that require prospective investigation.

Autoimmune Encephalitis and Paraneoplastic Neurological Syndromes with Progressive Supranuclear Palsy-like Manifestations.

Advances in diagnostic procedures have led to an increasing rate of diagnosis of autoimmune encephalitis or paraneoplastic neurological syndrome (AE/PNS) among patients with progressive supranuclear palsy (PSP)-like manifestations. In this narrative review, we first discuss the clinical characteristics of AE/PNS in comparison to those of PSP, followed by a discussion of diagnosis and treatment. The antibodies involved in these conditions include anti-IgLON5, -Ma2, and -Ri antibodies, each of which has a characteristic clinical presentation. The steps in the diagnosis of AE/PNS in patients with PSP-like manifestations include (i) suspicion of AE/PNS based on clinical presentations atypical of PSP and (ii) antibody detection measures. Methods used to identify antibodies include a combination of tissue-based assays and confirmatory tests. The primary confirmatory tests include cell-based assays and immunoblotting. Treatments can be divided into immunotherapy and tumor therapies, the former of which includes acute and maintenance therapies. One of the major challenges of diagnosis is that existing reports on PSP-like patients with AE/PNS include only case reports, with the majority discussing antibodies other than anti-IgLON5 antibody. As such, more patients need to be evaluated to establish the relationship between antibodies and PSP-like manifestations.

MRI-Based Multi-Class Relevance Vector Machine Classification of Neurodegenerative Diseases.

Machine learning algorithms are a promising automated candidate that can help mitigate the growing need for dementia experts. Despite the substantial development in MRI-based machine learning analyses, case misclassification is a universal finding, yet the reasons behind misclassification are poorly understood. We implemented a multi-class classification approach that uses relevance vector machine and logistic classification to classify research participants based on their whole-brain T1-weighted MRI scans. A total of 468 participants from seven diagnostic classes were included: 144 healthy controls, 84 Alzheimer's disease, 108 behavioral variant frontotemporal dementia (bvFTD), 30 semantic variant primary progressive aphasia (svPPA), 30 non-fluent variant primary progressive aphasia (nfvPPA), 30 corticobasal syndrome (CBS), and 42 progressive supranuclear palsy syndrome (PSPS). We compared the algorithm's diagnostic accuracy against the clinical, pathological, genetic, and quantitative imaging data. The exact neurodegenerative syndrome was predicted in 71% of the cases, the neurodegenerative disease spectrum was predicted in 80% of the cases, and the algorithm distinguished controls from any dementia in 85% of the cases. The algorithm showed high performance in diagnosing healthy controls, moderate performance in diagnosing AD, bvFTD, and svPPA, and low performance in diagnosing CBS, nfvPPA, and PSPS. Based on the quantitative imaging data, most of the misclassified neurodegenerative cases had minimal atrophy and brain volumes comparable to healthy controls. In AD, early-onset AD cases with minimal brain atrophy represented most of the misclassified cases. In bvFTD, FTD genetic mutation carriers (predominantly C9orf72 repeat expansion), FTD phenocopy, patients meeting only possible bvFTD criteria represented most misclassified cases. Case misclassification in machine learning studies in neurodegenerative diseases results from neurodegenerative disease heterogeneity and the limitations of structural MRI's ability to capture the whole gamut of biological changes. Larger and more inclusive datasets that are representative of population biologic heterogeneity are needed to train better machine learning techniques, and a margin of error is expected and should be acceptable, like the uncertainty of a clinical diagnosis by a dementia expert.

Predictors of Care Home Admission and Survival Rate in Patients With Syndromes Associated With Frontotemporal Lobar Degeneration in Europe.

Data on care home admission and survival rates of patients with syndromes associated with frontotemporal lobar degeneration (FTLD) are limited. However, their estimation is essential to plan trials and assess the efficacy of intervention. Population-based registers provide unique samples for this estimate. The aim of this study was to assess care home admission rate, survival rate, and their predictors in incident patients with FTLD-associated syndromes from the European FRONTIERS register-based study. We conducted a prospective longitudinal multinational observational registry study, considering incident patients with FTLD-associated syndromes diagnosed between June 1, 2018, and May 31, 2019, and followed for up to 5 years till May 31, 2023. We enrolled patients fulfilling diagnosis of the behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS), and FTD with motor neuron disease (FTD-MND). Kaplan-Meier analysis and Cox multivariable regression models were used to assess care home admission and survival rates. The survival probability score (SPS) was computed based on independent predictors of survivorship. A total of 266 incident patients with FTLD were included (mean age ± SD = 66.7 ± 9.0; female = 41.4%). The median care home admission rate was 97 months (95% CIs 86-98) from disease onset and 57 months (95% CIs 56-58) from diagnosis. The median survival was 90 months (95% CIs 77-97) from disease onset and 49 months (95% CIs 44-58) from diagnosis. Survival from diagnosis was shorter in FTD-MND (hazard ratio [HR] 4.59, 95% CIs 2.49-8.76, p < 0.001) and PSP/CBS (HR 1.56, 95% CIs 1.01-2.42, p = 0.044) compared with bvFTD; no differences between PPA and bvFTD were found. The SPS proved high accuracy in predicting 1-year survival probability (area under the receiver operating characteristic curve = 0.789, 95% CIs 0.69-0.87), when defined by age, European area of residency, extrapyramidal symptoms, and MND at diagnosis. In FTLD-associated syndromes, survival rates differ according to clinical features and geography. The SPS was able to predict prognosis at individual patient level with an accuracy of ∼80% and may help to improve patient stratification in clinical trials. Future confirmatory studies considering different populations are needed.