Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer's disease

Gilmor, Michelle L.; Erickson, Jeffrey D.; Varoqui, Hélène; Hersh, Louis B.; Bennett, David A.; Cochran, Elizabeth J.; Mufson, Elliott J.; Levey, Aĺlan I.

doi:10.1002/(sici)1096-9861(19990906)411:4<693::aid-cne13>3.0.co;2-d

Cited by 219 publications

(69 citation statements)

References 72 publications

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“…52 MCI was defined as those persons impaired on neuropsychological testing by the neuropsychologist but who were not found to have dementia by the examining neurologist as previously described. 37,38 These criteria are compatible with those used by others in the field. 43,46,[53][54][55][56] A consensus conference of neurologists and neuropsychologists, who reviewed all available clinical data and assigned a summary clinical diagnosis.…”

Section: Clinical Evaluationsupporting

confidence: 69%

“…All subjects were participants in the Religious Orders Study, a longitudinal clinical-pathological study of aging and AD of elderly retired Catholic clergy 13,[37][38][39] who agreed to an annual clinical evaluation beginning at 65 years of age and brain donation at time of death. Follow-up participation in the annual evaluations exceeds 95% of survivors, and the autopsy rate is greater than 90%.…”

Section: Subjectsmentioning

confidence: 99%

“…Details of the clinical evaluation have been previously reported. 13,[37][38][39][40][41] Briefly, a team of investigators led by a neurologist performed the evaluation annually. The evaluation included a medical history and interview for common problems of older persons, a complete neurological examination, and a battery of cognitive tests chosen to measure a range of cognitive abilities with emphasis on those affected by aging and AD.…”

Section: Clinical Evaluationmentioning

confidence: 99%

“…37,38 After removal from the calvarium, one hemisphere of each brain was cut on a brain slice apparatus into 1-cmthick slabs, immersion fixed in 4% paraformaldehyde in 0.1 mol/L phosphate buffer, pH 7.2, for 48 hours at 4°C, and cryoprotected in 10% glycerol plus 2% dimethyl sulfoxide (DMSO) in 0.1 mol/L phosphate buffer and at 4°C for 2 to 7 days, followed by immersion in a solution of 20% glycerol plus 2% DMSO. Brain slabs containing the CBF were cut into 18 series (720-m interval) of adjacent 40-m-thick sections on a freezing stage, sliding microtome and stored in cryoprotectant solution until processed.…”

Section: Brain Tissue Preparation and Pathological Evaluationmentioning

confidence: 99%

“…Brain slabs containing the CBF were cut into 18 series (720-m interval) of adjacent 40-m-thick sections on a freezing stage, sliding microtome and stored in cryoprotectant solution until processed. 37,38 Tissue from the opposite hemisphere was paraffin embedded, cut at 8 m, and stained with hematoxylin and eosin, modified Bielschowsky, thioflavin-S, and a ubiquitin antibody. 57 A complete neuropathological evaluation was performed in each case; special attention was given to dementia-related pathological lesions, such as strokes and cortical Lewy bodies, which may contribute to dementia.…”

Section: Brain Tissue Preparation and Pathological Evaluationmentioning

confidence: 99%

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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

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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: Clinical Evaluationsupporting

confidence: 69%

Section: Subjectsmentioning

confidence: 99%

Section: Clinical Evaluationmentioning

confidence: 99%

Section: Brain Tissue Preparation and Pathological Evaluationmentioning

confidence: 99%

Section: Brain Tissue Preparation and Pathological Evaluationmentioning

confidence: 99%

See 3 more Smart Citations

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

Self Cite

109

View full text Add to dashboard Cite

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Preservation of Brain Nerve Growth Factor in Mild Cognitive Impairment and Alzheimer Disease

Mufson¹,

Ikonomović²,

Styren³

et al. 2003

Arch Neurol

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Superior Frontal Cortex Cholinergic Axon Density in Mild Cognitive Impairment and Early Alzheimer Disease

et al. 2007

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Background: Loss of cortical choline acetyltransferase (ChAT) activity contributes to end-stage Alzheimer disease (AD) dementia. In general, ChAT activity levels are stable in the neocortex in mild to moderate AD (mAD) and there is a selective up-regulation in the superior frontal cortex (SFC) in mild cognitive impairment (MCI), indicating a transient, region-specific cholinergic neuroplastic response.Objective: To assess whether a proliferation of cholinergic axons underlies increased ChAT activity levels in the SFC in subjects with MCI.Design: Stereologic principles were applied to assess the density of ChAT-immunoreactive fibers and axon varicosities in SFC tissue obtained postmortem from subjects with no cognitive impairment, MCI, and mAD.Subjects: Thirty-six subjects enrolled in the Religious Orders Study, with records of annual clinical evalua-tion for frontal lobe specific and global cognitive functions.Results: Compared with the group with no cognitive impairment, SFC ChAT-immunoreactive fiber and axon varicosity densities were not altered in the MCI group but were significantly reduced in the group with mAD and correlated with impaired frontal lobe and global cognitive function. Conclusions:The lack of an increase in cholinergic axonal innervation of the SFC in MCI suggests that structural reorganization of cholinergic profiles is not the mechanism underlying the transient cholinergic plasticity reported in this region. Furthermore, the stability of cholinergic enzyme activity in mAD is likely the result of a biochemical up-regulation of ChAT protein or enzyme activity levels in the SFC, compensating for decreased regional cholinergic fibers and axon varicosities.

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Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer's disease

Cited by 219 publications

References 72 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

Preservation of Brain Nerve Growth Factor in Mild Cognitive Impairment and Alzheimer Disease

Superior Frontal Cortex Cholinergic Axon Density in Mild Cognitive Impairment and Early Alzheimer Disease

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