The 12th J. A. F. Stevenson Memorial Lecture: Aging, Alzheimer's disease, and the cholinergic system

1984 ◽  
Vol 62 (7) ◽  
pp. 741-754 ◽  
Author(s):  
Patrick L. McGeer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Substantia Nigra ◽  
Locus Coeruleus ◽  
Basal Forebrain ◽  
Cholinergic System ◽  
Memory Storage ◽  
Substantia Nigra Pars Compacta ◽  
Memorial Lecture ◽  
Reticular Activating System

Aging does not affect tissues in a uniform fashion. Within the brain, substantial neuronal dropout occurs with age in the cholinergic medial basal forebrain complex, the noradrenergic locus coeruleus, and the dopaminergic substantia nigra pars compacta. These areas are also struck by diseases that are sharply age dependent. Alzheimer's disease causes neuronal destruction in the cholinergic cells of the medial basal forebrain and noradrenergic cells of the locus coeruleus. Parkinson's disease causes neuronal destruction mainly in the substantia nigra but with some destruction in the locus coeruleus. Parkinsonism–dementia affects all three areas. Alzheimer's disease is responsible for 50–60% of all cases of dementia. Severe dementia rises in frequency from less than 1% of the population at age 65–70 to over 15% by age 85. The cause of the disease is unknown. No method of prevention is known and present treatments are ineffective, although modest improvement has been reported for various therapeutic regimens designed to stimulate the cholinergic system. The neuronal systems identified as being affected in Alzheimer's disease and in the dementia of Parkinsonism correspond with those shown many years ago to be associated with the reticular activating system. This correspondence permits a new hypothesis of cognition and memory to be put forward, as well as a reinterpretation of data from animal research on the reticular activating system performed over a quarter of a century ago. The locus coeruleus is proposed as the noradrenergic element sensitizing the cortex to conscious recognition of real time events. The medial basal forebrain complex is proposed as the system registering the conscious event for storage and as the readout device when it is subsequently redisplayed in the cortex as memory. Storage could either be in the temporal lobe, in several areas of cortex with feedback to the medial basal forebrain, or in the cholinergic cells themselves.

The Functional Organization of the Basal Forebrain Cholinergic System in Primates and the Role of this System in Alzheimer's Disease

1985 ◽  
Vol 444 (1 Memory Dysfun) ◽  
pp. 287-295 ◽  
Author(s):  
DONALD L. PRICE ◽  
LINDA C. CORK ◽  
ROBERT G. STRUBLE ◽  
PETER J. WHITEHOUSE ◽  
CHERYL A. KITT ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Basal Forebrain ◽  
Cholinergic System ◽  
Functional Organization

Aging, Alzheimer's disease, and the cholinergic system of the basal forebrain

Neurology ◽  
1984 ◽  
Vol 34 (6) ◽  
pp. 741-741 ◽  
Author(s):  
P. L. McGeer ◽  
E. G. McGeer ◽  
J. Suzuki ◽  
C. E. Dolman ◽  
T. Nagai
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Basal Forebrain ◽  
Cholinergic System

scholarly journals The cholinergic system in subtypes of Alzheimer’s disease: an in vivo longitudinal MRI study

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Alejandra Machado ◽  
◽  
Daniel Ferreira ◽  
Michel J. Grothe ◽  
Helga Eyjolfsdottir ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Basal Forebrain ◽  
Cholinergic System ◽  
Structural Mri ◽  
Specific Response ◽  
Healthy Controls ◽  
Hippocampal Sparing

Abstract Background The heterogeneity within Alzheimer’s disease (AD) seriously challenges the development of disease-modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD and explored the relevance of subtype stratification in a small clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain. Methods Structural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy-verified AD patients with structural MRI data at baseline and at 6- or 12-month follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach. Results All AD subtypes showed reduced basal forebrain volume as compared with the healthy controls. The limbic-predominant subtype showed the fastest basal forebrain atrophy rate, whereas the minimal atrophy subtype did not show any significant volume decline over time. Atrophy rates of the hippocampus and precuneus also differed across subtypes. Our preliminary data from the small NGF cohort suggest that the NGF treatment seemed to slow the rate of atrophy in the precuneus and hippocampus in some hippocampal-sparing AD patients and in one typical AD patient. Conclusions The cholinergic system is differentially affected in distinct atrophy subtypes of AD. Larger studies in the future should confirm that this differential involvement of the cholinergic system may contribute to subtype-specific response to cholinergic treatment. Our preliminary findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratified by subtype. Trial registration ClinicalTrials.gov identifier: NCT01163825. Registered 14 July 2010.

