The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method.

Pakkenberg, Bente; Møller, Arne; Gundersen, H.J.G.; Dam, Agnete Mouritzen; Pakkenberg, H.

doi:10.1136/jnnp.54.1.30

Cited by 375 publications

(236 citation statements)

References 10 publications

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“…13,14,[67][68][69] Anatomically, the region of interest included the CBF neurons extending from the crossing of the anterior commissure to its emergence at the level of the temporal pole of one hemisphere of the brain. The use of the optical fractionator method allows for the stereologic analysis of a well-defined portion of a structure independent of its size, shape, orientation, or tissue shrinkage.…”

Section: Stereological Quantification Of Neurons and Nt Lengthmentioning

confidence: 99%

Progression of Tau Pathology in Cholinergic Basal Forebrain Neurons in Mild Cognitive Impairment and Alzheimer's Disease

Vana

Kanaan

Ugwu

et al. 2011

The American Journal of Pathology

105

109

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Tau is a microtubule-associated protein that forms neurofibrillary tangles (NFTs) in the selective vulnerable long projection neurons of the cholinergic basal forebrain (CBF) in Alzheimer's disease (AD). Although CBF neurodegeneration correlates with cognitive decline during AD progression, little is known about the temporal changes of tau accumulation in this region. We investigated tau posttranslational modifications during NFT evolution within the CBF neurons of the nucleus basalis (NB) using tissue from subjects with no cognitive impairment, mild cognitive impairment, and AD. The pS422 antibody was used as an early tau pathology marker that labels tau phosphorylated at Ser422; the TauC3 antibody was used to detect later stage tau pathology. Stereologic evaluation of NB tissue immunostained for pS422 and TauC3 revealed an increase in neurons expressing these tau epitopes during disease progression. We also investigated the occurrence of pretangle tau events within cholinergic NB neurons by dual staining for the cholinergic cell marker, p75 NTR , which displays a phenotypic down-regulation within CBF perikarya in AD. As pS422؉ neurons increased in number, p75 NTR ؉ neurons decreased, and these changes correlated with both AD neuropathology and cognitive decline. Also, NFTs developed slower in the CBF compared with previously examined cortical regions. Taken together, these results suggest that changes in cognition are associated with pretangle events within NB cholinergic neurons before frank Degeneration of the cholinergic basal forebrain (CBF) neurons, which provide the major cholinergic innervation to the entire cortical mantle, hippocampus, and amygdala 1,2 correlates with dementia severity, disease duration, and cognitive impairment 3,4 in Alzheimer's disease (AD). 3,5-9 The viability of CBF neurons is dependent on the prototypic neurotrophic substance, nerve growth factor (NGF), 10 which is retrogradely transported to CBF neurons through a complex interaction of its two receptors, the high-affinity NGF-specific cell survival tyrosine kinase (trkA) and the putative cell death associated lowaffinity pan neurotrophin (p75 NTR ) receptor. 11,12 Previous studies have identified critical changes within the basocortical cholinergic system during the progression of AD, indicating a shift in the balance from pro-survival to apoptotic mechanisms, before frank cellular alteration, 13,14 which likely over time plays a mechanistic role in the CBF degeneration seen in AD. 5 In addition to altered neurotrophic factor dysfunction coincident with disease progression, CBF neurons also develop intracellular inclusions that appear as globose neurofibrillary tangles (NFTs) and neuropil threads (NTs), hallmark tau pathologies found in AD. [15][16][17] Tau is a microtubule-associated protein involved in normal cytoskeleton function, 18,19 but in AD tau transitions from its relatively soluble state into filamentous aggregates. 20 Braak and colleagues delineated six stages (I to VI) related to the spatial temporal distribution a...

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Section: Stereological Quantification Of Neurons and Nt Lengthmentioning

confidence: 99%

Progression of Tau Pathology in Cholinergic Basal Forebrain Neurons in Mild Cognitive Impairment and Alzheimer's Disease

Vana

Kanaan

Ugwu

et al. 2011

The American Journal of Pathology

105

109

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“…The fact that non-penetrance has been described in all three of the Parkinsonian dominant loci described to date suggests that other factors, genetic or environmental, may further modify expression at each locus. This can be inferred, despite the fact that approximately a 70 % loss of nigral neurons is required to express the Parkinsonian phenotype (Pakkenberg et al 1991). The biological and numerical importance of the genetic contribution to PD remains uncertain.…”

Section:   mentioning

confidence: 99%

Genetics of Parkinsonism: a review

VAUGHAN¹,

DAVIS²,

WOOD³

2001

Annals of Human Genetics

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Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, low heritability in the general population and genetic heterogeneity. Mutations in a further gene, UCHL1, have been described in familial PD although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and illustrates how the existence of genetic factors has now become firmly established.

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“…The normal adult human substantia nigra contains approximately 500,000 dopamineproducing neurons [56]. Unfortunately, approximately 95% of dopamine neurons die after transplantation of rat or human tissue.…”

Section: Number Of Donors -Tissue From 4 Donors Provides Sufficient Dmentioning

confidence: 99%

Dopamine Cell Transplantation for Parkinson's Disease: The Importance of Controlled Clinical Trials

2011

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The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method.

Cited by 375 publications

References 10 publications

Progression of Tau Pathology in Cholinergic Basal Forebrain Neurons in Mild Cognitive Impairment and Alzheimer's Disease

Progression of Tau Pathology in Cholinergic Basal Forebrain Neurons in Mild Cognitive Impairment and Alzheimer's Disease

Genetics of Parkinsonism: a review

Dopamine Cell Transplantation for Parkinson's Disease: The Importance of Controlled Clinical Trials

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