Progressive Supranuclear Palsy with Dementia: Cortical Pathology

Bigio, Eileen H.; Brown, Daniel F.; White, Charles L.

doi:10.1097/00005072-199904000-00006

Cited by 78 publications

(47 citation statements)

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“…The activated astrocytes did not stain with tau protein-specific antibodies and were therefore clearly different from the tau-positive tufted astrocytes, typical for progressive supranuclear palsy. 54 The majority of patients suffering from FTDP-17 and other tauopathies develop tau protein deposits in both neurons and glial cells. The mouse thy-1 promoter used by us caused a widespread expression selectively in neurons of the CNS of htau40 transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Prominent Axonopathy in the Brain and Spinal Cord of Transgenic Mice Overexpressing Four-Repeat Human tau Protein

Spittaels¹,

Haute²,

Dorpe³

et al. 1999

The American Journal of Pathology

361

304

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Mutations in the human tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Some mutations, including mutations in intron 10, induce increased levels of the functionally normal four-repeat tau protein isoform, leading to neurodegeneration. We generated transgenic mice that overexpress the four-repeat human tau protein isoform specifically in neurons. The transgenic mice developed axonal degeneration in brain and spinal cord. In the model, axonal dilations with accumulation of neurofilaments, mitochondria, and vesicles were documented. The axonopathy and the accompanying dysfunctional sensorimotor capacities were transgene-dosage related. These findings proved that merely increasing the concentration of the four-repeat tau protein isoform is sufficient to injure neurons in the central nervous system, without formation of intraneuronal neurofibrillary tangles. Evidence for astrogliosis and ubiquitination of accumulated proteins in the dilated part of the axon supported this conclusion. This transgenic model, overexpressing the longest isoform of human tau protein, recapitulates features of known neurodegenerative diseases, including Alzheimer's disease and other tauopathies. The model makes it possible to study the interaction with additional factors, to be incorporated genetically, or with other biological triggers that are implicated in neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Prominent Axonopathy in the Brain and Spinal Cord of Transgenic Mice Overexpressing Four-Repeat Human tau Protein

Spittaels¹,

Haute²,

Dorpe³

et al. 1999

The American Journal of Pathology

361

304

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“…Hence this case represents PSP on neuropathological grounds, albeit atypical. Widespread cortical and white matter pathology in PSP has been appreciated by others [3, 26]. …”

Section: Discussionmentioning

confidence: 99%

Progressive Nonfluent Aphasia and Subsequent Aphasic Dementia Associated with Atypical Progressive Supranuclear Palsy Pathology

et al. 2003

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We describe a right-handed man who developed progressive nonfluent aphasia and apraxia of speech beginning at age 71. By age 74 he had behavioral changes, aphasic dementia, as well as mild parkinsonism; extraocular movements were normal except for mild limitation of upgaze. Serial neuropsychometric testing and single photon emission computed tomography (SPECT) scans showed progressive changes reflecting left>right cerebral hemisphere dysfunction. Neuropathologic examination revealed findings characteristic of progressive supranuclear palsy (PSP) except that the cortical pathology was more widespread than is typical of PSP. We conclude that the clinical manifestations in this case were more similar to the syndrome of progressive nonfluent aphasia with subsequent aphasic dementia and mild parkinsonism, rather than those of PSP. Hence, PSP can present clinically as an atypical dementing syndrome dominated by progressive aphasia/apraxia of speech.

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“…The pathological process that underlies PSP and MSA is more localised to subcortical regions in the early stages of the disease although some restricted cortical pathology is known to occur as both diseases progress [9,10,11]. MRI derived whole brain and regional atrophy rates have recently been described [12,13].…”

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confidence: 99%

MRI derived brain atrophy in PSP and MSA-P

Paviour

Price

Lees³

et al. 2007

J Neurol

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Progressive supranuclear palsy (PSP) and multiple system (MSA) atrophy are associated with progressive brain atrophy. Serial MRI can be applied in order to measure this change in brain volume and to calculate atrophy rates. We evaluated MRI derived whole brain and regional atrophy rates as potential markers of progression in PSP and the Parkinsonian variant of multiple system atrophy (MSA-P). 17 patients with PSP, 9 with MSA-P and 18 healthy controls underwent two MRI brain scans. MRI scans were registered, and brain and regional atrophy rates (midbrain, pons, cerebellum, third and lateral ventricles) measured. Sample sizes required to detect the effect of a proposed disease-modifying treatment were estimated. The effect of scan interval on the variance of the atrophy rates and sample size was assessed. Based on the calculated yearly rates of atrophy, for a drug effect equivalent to a 30% reduction in atrophy, fewer PSP subjects are required in each treatment arm when using midbrain rather than whole brain atrophy rates (183 cf. 499). Fewer MSA-P subjects are required, using pontine/cerebellar, rather than whole brain atrophy rates (164/129 cf. 794). A reduction in the variance of measured atrophy rates was observed with a longer scan interval. Regional rather than whole brain atrophy rates calculated from volumetric serial MRI brain scans in PSP and MSA-P provide a more practical and powerful means of monitoring disease progression in clinical trials.

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Progressive Supranuclear Palsy with Dementia: Cortical Pathology

Cited by 78 publications

References 0 publications

Prominent Axonopathy in the Brain and Spinal Cord of Transgenic Mice Overexpressing Four-Repeat Human tau Protein

Prominent Axonopathy in the Brain and Spinal Cord of Transgenic Mice Overexpressing Four-Repeat Human tau Protein

Progressive Nonfluent Aphasia and Subsequent Aphasic Dementia Associated with Atypical Progressive Supranuclear Palsy Pathology

MRI derived brain atrophy in PSP and MSA-P

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