Journal of Alzheimer's Disease - Volume 91, issue 4

Authors: García-Alberca, José María | Gris, Esther | de la Guía, Paz | Mendoza, Silvia | de la Rica, María López

Article Type: Research Article

Abstract: Background: Souvenaid® is a medical food that contains nutrients that can help synapse synthesis in Alzheimer’s disease (AD). The potential effectiveness of combination therapy of Souvenaid with cholinesterase inhibitors (AChEI) is currently not well-known. Objective: To look into the effect of combination therapy with Souvenaid plus AChEI in people with mild AD in the real-world. Methods: We carried out a retrospective analysis in mild AD patients attending a memory clinic. Three groups were studied according to the treatment they received: Souvenaid alone (n  = 66), AChEI alone (n  = 84), and Souvenaid+AChEI (n  = 70). Treatment effects were …evaluated at baseline, 6 and 12 months. Cognitive functioning was assessed by Mini-Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit Modalities Test (SDMT), Boston Naming Test (BNT), Trail Making Test (TMT/A-B), Phonemic and Semantic Verbal Fluency Test (PVFT/SVFT); neuropsychiatric symptoms were evaluated by the Neuropsychiatric Inventory (NPI); functional capacity was assessed by the Bayer Activities Daily Living Scale (BAYER-S). A Mixed Model for Repeated Measures analysis was carried out to evaluate changes in outcome scores. Results: After 12 months Souvenaid+AChEI showed significant improvement in MMSE (p  < 0.001), RAVLT (p  < 0.0001), SVFT (p  = 0.002), PVFT (p  = 0.007), TMTA (p  = 0.039), TMTB (p  = 0.001), and NPI (p  < 0.0001) compared to AChEI alone. Conclusion: Souvenaid showed cognitive and behavioral benefits in mild AD patients. These effects increased when Souvenaid and AChEI were used in combination. This study can serve as a model for the design of prospective controlled trials that help to support the combined use of Souvenaid and antidementia drugs in AD. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, cognitive dysfunction, medical food, Souvenaid

DOI: 10.3233/JAD-221003

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1459-1469, 2023

Authors: Wang, Xin | Zhou, Xueyan | Lee, Jingyun | Furdui, Cristina M. | Ma, Tao

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common dementia syndrome in the elderly characterized by synaptic failure and unique brain pathology. De novo protein synthesis is required for the maintenance of memory and synaptic plasticity. Mounting evidence links impaired neuronal protein synthesis capacity and overall protein synthesis deficits to AD pathogenesis. Meanwhile, identities of AD-associated dysregulation of “newly synthesized proteome” remain elusive. Objective: To investigate de novo proteome alterations in the hippocampus of aged Tg19959 AD model mice. Methods: In this study, we combined the bioorthogonal noncanonical amino acid tagging (BONCAT) method with the unbiased large-scale …proteomic analysis in acute living brain slices (we name it “BONSPEC”) to investigate de novo proteome alterations in the hippocampus of Tg19959 AD model mice. We further applied multiple bioinformatics methods to analyze in-depth the proteomics data. Results: In total, 1,742 proteins were detected across the 10 samples with the BONSPEC method. After exclusion of those only detected in less than half of the samples in both groups, 1,362 proteins were kept for further analysis. 37 proteins were differentially expressed (based on statistical analysis) between the WT and Tg19959 groups. Among them, 19 proteins were significantly decreased while 18 proteins were significantly increased in the hippocampi of Tg19959 mice compared to WT mice. The results suggest that proteins involved in synaptic function were enriched in de novo proteome of AD mice. Conclusion: Our study could provide insights into the future investigation into the molecular signaling mechanisms underlying AD and related dementias (ADRDs). Show more

Keywords: Aging, Alzheimer’s disease, mass spectrometry, protein synthesis, proteomics

DOI: 10.3233/JAD-221044

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1471-1482, 2023

Authors: Marin-Marin, Lidón | Miró-Padilla, Anna | Costumero, Víctor

Article Type: Research Article

Abstract: Background: Malfunctioning of the default mode network (DMN) has been consistently related to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, evidence on differences in this network between MCI converters (MCI-c) and non-converters (MCI-nc), which could mark progression to AD, is still inconsistent. Objective: To multimodally investigate the DMN in the AD continuum. Methods: We measured gray matter (GM) volume, white matter (WM) integrity, and functional connectivity (FC) at rest in healthy elderly controls, MCI-c, MCI-nc, and AD patients, matched on sociodemographic variables. Results: Significant differences between AD patients and controls were found …in the structure of most of the regions of the DMN. MCI-c only differed from MCI-nc in GM volume of the left parahippocampus and bilateral hippocampi and middle frontal gyri, as well as in WM integrity of the parahippocampal cingulum connecting the left hippocampus and precuneus. We found significant correlations between integrity in some of those regions and global neuropsychological status, as well as an excellent discrimination ability between converters and non-converters for the sum of GM volume of left parahippocampus, bilateral hippocampi, and middle frontal gyri, and WM integrity of left parahippocampal cingulum. However, we found no significant differences in FC. Conclusion: These results further support the relationship between abnormalities in the DMN and AD, and suggest that structural measures could be more accurate than resting-state estimates as markers of conversion from MCI to AD. Show more

