scholarly journals In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Arianna Sala ◽  
Silvia Paola Caminiti ◽  
Luca Presotto ◽  
Andrea Pilotto ◽  
Claudio Liguori ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Neuropsychiatric Symptoms ◽  
System Level ◽  
Binding Potential ◽  
Control Group ◽  
Molecular Connectivity ◽  
Dice Coefficient

Abstract Background Preclinical and pathology evidence suggests an involvement of brain dopamine (DA) circuitry in Alzheimer’s disease (AD). We in vivo investigated if, when, and in which target regions [123I]FP-CIT-SPECT regional binding and molecular connectivity are damaged along the AD course. Methods We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D), and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial correlation analysis. Results were deemed significant at p < 0.05, after Bonferroni correction for multiple comparisons. Results We found significant reductions of [123I]FP-CIT binding in both AD-MCI and AD-D compared to controls. Binding reductions were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced [123I]FP-CIT binding, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient ≤ 0.25) and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). Conclusion Local- and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.

scholarly journals In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

2021 ◽  
Author(s):  
Daniela Perani ◽  
Arianna Sala ◽  
Silvia Paola Caminiti ◽  
Luca Presotto ◽  
Andrea Pilotto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Neuropsychiatric Symptoms ◽  
System Level ◽  
Binding Potential ◽  
Control Group ◽  
Molecular Connectivity ◽  
Dice Coefficient

Abstract Background Preclinical and pathology evidence suggest an involvement of brain dopamine (DA) circuitry in Alzheimer’s Disease (AD). We in vivo investigated, if, when and in which target regions, DA signaling and molecular connectivity are damaged along the AD course. Methods We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D) and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial-correlation analysis. Results were deemed significant at p<0.05, after Bonferroni correction for multiple comparisons. Results We found significant reductions of dopamine transporter density in both AD-MCI and AD-D compared to controls. Dopaminergic deficits were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced dopaminergic transporter density, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient < 0.25), and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). Conclusion Local and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.

ChK1 Activation Induces Reactive Astrogliosis Through CIP2A/PP2A/STAT3 Pathway In Alzheimer's Disease

2021 ◽  
Author(s):  
Ying Zhou ◽  
Xiaoyuan Liu ◽  
Shuqing Ma ◽  
Dichen Yang ◽  
Nan Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Damage ◽  
Cognitive Deficits ◽  
Immunofluorescent Staining ◽  
Experimental Conditions ◽  
Stat3 Pathway ◽  
Reactive Astrogliosis

Abstract Background: In Alzheimer’s disease (AD), activation of astrocyte participates in the development of neurodegenerative diseases through neuroinflammation and disturbs glia-neuron interaction. Cancerous Inhibitor of PP2A (CIP2A) is an endogenous PP2A inhibitor. CIP2A upregulation specifically in astrocytes causes reactive astrogliosis, synaptic degeneration and cognitive deficits. However, the underlying mechanism of CIP2A upregulation remains unclear. Methods: In 3xTg-AD mice, we determined ChK1 was activated and related to DNA damage upregulating CIP2A by WB. We transfected EGFP-ChK1 plasmid into HEK293-T cell to determine ChK1 induces CIP2A upregulation and PP2A inhibition. We incubated Aβ and infected GFAP-ChK1-LV into primary astrocytes to confirm the signaling pathway in astrocytes and astrogliosis in AD. GFAP-ChK1-AAV was injected into C57/BL6 mice to induce specific expression of target protein in astrocytes. ChK1 inhibitor (SB) was performed to reverse the ChK1 activity. Outcomes were assessed using molecular (immunofluorescent staining, Western Blot and Golgi staining) measures to estimate symptomatic pathology and behavioral (NORT, OLT, MWM and FCT) measures to assess cognitive function. For most experiments, subjects were randomly assigned to experimental groups, and data were collected under blinded experimental conditions.Results: We demonstrated that DNA damage related Checkpoint kinase 1 (ChK1) was activated in 3xTg-AD mice. ChK1-mediated CIP2A overexpression drove inhibition of PP2A and activated STAT3, then led to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induced reactive astrogliosis, degeneration of neurons and deterioration of AD through CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 might be a potential therapeutic approach for AD treatment.Conclusions: These results suggest that ChK1 is upregulated in 3xTg-AD mice, ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis, neurodegeneration and AD-like cognitive deficits in vitro and in vivo.

