Long-Term Effects of Tacrine on Regional Cerebral Blood Flow Changes in Alzheimer’s Disease

Minthon, Lennart; Nilsson, Karin; Edvinsson, Lars; Wendt, P.; Gustafson, Lars

doi:10.1159/000106954

Cited by 9 publications

(8 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, another property represented here by tacrine is responsible for a circulatory facilitation in a cortical area deafferented from the NBM, an effect that might be of importance with respect to brain perfusion in Alzheimer's disease. This is corroborated by studies showing that (1) cortical blood flow is highly sensitive to NBM activation, 15 an effect that is strongly age dependent, 24 (2) brain microvessels are the site of pathophysiologic changes in Alzheimer's disease, 25,26 primarily involving perivascular astrocytes, 27 and (3) enhancement of the circulation is beneficial in Alzheimer's disease 28,29. Thus, our results support the idea that impairment of the mechanisms of blood flow regulation might constitute a link between a cholinergic deficit and neurodegenerative processes.…”

Section: Resultssupporting

confidence: 86%

Differentiated Cerebrovascular Effects of Physostigmine and Tacrine in Cortical Areas Deafferented from the Nucleus Basalis Magnocellularis Suggest Involvement of Basalocortical Projections to Microvessels

Peruzzi

Euw

Lacombe

2000

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

Cholinesterase inhibitors used to treat Alzheimer's disease according to the principle of cholinergic replacement therapy have proved to be less beneficial than expected. The present study was designed to investigate the cerebrovascular response to physostigmine and tacrine in the experimental model of lesioning of the nucleus basalis magnocellularis (NBM), a model involving a cholinergic deficit. Regional cerebral blood flow was measured by the [14C]iodoantipyrine tissue sampling technique in conscious rats infused with i.v. physostigmine (0.2 mg/kg/h), tacrine (8 mg/kg/h), or saline, 3-5 weeks after unilateral lesion of the NBM with ibotenic acid. Physostigmine and tacrine dose-dependently increased blood flow in most cortical and subcortical regions compared to the control group. However, physostigmine caused smaller blood flow increases in several areas, mostly cortical, of the lesioned compared to the intact hemisphere. The converse was observed with tacrine. A facilitated circulatory response appeared in cortical areas deafferented from the NBM, especially in the frontal cortex. These results provide evidence for distinct NBM-dependent components of the cortical cerebrovascular effects of physostigmine and tacrine. They suggest the involvement of different cellular postsynaptic targets of the NBM. The physostigmine-type effects could involve direct projects onto an inhibitory cortical interneuron supersensitized by deafferentation. This arrangement may explain why physostigmine and perhaps other cholinergic agonists are unable to specifically compensate for a deficit in NBM functioning. The tacrine-type effects presumably involve projections to the microvasculature, including perivascular astrocytes. The neurovascular junction would be sensitized by deafferentation from the NBM. Our data suggest that the regulatory mechanisms of blood flow originating in the NBM might constitute a target of neurodegenerative processes of Alzheimer's disease.

show abstract

Section: Resultssupporting

confidence: 86%

Differentiated Cerebrovascular Effects of Physostigmine and Tacrine in Cortical Areas Deafferented from the Nucleus Basalis Magnocellularis Suggest Involvement of Basalocortical Projections to Microvessels

Peruzzi

Euw

Lacombe

2000

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

show abstract

“…Acute treatment with physostigmine [39,40], vclnacrine [41] and tacrine [42] have been reported to increase cortical blood flow in AD patients when measured by SPECT. Similarly, an increase in cerebral blood flow measured by l33Xe inhalation was found in AD patients responding to long-term tacrine treatment [43,44], Improvement of cerebral blood flow has also been reported by PET after long-term treatment with nerve growth factor to an AD patient [45]. Increases in glucose metabolism in AD brains have been observed following 3 weeks' treatment with phosphatidylserine [46].…”

Section: Discussionmentioning

confidence: 70%

Imaging of Nicotinic and Muscarinic Receptors in Alzheimer's Disease: Effect of Tacrine Treatment