Keywords: Atrophy, default mode network, dementia, functional MRI, mild cognitive impairment

DOI: 10.3233/JAD-220603

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1483-1494, 2023

Authors: Corrigan, Rachel R. | Labrador, Luis | Grizzanti, John | Mey, Megan | Piontkivska, Helen | Casadesús, Gemma

Article Type: Research Article

Abstract: Background: Amylin, a pancreatic amyloid peptide involved in energy homeostasis, is increasingly studied in the context of Alzheimer’s disease (AD) etiology. To date, conflicting pathogenic and neuroprotective roles for this peptide and its analogs for AD pathogenesis have been described. Objective: Whether the benefits of amylin are associated with peripheral improvement of metabolic tone/function or directly through the activation of central amylin receptors is also unknown and downstream signaling mechanisms of amylin receptors are major objectives of this study. Methods: To address these questions more directly we delivered the amylin analog pramlintide systemically (IP), at previously …identified therapeutic doses, while centrally (ICV) inhibiting the receptor using an amylin receptor antagonist (AC187), at doses known to impact CNS function. Results: Here we show that pramlintide improved cognitive function independently of CNS receptor activation and provide transcriptomic data that highlights potential mechanisms. Furthermore, we show than inhibition of the amylin receptor increased amyloid-beta pathology in female APP/PS1 mice, an effect than was mitigated by peripheral delivery of pramlintide. Through transcriptomic analysis of pramlintide therapy in AD-modeled mice we found sexual dimorphic modulation of neuroprotective mechanisms: oxidative stress protection in females and membrane stability and reduced neuronal excitability markers in males. Conclusion: These data suggest an uncoupling of functional and pathology-related events and highlighting a more complex receptor system and pharmacological relationship that must be carefully studied to clarify the role of amylin in CNS function and AD. Show more

Keywords: Alzheimer’s disease, amylin, amyloid-β, metabolism, receptor antagonism, RNA sequencing

DOI: 10.3233/JAD-221057

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1495-1514, 2023

Authors: Jun, Yu Kyung | Lee, Seung Woo | Kim, Kwang Woo | Moon, Jung Min | Koh, Seong-Joon | Lee, Hyun Jung | Kim, Joo Sung | Han, Kyungdo | Im, Jong Pil

Article Type: Research Article

Abstract: Background: The fecal immunochemical test (FIT) is widely used in screening for colorectal cancer (CRC), but FIT results can be positive for diseases other than CRC. Objective: We investigated the association between positive results of FIT and the incidence of dementia using a nationwide database. Methods: FIT-positive participants were collected from a database provided by the Korean National Health Insurance Service. Results: The incidence of all kinds of dementia was higher in FIT-positive than FIT-negative subjects (p  < 0.0001). FIT-positive participants had a higher risk of Alzheimer’s disease (AD) (p  < 0.0001) and vascular dementia (p … = 0.0002), compared to participants with FIT negativity. The risk of all kinds of dementia or AD in FIT-positive participants was higher in younger (age < 65 years) than older participants (p  < 0.0001 for all kinds of dementia; p  = 0.0002 for AD). Conclusion: FIT positivity was correlated with an increased risk of dementia, especially in participants under 65 years of age. The study suggests that clinicians can consider dementia when FIT-positive participants fail to show any malignancies. Show more

Keywords: Alzheimer’s disease, dementia, occult blood, population surveillance, vascular dementia

DOI: 10.3233/JAD-220770

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1515-1525, 2023

Authors: Yang, Mingming | Qi, Rongrong | Liu, Yuxiao | Shen, Xin | Zhao, Yulou | Jin, Nana | Wu, Ruozhen | Liu, Fei | Gu, Jianlan

Article Type: Research Article

Abstract: Background: Neurofibrillary tangle aggregated from anomalous hyperphosphorylated tau is a hallmark of Alzheimer’s disease (AD). Trans-active response DNA-binding protein of 43 kDa (TDP-43) enhances the instability and exon (E) 10 inclusion of tau mRNA. Cytoplasmic inclusion of hyperphosphorylated TDP-43 in the neurons constitutes the third most prevalent proteinopathy of AD. Casein kinase 1δ (CK1δ ) is elevated in AD brain and phosphorylates TDP-43 in vitro . Objective: To determine the roles of CK1δ in phosphorylation, aggregation, and function of TDP-43 in the processing of tau mRNA. Methods: The interaction and colocalization of TDP-43 and …CK1δ were analyzed by co-immunoprecipitation and immunofluorescence staining. TDP-43 phosphorylation by CK1δ was determined in vitro and in cultured cells. RIPA-insoluble TDP-43 aggregates obtained by ultracentrifugation were analyzed by immunoblots. The instability and E10 splicing of tau mRNA were studied by using a reporter of green fluorescence protein tailed with 3’-untranslational region of tau mRNA and a mini-tau gene and analyzed by real-time quantitative PCR and reverse transcriptional PCR. Results: We found that CK1δ interacted and co-localized with TDP-43. TDP-43 was phosphorylated by CK1δ at Ser379, Ser403/404, and Ser409/410 in vitro and in cultured cells, which was mutually enhanced. CK1δ overexpression promoted the aggregation of TDP-43 and suppressed its activity in enhancing the instability and E10 inclusion of tau mRNA. Conclusion: CK1δ phosphorylates TDP-43, promotes its aggregation, and inhibits its activity in promoting the instability of tau mRNA and inclusion of tau E10. Elevated CK1δ in AD brain may contribute to TDP-43 and tau pathologies directly or indirectly. Show more