scholarly journals Phytocannabinoids use in Alzheimer’s disease

2021 ◽  
Author(s):  
Júlia Maia Seixas ◽  
Hygor Kleber Cabral Silva ◽  
Maria Alice Rocha Lopes ◽  
Kamila Castro Oliveira Camargos ◽  
Lara Silveira Marques ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Effects ◽  
Cognitive Deficits ◽  
Endocannabinoid System ◽  
In Vivo Studies ◽  
Publication Date ◽  
Β Amyloid

Background: Alzheimer’s disease (AD) is the most common cause of dementia among older adults impacting quality of life. Nowadays, four drugs are indicated to manage AD symptoms, however, none of them have shown effectiveness to prevent the disease’s progress, and they are associated with adverse effects. In this scenario, the endocannabinoid system has the attention of researchers and physicians, because of its relation with processes involved in the AD physiopathology. Therefore, in the last decade, studies that evaluate the use of Cannabidiol (CBD) and other phytocannabinoids, like tetrahydrocannabinol (THC) and cannabinol (CBN), as an alternative treatment to this illness, have multiplied. Objectives: To bring updated information about this new and promising therapeutic. Methods: A bibliographic research in PubMed with the terms “Cannabidiol and Alzheimer” was made, with the filters “Free full text” and “Publication Date 5 years”. The research obtained 31 results, from which were chosen 10. Results: In vivo studies with CBD, THC and CBN have shown their properties: anti-inflammatory, antioxidant, attenuation of toxic accumulation of β-amyloid protein and to reverse cognitive deficits, all AD physiopathological processes. It was also demonstrated that the combination between THC and CBD shows better efficiency and fewer adverse effects than CBD isolated use. Conclusions: Despite needing deeper and stronger studies with better conducted clinical trials, the researches about phytocannabinoids use in AD seem promising, and they might become the biggest ally in the treatment of this and other neurodegenerative conditions.

scholarly journals Integrative glycoproteomics reveals protein N-glycosylation aberrations and glycoproteomic network alterations in Alzheimer’s disease

2020 ◽  
Vol 6 (40) ◽  
pp. eabc5802
Author(s):  
Qi Zhang ◽  
Cheng Ma ◽  
Lih-Shen Chin ◽  
Lian Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Large Scale ◽  
Site Occupancy ◽  
Glycosylation Site ◽  
System Level ◽  
Disease Signatures ◽  
And Control

Protein N-glycosylation plays critical roles in controlling brain function, but little is known about human brain N-glycoproteome and its alterations in Alzheimer’s disease (AD). Here, we report the first, large-scale, site-specific N-glycoproteome profiling study of human AD and control brains using mass spectrometry–based quantitative N-glycoproteomics. The study provided a system-level view of human brain N-glycoproteins and in vivo N-glycosylation sites and identified disease signatures of altered N-glycopeptides, N-glycoproteins, and N-glycosylation site occupancy in AD. Glycoproteomics-driven network analysis showed 13 modules of co-regulated N-glycopeptides/glycoproteins, 6 of which are associated with AD phenotypes. Our analyses revealed multiple dysregulated N-glycosylation–affected processes and pathways in AD brain, including extracellular matrix dysfunction, neuroinflammation, synaptic dysfunction, cell adhesion alteration, lysosomal dysfunction, endocytic trafficking dysregulation, endoplasmic reticulum dysfunction, and cell signaling dysregulation. Our findings highlight the involvement of N-glycosylation aberrations in AD pathogenesis and provide new molecular and system-level insights for understanding and treating AD.

