P1-199: In vivo MRI morphometric measurement indicates volume loss within the cholinergic basal forebrain region in subjects with amnestic mild cognitive impairment

ObjectiveTo investigate in vivo whether synaptic loss and neurofibrillary tangle load spatially overlap and correlate with clinical symptoms in patients with amnestic mild cognitive impairment (aMCI).MethodsIn this cross-sectional study, 10 patients with aMCI and 10 healthy controls underwent triple PET-MRI with 11C-UCB-J (synaptic vesicle protein 2A), 18F-MK-6240 (tau deposition), and 11C-Pittsburgh compound B (β-amyloid) and neuropsychological assessment. Gray matter atrophy was assessed by voxel-based morphometry with T1-weighted MRIs. Voxel-wise and volume-of-interest analyses were conducted on PET data. The interrelationship of synaptic density and tau deposition was investigated. We also investigated correlations of 18F-MK-6240 and 11C-UCB-J binding with cognitive performance.ResultsCompared to controls, patients with aMCI showed a decreased 11C-UCB-J binding mainly in substructures of the medial temporal lobe (MTL; 48%–51%, pcluster = 0.02). Increased 18F-MK6240 binding in the same region was observed (42%–44%, pcluster = 0.0003), spreading to association cortices. In the MTL, higher 18F-MK-6240 binding inversely related to lower 11C-UCB-J binding (p = 0.02, r = −0.76). Decreased performance on cognitive tests was associated with both increased 18F-MK-6240 and decreased 11C-UCB-J binding in the hippocampus (p < 0.01, r > 0.7), although in a multivariate analysis only 18F-MK-6240 binding was significantly related to cognitive performance.ConclusionsPatients with aMCI have high tau deposition and synaptic density loss mainly in key regions known to be involved in early cognitive impairment, indicating that these are interrelated in the MTL, while tau binding had already spread toward association cortices. Longitudinal data are needed to provide further insight into the temporal aspects of this relationship.

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Divergent Connectivity Changes in Gray Matter Structural Covariance Networks in Subjective Cognitive Decline, Amnestic Mild Cognitive Impairment, and Alzheimer’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.686598 ◽

2021 ◽

Vol 13 ◽

Author(s):

Zhenrong Fu ◽

Mingyan Zhao ◽

Yirong He ◽

Xuetong Wang ◽

Jiadong Lu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Gray Matter ◽

Amnestic Mild Cognitive Impairment ◽

Subjective Cognitive Decline ◽

Structural Covariance ◽

Cholinergic Basal Forebrain

Alzheimer’s disease (AD) has a long preclinical stage that can last for decades prior to progressing toward amnestic mild cognitive impairment (aMCI) and/or dementia. Subjective cognitive decline (SCD) is characterized by self-experienced memory decline without any evidence of objective cognitive decline and is regarded as the later stage of preclinical AD. It has been reported that the changes in structural covariance patterns are affected by AD pathology in the patients with AD and aMCI within the specific large-scale brain networks. However, the changes in structural covariance patterns including normal control (NC), SCD, aMCI, and AD are still poorly understood. In this study, we recruited 42 NCs, 35 individuals with SCD, 43 patients with aMCI, and 41 patients with AD. Gray matter (GM) volumes were extracted from 10 readily identifiable regions of interest involved in high-order cognitive function and AD-related dysfunctional structures. The volume values were used to predict the regional densities in the whole brain by using voxel-based statistical and multiple linear regression models. Decreased structural covariance and weakened connectivity strength were observed in individuals with SCD compared with NCs. Structural covariance networks (SCNs) seeding from the default mode network (DMN), salience network, subfields of the hippocampus, and cholinergic basal forebrain showed increased structural covariance at the early stage of AD (referring to aMCI) and decreased structural covariance at the dementia stage (referring to AD). Moreover, the SCN seeding from the executive control network (ECN) showed a linearly increased extent of the structural covariance during the early and dementia stages. The results suggest that changes in structural covariance patterns as the order of NC-SCD-aMCI-AD are divergent and dynamic, and support the structural disconnection hypothesis in individuals with SCD.

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Changes in Parahippocampal White Matter Integrity in Amnestic Mild Cognitive Impairment: A Diffusion Tensor Imaging Study

Behavioural Neurology ◽

10.1155/2009/408037 ◽

2009 ◽

Vol 21 (1-2) ◽

pp. 51-61 ◽

Cited By ~ 37

Author(s):

E. J. Rogalski ◽

C. M. Murphy ◽

L. deToledo-Morrell ◽

R. C. Shah ◽

M. E. Moseley ◽

...

