Excessive dopamine neuron loss in progressive supranuclear palsy

Murphy, Karen E.; Karaconji, Tanya; Hardman, Craig D.; Halliday, Glenda M.

doi:10.1002/mds.21907

Cited by 28 publications

(18 citation statements)

References 7 publications

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“…These results are supported by a pathology study that found a more widespread loss of dopamine neurons in PSP than in PD (30). In terms of the ventrodorsal gradient, we also found a more profound DAT loss in the AC than in the VS; this feature provided the best diagnostic value for differentiating the PSP group from other groups.…”

Section: Discussionsupporting

confidence: 87%

Subregional Patterns of Preferential Striatal Dopamine Transporter Loss Differ in Parkinson Disease, Progressive Supranuclear Palsy, and Multiple-System Atrophy

Oh¹,

Kim²,

Kim³

et al. 2012

J Nucl Med

236

188

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Parkinson disease (PD), progressive supranuclear palsy (PSP), and multiple-system atrophy (MSA) are known to affect dopaminergic neurons of the brain stem and striatum with different preferential involvement. Here we investigated differences in striatal subregional dopamine transporter loss in PD, PSP, and MSA and assessed the diagnostic value of 18 F-fluorinated-N-3-fluoropropyl-2-b-carboxymethoxy-3-b-(4-iodophenyl)nortropane ( 18 F-FP-CIT) PET in differentiating PSP and MSA from PD. Methods: Forty-nine patients with PD, 19 patients with PSP, 24 patients with MSA, and 21 healthy people (healthy controls) were examined with 18 F-FP-CIT PET. The PET images were spatially normalized and analyzed with 12 striatal subregional volume-of-interest (VOI) templates (bilateral ventral striatum [VS], anterior caudate [AC], posterior caudate, anterior putamen, posterior putamen [PP], and ventral putamen [VP]) and 1 occipital VOI template. The nondisplaceable binding potential (BP ND ) and intersubregional ratio (ISR; defined as the ratio of the BP ND of one striatal subregion to that of another striatal subregion) of subregional VOIs were calculated. Results: The BP ND of all VOIs in the PD, MSA, and PSP groups were significantly lower than those in the healthy controls (P , 0.05). The BP ND of AC and the AC/VS ISR in the PSP group were significantly lower than those in the PD group. The BP ND of VP was significantly lower, but the PP/VP ISR was significantly higher in the MSA group than in the PD group. At the cutoff value for the AC/VS ISR (,0.7), the sensitivity and specificity for differentiating PSP from PD were 94% and 92%, respectively. At the cutoff value for the PP/VP ISR (.0.65), the sensitivity and specificity for differentiating MSA from PD were 90% and 45%, respectively. The diagnostic accuracy of visual analysis was similar to that of quantitative analysis for differentiating PSP from PD but was significantly higher for differentiating MSA from PD. Conclusion: Compared with PD, PSP and MSA showed more prominent and earlier dopamine transporter loss in the AC and VP, respectively. These findings could be useful for suggesting PSP or MSA in parkinsonian cases without characteristic atypical features.

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Section: Discussionsupporting

confidence: 87%

Subregional Patterns of Preferential Striatal Dopamine Transporter Loss Differ in Parkinson Disease, Progressive Supranuclear Palsy, and Multiple-System Atrophy

Oh¹,

Kim²,

Kim³

et al. 2012

J Nucl Med

236

188

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“…Our work therefore directly demonstrates that iPSCs, especially isogenic iPSCs, are a powerful tool not only for disease modeling but also for studies of disease mechanisms. Interestingly, dopaminergic neurons are especially vulnerable to TAU-A152T-induced neurotoxicity, which is in line with the observation that tauopathy in PSP is associated with excessive dopaminergic neuron loss (Murphy et al., 2008). The underlying mechanism remains to be determined.…”

Section: Discussionsupporting

confidence: 85%

Genetic Correction of Tauopathy Phenotypes in Neurons Derived from Human Induced Pluripotent Stem Cells

et al. 2013

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SummaryTauopathies represent a group of neurodegenerative disorders characterized by the accumulation of pathological TAU protein in brains. We report a human neuronal model of tauopathy derived from induced pluripotent stem cells (iPSCs) carrying a TAU-A152T mutation. Using zinc-finger nuclease-mediated gene editing, we generated two isogenic iPSC lines: one with the mutation corrected, and another with the homozygous mutation engineered. The A152T mutation increased TAU fragmentation and phosphorylation, leading to neurodegeneration and especially axonal degeneration. These cellular phenotypes were consistent with those observed in a patient with TAU-A152T. Upon mutation correction, normal neuronal and axonal morphologies were restored, accompanied by decreases in TAU fragmentation and phosphorylation, whereas the severity of tauopathy was intensified in neurons with the homozygous mutation. These isogenic TAU-iPSC lines represent a critical advancement toward the accurate modeling and mechanistic study of tauopathies with human neurons and will be invaluable for drug-screening efforts and future cell-based therapies.

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“…Therefore, although pathology in PSP‐P was not distinctive, the restricted, mild tau pathology in PSP‐P supported its clinical distinction from PSP‐RS . For instance, the excessive loss of dopaminergic neurons in SN and extranigral midbrain cell groups in PSP‐RS may compromise any therapeutic response to l ‐dopa, and contribute to behavioral and motor symptoms characteristic for PSP. Less severe pathology in the extranigral midbrain in PSP‐P may be associated with moderate l ‐dopa responsiveness in this PSP variant.…”

Section: Discussionmentioning

confidence: 97%

Transcranial brain sonography findings in two main variants of progressive supranuclear palsy

Kostić

Mijajlović

Smajlović

et al. 2012

Euro J of Neurology

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Excessive dopamine neuron loss in progressive supranuclear palsy

Cited by 28 publications

References 7 publications

Subregional Patterns of Preferential Striatal Dopamine Transporter Loss Differ in Parkinson Disease, Progressive Supranuclear Palsy, and Multiple-System Atrophy

Subregional Patterns of Preferential Striatal Dopamine Transporter Loss Differ in Parkinson Disease, Progressive Supranuclear Palsy, and Multiple-System Atrophy

Genetic Correction of Tauopathy Phenotypes in Neurons Derived from Human Induced Pluripotent Stem Cells

Transcranial brain sonography findings in two main variants of progressive supranuclear palsy

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