The Precuneus – A Witness for Excessive Aβ Gathering in Alzheimer’s Disease Pathology

2018 ◽  
Vol 18 (5-6) ◽  
pp. 302-309 ◽  
Author(s):  
Gayane Aghakhanyan ◽  
Andrea Vergallo ◽  
Marta Gennaro ◽  
Sara Mazzarri ◽  
Federica Guidoccio ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Duration ◽  
Standardized Uptake Value ◽  
Positive Association ◽  
Analysis Of Covariance ◽  
Qualitative Assessment ◽  
Control Group ◽  
Positron Emission

Evidence of cortical beta-amyloid (Aβ) load, assessed by Aβ positron emission tomography (Aβ-PET), is an established in vivo biomarker of Alzheimer’s disease (AD)-related pathophysiology. Qualitative assessment of Aβ-PET provides binary information; meanwhile semiquantitative approaches require a parcellation of PET image either manually or by placement of atlas-based volumes of interest. We supposed that a whole-brain approach with voxel-by-voxel standardized uptake value ratio (SUVr) parametric images may better elucidate the spatial trajectories of Aβ burden along the continuum of AD. Methods: We recruited 32 subjects with a diagnosis of probable AD dementia (ADD, n = 20) and mild cognitive impairment due to AD (MCI-AD, n = 12) according to the NIA-AA 2011 criteria. We also enrolled a control group of 6 cognitively healthy individuals (HCs) with preserved cognitive functions and negative Aβ-PET scan. The PET images were spatially normalized using the AV45 PET template in the MNI brain space. Subsequently, parametric SUVr images were calculated using the whole cerebellum as a reference region. A voxel-wise analysis of covariance was used to compare (between groups) the Αβ distribution pattern considering age as a nuisance covariate. Results: Both ADD and MCI-AD subjects showed a widespread increase in radiotracer uptake when compared with HC participants (p < 0.001, uncorrected). After applying a multiple comparison correction (p < 0.05, corrected), a relative large cluster of increased [18F]-flor­betapir uptake was observed in the precuneus in the ADD and MCI-AD groups compared to HCs. Voxel-wise regression analysis showed a significant positive linear association between the voxel-wise SUVr values and the disease duration. Conclusions: The voxel-wise semiquantitative analysis shows that the precuneus is a region with higher vulnerability to Aβ depositions when compared to other cortical regions in both MCI-AD and ADD subjects. We think that the precuneus is a promising PET-based outcome measure for clinical trials of drugs targeting brain Aβ. We found a positive association between the overall Aβ-PET SUVr and the disease duration suggesting that the region-specific slow saturation of Aβ deposition continuously takes place as the disease progresses.

scholarly journals Approach to atypical Alzheimer’s disease and case studies of the major subtypes

CNS Spectrums ◽  
2017 ◽  
Vol 22 (6) ◽  
pp. 439-449 ◽  
Author(s):  
Bradford C. Dickerson ◽  
Scott M. McGinnis ◽  
Chenjie Xia ◽  
Bruce H. Price ◽  
Alireza Atri ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuropsychiatric Symptoms ◽  
Current Approach ◽  
Molecular Biomarkers ◽  
Diagnostic Tools ◽  
Prodromal Phase ◽  
Atypical Form ◽  
Atypical Symptoms

