Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning
William J. ScottonCameron ShandEmily ToddMartina BocchettaDavid M. CashLawren VandeVredeHilary W. HeuerAlyssa CostantiniHenry HouldenChristopher KobyleckiJoshua ShulmanNigel LeighBradley F. BoeveBrad C. DickersonCarmela M TartagliaIrene LitvanMurray GrossmanAlex PantelyatEdward D. HueyDavid J. IrwinAnne M. FaganSuzanne L. BakerArthur W. TogaAlexandra L. YoungNeil P. OxtobyDaniel C. AlexanderJames B. RoweHuw R. MorrisAdam L. BoxerJonathan D. RohrerP. A. Wijeratne
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Abstract To better understand the pathological and phenotypic heterogeneity of progressive supranuclear palsy and the links between the two, we applied a novel unsupervised machine learning algorithm (Subtype and Stage Inference) to the largest MRI data set to date of people with clinically diagnosed progressive supranuclear palsy (including progressive supranuclear palsy–Richardson and variant progressive supranuclear palsy syndromes). Our cohort is comprised of 426 progressive supranuclear palsy cases, of which 367 had at least one follow-up scan, and 290 controls. Of the progressive supranuclear palsy cases, 357 were clinically diagnosed with progressive supranuclear palsy–Richardson, 52 with a progressive supranuclear palsy–cortical variant (progressive supranuclear palsy–frontal, progressive supranuclear palsy–speech/language, or progressive supranuclear palsy–corticobasal), and 17 with a progressive supranuclear palsy–subcortical variant (progressive supranuclear palsy–parkinsonism or progressive supranuclear palsy–progressive gait freezing). Subtype and Stage Inference was applied to volumetric MRI features extracted from baseline structural (T1-weighted) MRI scans and then used to subtype and stage follow-up scans. The subtypes and stages at follow-up were used to validate the longitudinal consistency of subtype and stage assignments. We further compared the clinical phenotypes of each subtype to gain insight into the relationship between progressive supranuclear palsy pathology, atrophy patterns, and clinical presentation. The data supported two subtypes, each with a distinct progression of atrophy: a ‘subcortical’ subtype, in which early atrophy was most prominent in the brainstem, ventral diencephalon, superior cerebellar peduncles, and the dentate nucleus, and a ‘cortical’ subtype, in which there was early atrophy in the frontal lobes and the insula alongside brainstem atrophy. There was a strong association between clinical diagnosis and the Subtype and Stage Inference subtype with 82% of progressive supranuclear palsy–subcortical cases and 81% of progressive supranuclear palsy–Richardson cases assigned to the subcortical subtype and 82% of progressive supranuclear palsy–cortical cases assigned to the cortical subtype. The increasing stage was associated with worsening clinical scores, whilst the ‘subcortical’ subtype was associated with worse clinical severity scores compared to the ‘cortical subtype’ (progressive supranuclear palsy rating scale and Unified Parkinson’s Disease Rating Scale). Validation experiments showed that subtype assignment was longitudinally stable (95% of scans were assigned to the same subtype at follow-up) and individual staging was longitudinally consistent with 90% remaining at the same stage or progressing to a later stage at follow-up. In summary, we applied Subtype and Stage Inference to structural MRI data and empirically identified two distinct subtypes of spatiotemporal atrophy in progressive supranuclear palsy. These image-based subtypes were differentially enriched for progressive supranuclear palsy clinical syndromes and showed different clinical characteristics. Being able to accurately subtype and stage progressive supranuclear palsy patients at baseline has important implications for screening patients on entry to clinical trials, as well as tracking disease progression.Keywords:
Corticobasal degeneration
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are both sporadic disorders with tau pathology. Criteria have been defined that in most instances allow for adequate diagnosis of the two disorders both clinically and neuropathologically; however, overlap is not uncommon. For example, patients with PSP may present with severe unilateral apraxia and supranuclear gaze palsy can occur in CBD. Pathological overlap also occurs and pathologically "mixed" cases are encountered. Common to both these two tauopathies is that isoforms of four-repeat tau due to splicing of exon 10 define the tau filamentous aggregates. This is in contrast to other tau disorders such as Pick's with three-repeat tau aggregates. Additional evidence for a causal link between PSP and CBD is the finding that both disorders are homozygous for the H1 tau haplotype. Furthermore, in some families with parkinsonism linked to defined mutations of the tau gene (FTDP-17), involved relatives have presented with PSP whereas others with the CBD phenotype. Although PSP and CBD frequently can be clearly separated clinically and pathologically, the degree of clinicopathological and genetic overlap is important and suggests that they represent different phenotypes of the same disorder, with differences occurring perhaps in relation to different genetic background. That PSP and CBD are distinct nosological entities occurring in patients with similar genetic predisposition cannot be ruled out. © 2005 Movement Disorder Society
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The five studies forming this thesis deal with two closely related neurodegenerative diseases,progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), both of which are characterised by abundant tau-positive neuronal and glial filamentous inclusions and by
shared genetic risk factors[19, 70]. Four studies focus on demonstrating neuropathological, biochemical and genetic differences between the classical/typical form and atypical PSP while the fifth study discusses issues relevant for understanding disease progression in CBD.