Nordberg¹,

Lundqvist

Hartvig

et al. 1997

Dement Geriatr Cogn Disord

View full text Add to dashboard Cite

Functional imaging techniques offer new possibilities for further understanding of changes in functional correlates of structural and biological changes in dementia disorders like Alzheimer''s disease (AD). Regional disturbances in glucose metabolism and cerebral blood flow are known to occur in AD brains and probably roughly correlate to changes in neurotransmitter activities. A proper estimate would be to visualize the neuroreceptors themselves. In this study the cholinergic nicotinic and muscarinic receptors were studied in brain by positron emission tomography (PET). The rate constant k₂* (s) (–)¹¹C-nicotine was significantly higher (+43%) in temporal cortex of AD patients compared to controls (p < 0.017) indicating a lower binding of ¹¹C-nicotine in AD brains compared to controls. Treatment with the cholinesterase inhibitor tacrine (80 mg daily) during 3 months to AD patients resulted in a mean plasma concentration of 7.7 ± 0.8 ng/ml and a corresponding inhibition of the cholinesterase activity in plasma by 34 ± 5%. A significantly lower k₂* (increased binding) for ¹¹C-nicotine binding (–15%; p < 0.006) was obtained in the temporal cortex after 3 months of treatment compared to prior treatment. The muscarinic antagonist ¹¹C-benztropine was used to visualize muscarinic receptors and the binding capacity of ¹¹C-benztropine (K_R) was found to be decreased in the temporal cortex after 3 months of tacrine treatment.

show abstract

“…One method for assessing treatment effects [32,33] is to monitor the annual changes in MMSE and ADAS-cog scores and compare them with an estimated naturalistic change. In untreated AD patients, the naturalistic mean ARC in MMSE score has been estimated at 2-4 points [22][23][24] and the ARC in ADAScog score at 4-9 [25][26][27][28][29], or 9-11 [28] points a year.…”

Section: Discussionmentioning

confidence: 99%

“…The division was based on a summary of 3 types of ratings (MMSE, ADAS-cog and global ratings), and a comparison with the baseline values. This method has been previously used and is described in detail by Minthon et al [29]. We identified a subgroup of patients with scores remaining clearly above baseline MMSE and ADAS-cog ratings for 12 months and in some cases even longer ( fig.…”

Section: Discussionmentioning

confidence: 99%

“…At each follow-up, we defined 3 outcome groups: responders (RE), unchanged (UC) and deteriorated (DP), in a way similar to that of Minthon et al [7,29], i.e., based on changes in the MMSE, ADAScog and global ratings. Patients defined as RE were those who had changed for the better on at least 2 of the 3 types of ratings and had changed for the worse on none; those defined as UC had not changed at all on 1-3 of the ratings and had changed on at most 1 rating for the better and 1 rating for the worse, and those defined as DP had changed for the worse on at least 2 ratings, and had changed for the better on none.…”

Section: Definition Of Treatment Responsementioning

confidence: 99%

See 1 more Smart Citation

Five-Year Outcome of Cholinergic Treatment of Alzheimer’s Disease: Early Response Predicts Prolonged Time until Nursing Home Placement, but Does Not Alter Life Expectancy

Wallin

Gustafson²,

Sjögren

et al. 2004

Dement Geriatr Cogn Disord

Self Cite

View full text Add to dashboard Cite

Fifty consecutive outpatients with Alzheimer’s disease (AD) received treatment with the cholinesterase inhibitor tacrine in an open longitudinal study. Assessments using Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale – cognitive subscale, and a global rating were made at baseline and at 6, 12, 24, 36, 48 and 60 months. Three outcome groups were characterized: responders, unchanged and deteriorated. Additional outcome measures were time until nursing home placement, and mortality rate. At 6 months –75%, at 12 months –42%, at 24 months –20%, and after that 10% of the patients still on medication had improved or remained stable. The mortality rate did not differ between the outcome groups. Response to tacrine treatment at 6 or 12 months was found to predict a prolonged time until nursing home placement. No predictors for a positive treatment response could be identified at baseline.

show abstract

Long-Term Effects of Tacrine on Regional Cerebral Blood Flow Changes in Alzheimer’s Disease

Cited by 9 publications

References 19 publications

Differentiated Cerebrovascular Effects of Physostigmine and Tacrine in Cortical Areas Deafferented from the Nucleus Basalis Magnocellularis Suggest Involvement of Basalocortical Projections to Microvessels

Differentiated Cerebrovascular Effects of Physostigmine and Tacrine in Cortical Areas Deafferented from the Nucleus Basalis Magnocellularis Suggest Involvement of Basalocortical Projections to Microvessels

Imaging of Nicotinic and Muscarinic Receptors in Alzheimer's Disease: Effect of Tacrine Treatment

Five-Year Outcome of Cholinergic Treatment of Alzheimer’s Disease: Early Response Predicts Prolonged Time until Nursing Home Placement, but Does Not Alter Life Expectancy

Contact Info

Product

Resources

About