Alzheimer’s disease (AD) has long been recognized as a heterogeneous illness, with a common clinical presentation of progressive amnesia and less common “atypical” clinical presentations, including syndromes dominated by visual, aphasic, “frontal,” or apraxic symptoms. Our knowledge of atypical clinical phenotypes of AD comes from clinicopathologic studies, but with the growing use of in vivo molecular biomarkers of amyloid and tau pathology, we are beginning to recognize that these syndromes may not be as rare as once thought. When a clinician is evaluating a patient whose clinical phenotype is dominated by progressive aphasia, complex visual impairment, or other neuropsychiatric symptoms with relative sparing of memory, the differential diagnosis may be broader and a confident diagnosis of an atypical form of AD may require the use of molecular biomarkers. Despite the evolving sophistication in our diagnostic tools, and the acknowledgment of atypical AD syndromes in the 2011 revised diagnostic criteria for AD, the assessment of such patients still poses substantial challenges. We use a case-based approach to review the clinical and imaging phenotypes of a series of patients with typical and atypical AD, and discuss our current approach to their evaluation. One day, we hope that regardless of whether a patient exhibits typical or atypical symptoms of AD pathology, we will be able to identify the condition at a prodromal phase and institute a combination of symptomatic and disease-modifying therapies to support cognitive processes, function, and behavior, and slow or halt progression to dementia.

scholarly journals Comparative Efficacy of Active Group Music Intervention versus Group Music Listening in Alzheimer’s Disease

2021 ◽  
Vol 18 (15) ◽  
pp. 8067
Author(s):  
María Gómez-Gallego ◽  
Juan Cándido Gómez-Gallego ◽  
María Gallego-Mellado ◽  
Javier García-García
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nursing Homes ◽  
Usual Care ◽  
Functional State ◽  
Cognitive Deficits ◽  
Control Group ◽  
Clinical Effects ◽  
Music Intervention ◽  
Behavioural Symptoms

Background: Music interventions are promising therapies for the management of symptoms in Alzheimer’s disease (AD). Globally, music interventions can be classified as active or receptive depending on the participation of the subjects. Active and receptive music tasks engage different brain areas that might result in distinctive clinical effects. This study aims to compare the clinical effects of two types of music interventions and a control activity. Methods: Ninety AD patients from six nursing homes participated in the study. Nursing homes were randomly and blindly assigned to receive either active music intervention, receptive music intervention, or the usual care. Effects on cognition, behaviour, daily living activities, and motor function were assessed. Results: Active music intervention improved cognition, behaviour, and functional state in a higher extent than both receptive music intervention and usual care. The effect size of active music intervention for cognitive deficits and behavioural symptoms was large (η2 = 0.62 and 0.61, respectively), while for functional state, it was small-to-medium sized (η2 = 0.18). Receptive music intervention had a stabilizing effect on behavioural symptoms compared to control intervention (mean change from baseline ± standard deviation = −0.76 ± 3.66 and 3.35 ± 3.29, respectively). In the active music intervention, the percentage of patients who showed improvement in cognitive deficits (85.7), behavioural symptoms (92.9), and functional state (46.4) was higher than in both receptive listening (11.8, 42.9, and 14.3, respectively) and control group (6.3, 12.2, and 17.1, respectively). Conclusions: Active music intervention is useful to improve symptoms of AD and should be prescribed as a complement to the usual treatment.

scholarly journals Quantitative Gradient Echo MRI Identifies Dark Matter as a New Imaging Biomarker of Neurodegeneration that Precedes Tisssue Atrophy in Early Alzheimer’s Disease

2021 ◽  
pp. 1-20
Author(s):  
Satya V.V.N. Kothapalli ◽  
Tammie L. Benzinger ◽  
Andrew J. Aschenbrenner ◽  
Richard J. Perrin ◽  
Charles F. Hildebolt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dark Matter ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Imaging Biomarker ◽  
Control Group ◽  
Histopathological Study ◽  
Preclinical Ad

Background: Currently, brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer’s disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis. Objective: To apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus. Methods: Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®) = 0, amyloid β (Aβ)-negative, n = 34]; Preclinical AD (CDR = 0, Aβ-positive, n = 19); and mild AD (CDR = 0.5 or 1, Aβ-positive, n = 17). Results: In hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as “Dark Matter”, and the other, with relatively preserved neurons, “Viable Tissue”. Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group; neuronal loss ranged between 31% and 43%, while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration. Conclusion: In vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection.

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