Keywords: Casein kinase 1δ , mRNA processing, phosphorylation, tau, TDP-43

DOI: 10.3233/JAD-220985

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1527-1539, 2023

Authors: Sun, Ruihua | Shang, Junkui | Yan, Xi | Zhao, Jingran | Wang, Wan | Wang, Wenjing | Li, Wei | Gao, Chenhao | Wang, Fengyu | Zhang, Haohan | Wang, Yanliang | Cao, Huixia | Zhang, Jiewen

Article Type: Research Article

Abstract: Background: Chronic cerebral hypoperfusion (CCH) is associated with neuronal loss and blood-brain barrier (BBB) impairment in vascular dementia (VaD). However, the relationship and the molecular mechanisms between BBB dysfunction and neuronal loss remain elusive. Objective: We explored the reasons for neuron loss following CCH. Methods: Using permanent bilateral common carotid artery occlusion (2VO) rat model, we observed the pathological changes of cortical neurons and BBB in the sham group as well as rats 3d, 7d, 14d and 28d post 2VO. In order to further explore the factors influencing neuron loss following CCH with regard to cortical …blood vessels, we extracted cortical brain microvessels at five time points for transcriptome sequencing. Finally, integrin receptor a4β1 (VLA-4) inhibitor was injected into the tail vein, and cortical neuron loss was detected again. Results: We found that cortical neuron loss following CCH is a continuous process, but damage to the BBB is acute and transient. Results of cortical microvessel transcriptome analysis showed that biological processes related to vascular inflammation mainly occurred in the chronic phase. Meanwhile, cell adhesion molecules, cytokine-cytokine receptor interaction were significantly changed at this phase. Among them, the adhesion molecule VCAM1 plays an important role. Using VLA-4 inhibitor to block VCAM1-VLA-4 interaction, cortical neuron damage was ameliorated at 14d post 2VO. Conclusion: Injury of the BBB may not be the main reason for persistent loss of cortical neurons following CCH. The continuous inflammatory response within blood vessels maybe an important factor in the continuous loss of cortical neurons following CCH. Show more

Keywords: Blood-brain barrier, chronic cerebral hypoperfusion, inflammation, neuron, VCAM1

DOI: 10.3233/JAD-221059

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1541-1555, 2023

Authors: Azami, Hamed | Moguilner, Sebastian | Penagos, Hector | Sarkis, Rani A. | Arnold, Steven E. | Gomperts, Stephen N. | Lam, Alice D.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with EEG changes across the sleep-wake cycle. As the brain is a non-linear system, non-linear EEG features across behavioral states may provide an informative physiologic biomarker of AD. Multiscale fluctuation dispersion entropy (MFDE) provides a sensitive non-linear measure of EEG information content across a range of biologically relevant time-scales. Objective: To evaluate MFDE in awake and sleep EEGs as a potential biomarker for AD. Methods: We analyzed overnight scalp EEGs from 35 cognitively normal healthy controls, 23 participants with mild cognitive impairment (MCI), and 19 participants with mild dementia due …to AD. We examined measures of entropy in wake and sleep states, including a slow-to-fast-activity ratio of entropy (SFAR-entropy). We compared SFAR-entropy to linear EEG measures including a slow-to-fast-activity ratio of power spectral density (SFAR-PSD) and relative alpha power, as well as to cognitive function. Results: SFAR-entropy differentiated dementia from MCI and controls. This effect was greatest in REM sleep, a state associated with high cholinergic activity. Differentiation was evident in the whole brain EEG and was most prominent in temporal and occipital regions. Five minutes of REM sleep was sufficient to distinguish dementia from MCI and controls. Higher SFAR-entropy during REM sleep was associated with worse performance on the Montreal Cognitive Assessment. Classifiers based on REM sleep SFAR-entropy distinguished dementia from MCI and controls with high accuracy, and outperformed classifiers based on SFAR-PSD and relative alpha power. Conclusion: SFAR-entropy measured in REM sleep robustly discriminates dementia in AD from MCI and healthy controls. Show more

Keywords: Alzheimer’s disease, EEG, entropy, mild cognitive impairment, REM sleep, sleep

DOI: 10.3233/JAD-221152

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1557-1572, 2023