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Patients who have parkinsonian features, especially without tremor, that are not responsive to levodopa, usually have one of these three major neurodegenerative disorders rather than Parkinson disease: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or corticobasal degeneration (CBD). Each of these disorders eventually develops signs and symptoms that distinguish it from idiopathic Parkinson disease, but these may not be present at disease onset. Although these conditions are not generally treatable, it is still important to correctly diagnose the condition as soon as possible.In recent years, it has been increasingly recognized that the symptoms of these diseases do not accurately predict the pathology, and the pathology does not accurately predict the clinical syndrome. Despite this, interest has grown in treating these diseases by targeting misfolded tau (in the case of PSP and CBD) and misfolded α-synuclein (in the case of MSA).Knowledge of the characteristic signs and symptoms of PSP, MSA, and CBD are essential in diagnosing and managing patients who have atypical parkinsonian syndromes.
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Idiopathic Parkinson's disease (PD) is the most common cause of parkinsonism, accounting for about 75% of all cases. Other causes of parkinsonism include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and a variety of other neurodegenerative disorders in which rest tremor, bradykinesia, rigidity, and other parkinsonian features are present. Since these disorders are often associated with other neurological deficits, such as dysautonomia (in MSA), vertical ophthalmoparesis (in PSP), and apraxia (in CBD), they are referred to as "parkinsonism plus syndromes." Whereas the above disorders are degenerative in nature, there are other forms of parkinsonism, which are secondary to a variety of etiologic factors including vascular parkinsonism (VP), hemiatrophy hemiparkinsonism, and toxic and metabolic causes.
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Coritcobasal degeneratin (CBD) has various neurological findings, such as cortical sign, parkinsonism, supranuclear palsy, myoclonus, and dementia. This disease used to be rare, but 20 years later, many case have been reported. Corticobasal degeneration is investigated from a wide range of specific analyses. It presents with a clinical resemblance to progressive supranuclear palsy (PSP) and it is important to determine whether CBD and PSP are the same entity. I will attempt to review the difference and similarities between PSP and CBD from a clinical standpoint.
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The clinical and neuropathological features characteristic of progressive supranuclear palsy and corticobasal degeneration are described in detail. These disorders are not as rare as previously believed, but are poorly recognized. In patients with parkinsonism, a high index of clinical suspicion, sometimes complemented by specific laboratory tests, should improve diagnostic accuracy. Biological treatments are at present not available, but suggested symptomatic therapies may improve the quality of life of patients with these disorders.
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Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are sporadic neurodegenerative diseases with intracytoplasmic aggregates of the microtubule-associated protein, tau, in neurons and glial cells. Immunoblot analysis of detergent-insoluble brain extracts of patients with CBD and PSP shows distinctive patterns of tau fragments. These results suggest differing intracellular processing of aggregated tau in these two diseases despite an identical composition of tau isoforms. Such biochemical differences may be related to the neuropathological features of these diseases.
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