Keyword(s):

Cognitive Impairment ◽

Diffusion Tensor Imaging ◽

Mild Cognitive Impairment ◽

White Matter ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Amnestic Mild Cognitive Impairment ◽

Perforant Path ◽

Tissue Loss

In the present study, changes in the parahippocampal white matter (PWM), in the region that includes the perforant path, were investigated, in vivo, in 14 individuals with amnestic mild cognitive impairment (aMCI) compared to 14 elderly controls with no cognitive impairment (NCI). For this purpose, (1) volumetry; (2) diffusion tensor imaging (DTI) derived measures of mean diffusivity (MD) and fractional anisotropy (FA); and (3) tractography were used. In addition, regression models were utilized to examine the association of PWM measurements with memory decline. The results from this study confirm previous findings in our laboratory and others, showing that compared to controls, individuals with aMCI have PWM volume loss. In addition to volume reduction, participants with aMCI demonstrated a significant increase in MD, but no difference in FA, both in the PWM region and in fibers modeled to pass through the PWM region. Further, the DTI metric of MD was associated with declarative memory performance, suggesting it may be a sensitive marker for memory dysfunction. These results indicate that there is general tissue loss and degradation (decreased volume; increased MD) in individuals with aMCI compared to older people with normal cognitive function. However, the microstructural organization of remaining fibers, as determined by measures of anisotropic diffusion, is not significantly different from that of controls.

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Shift in the ratio of three-repeat tau and four-repeat tau mRNAs in individual cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2005.03641.x ◽

2006 ◽

Vol 96 (5) ◽

pp. 1401-1408 ◽

Cited By ~ 69

Author(s):

Stephen D. Ginsberg ◽

Shaoli Che ◽

Scott E. Counts ◽

Elliott J. Mufson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Basal Forebrain ◽

Cholinergic Basal Forebrain ◽

Forebrain Neurons

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Upregulation of select rab GTPases in cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease

Journal of Chemical Neuroanatomy ◽

10.1016/j.jchemneu.2011.05.012 ◽

2011 ◽

Vol 42 (2) ◽

pp. 102-110 ◽

Cited By ~ 67

Author(s):

Stephen D. Ginsberg ◽

Elliott J. Mufson ◽

Melissa J. Alldred ◽

Scott E. Counts ◽

Joanne Wuu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Basal Forebrain ◽

Rab Gtpases ◽

Cholinergic Basal Forebrain ◽

Forebrain Neurons

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

American Journal Of Pathology ◽

10.1016/j.ajpath.2011.07.044 ◽

2011 ◽

Vol 179 (5) ◽

pp. 2533-2550 ◽

Cited By ~ 70

Author(s):

Laurel Vana ◽

Nicholas M. Kanaan ◽

Isabella C. Ugwu ◽

Joanne Wuu ◽

Elliott J. Mufson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Basal Forebrain ◽

Tau Pathology ◽

Cholinergic Basal Forebrain ◽

Forebrain Neurons

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The relationship between cholinergic system brain structure and function in healthy adults and patients with mild cognitive impairment

Scientific Reports ◽

10.1038/s41598-021-95573-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jessica Peter ◽

Isabella Mayer ◽

Thomas Kammer ◽

Lora Minkova ◽

Jacob Lahr ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Structure Function ◽

Healthy Volunteers ◽

Basal Forebrain ◽

Cholinergic System ◽

Signal Transmission ◽

Structure Function Relationship ◽

Function Relationship

AbstractWe assessed the structure–function relationship of the human cholinergic system and hypothesized that structural measures are associated with short-latency sensory afferent inhibition (SAI), an electrophysiological measure of central cholinergic signal transmission. Healthy volunteers (n = 36) and patients with mild cognitive impairment (MCI, n = 20) underwent median nerve SAI and 3T structural MRI to determine the volume of the basal forebrain and the thalamus. Patients with MCI had smaller basal forebrain (p < 0.001) or thalamus volumes (p < 0.001) than healthy volunteers. Healthy SAI responders (> 10% SAI) had more basal forebrain volume than non-responders (p = 0.004) or patients with MCI (p < 0.001). More basal forebrain volume was associated with stronger SAI in healthy volunteers (r = 0.33, p < 0.05) but not patients with MCI. There was no significant relationship between thalamus volumes and SAI. Basal forebrain volume is associated with cholinergic function (SAI) in healthy volunteers but not in MCI patients. The in-vivo investigation of the structure–function relationship could further our understanding of the human cholinergic system in patients with suspected or known cholinergic system degeneration.

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