Amyloid-β, tau, and the cholinergic system in Alzheimer’s disease: seeking direction in a tangle of clues

2020 ◽  
Vol 31 (4) ◽  
pp. 391-413 ◽  
Author(s):  
Alireza Majdi ◽  
Saeed Sadigh-Eteghad ◽  
Sepideh Rahigh Aghsan ◽  
Fereshteh Farajdokht ◽  
Seyed Mehdi Vatandoust ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Basal Forebrain ◽  
Cholinergic System ◽  
Amyloid Β ◽  
Cholinergic Neurons ◽  
Clinical Findings ◽  
App Metabolism ◽  
Main Culprit

AbstractThe link between histopathological hallmarks of Alzheimer’s disease (AD), i.e. amyloid plaques, and neurofibrillary tangles, and AD-associated cognitive impairment, has long been established. However, the introduction of interactions between amyloid-beta (Aβ) as well as hyperphosphorylated tau, and the cholinergic system to the territory of descriptive neuropathology has drastically changed this field by adding the theory of synaptic neurotransmission to the toxic pas de deux in AD. Accumulating data show that a multitarget approach involving all amyloid, tau, and cholinergic hypotheses could better explain the evolution of events happening in AD. Various species of both Aβ and tau could be traced in cholinergic neurons of the basal forebrain system early in the course of the disease. These molecules induce degeneration in the neurons of this system. Reciprocally, aberrant cholinergic system modulation promotes changes in amyloid precursor protein (APP) metabolism and tau phosphorylation, resulting in neurotoxicity, neuroinflammation, and neuronal death. Altogether, these changes may better correlate with the clinical findings and cognitive impairment detected in AD patients. Failure of several of Aβ- and tau-related therapies further highlights the need for special attention to molecules that target all of these mentioned pathologic changes. Another noteworthy fact here is that none of the popular hypotheses of AD such as amyloidopathy or tauopathy seem to be responsible for the changes observed in AD alone. Thus, the main culprit should be sought higher in the stream somewhere in APP metabolism or Wnt signaling in the cholinergic system of the basal forebrain. Future studies should target these pathological events.

scholarly journals The cholinergic system and treatment response in subtypes of Alzheimer’s disease

2020 ◽  
Author(s):  
Alejandra Machado ◽  
Daniel Ferreira ◽  
Michel J. Grothe ◽  
Helga Eyjolfsdottir ◽  
Per M. Almqvist ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Basal Forebrain ◽  
Cholinergic System ◽  
Structural Mri ◽  
Assessment Method ◽  
Atrophy Rate ◽  
Link Type ◽  
Hippocampal Sparing

AbstractBACKGROUNDThe heterogeneity within Alzheimer’s disease (AD) seriously challenges the development of disease modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD, and explored the relevance of subtype stratification in a clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain.METHODSStructural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy verified AD patients with structural MRI data at baseline and at 6- or 12-months follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach.RESULTSAll AD subtypes showed reduced basal forebrain volume as compared with controls. Limbic-predominant subtype showed fastest basal forebrain atrophy rate, whereas minimal atrophy subtype did not show significant volume decline over time. Atrophy rates of hippocampus and precuneus also differed across subtypes. The NGF treatment seemed to slow the rate of atrophy in precuneus and hippocampus, particularly in the hippocampal-sparing AD subtype.CONCLUSIONSThe cholinergic system is differentially affected in distinct atrophy subtypes of AD, possibly contributing to their differential response to cholinergic treatment. Our findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratifying by subtype.Trial registrationClinicalTrials.gov identifier: NCT01163825. Registered 14 July 2010 - https://clinicaltrials.gov/ct2/show/NCT01163825

scholarly journals Reduction of Basal Forebrain Cholinergic System Parallels Cognitive Impairment in Patients at High Risk of Developing Alzheimer's Disease

2009 ◽  
Vol 20 (7) ◽  
pp. 1685-1695 ◽  
Author(s):  
M. Grothe ◽  
L. Zaborszky ◽  
M. Atienza ◽  
E. Gil-Neciga ◽  
R. Rodriguez-Romero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
High Risk ◽  
Basal Forebrain ◽  
Cholinergic System

Beyond Acetylcholinesterase Inhibitors: Novel Cholinergic Treatments for Alzheimer’s Disease

2017 ◽  
Vol 14 (4) ◽  
pp. 377-392 ◽  
Author(s):  
Asante R. Kamkwalala ◽  
Paul A. Newhouse
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Performance ◽  
Basal Forebrain ◽  
Cholinergic System ◽  
Acetylcholinesterase Inhibitor ◽  
Muscarinic Acetylcholine Receptors ◽  
Acetylcholinesterase Inhibition ◽  
Receptor System ◽  
Limited Effectiveness

The major components of the cholinergic receptor system of the human brain include projections from the basal forebrain nuclei, and utilize the two types of receptors that they synapse on, nicotinic and muscarinic acetylcholine receptors. With the widespread cortical and subcortical projections of the basal forebrain, activity of these two receptor systems provide modulation of neurotransmitter activity underlying normal cognitive processes, such as attention, episodic memory, and working memory. Alzheimer’s disease (AD) targets and damages cholinergic neurons in the basal forebrain, and as these projections are lost, cognitive performance progressively declines. Currently, the most widely prescribed treatment for AD is acetylcholinesterase inhibitor medications, which work by partially blocking the degradation of acetylcholine in the synapse and enabling more of the neurotransmitter to reach and activate cholinergic receptors. However since these medications have limited effectiveness, alternate treatments that focus on augmenting the activity of the receptors themselves, independent of acetylcholinesterase inhibition, are being explored. This review will discuss: 1) the role of the cholinergic system in modulating cognition, 2) novel cholinergic treatment strategies for AD-related cognitive decline, in particular treatments intended to increase cholinergic system activity by selectively targeting muscarinic and nicotinic acetylcholinergic receptors to improve cognitive performance, 3) risks, and additional considerations for cholinergic cognitive treatments for AD.

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