Journal of Alzheimer's Disease - Volume 76, issue 3

Authors: Griswold, Anthony J. | Sivasankaran, Sathesh K. | Van Booven, Derek | Gardner, Olivia K. | Rajabli, Farid | Whitehead, Patrice L. | Hamilton-Nelson, Kara L. | Adams, Larry D. | Scott, Aja M. | Hofmann, Natalia K. | Vance, Jeffery M. | Cuccaro, Michael L. | Bush, William S. | Martin, Eden R. | Byrd, Goldie S. | Haines, Jonathan L. | Pericak-Vance, Margaret A. | Beecham, Gary W.

Article Type: Research Article

Abstract: Background: Significant work has identified genetic variants conferring risk and protection for Alzheimer’s disease (AD), but functional effects of these variants is lacking, particularly in under-represented ancestral populations. Expression studies performed in easily accessible tissue, such as whole blood, can recapitulate some transcriptional changes occurring in brain and help to identify mechanisms underlying neurodegenerative processes. Objective: We aimed to identify transcriptional differences between AD cases and controls in a cohort of diverse ancestry. Methods: We analyzed the protein coding transcriptome using RNA sequencing from peripheral blood collected from 234 African American (AA) (115 AD, 119 controls) …and 240 non-Hispanic Whites (NHW) (121 AD, 119 controls). To identify case-control differentially expressed genes and pathways, we performed stratified, joint, and interaction analyses using linear regression models within and across ancestral groups followed by pathway and gene set enrichment analyses. Results: Overall, we identified 418 (291 upregulated, 127 downregulated) and 488 genes (352 upregulated, 136 downregulated) differentially expressed in the AA and NHW datasets, respectively, with only 16 genes commonly differentially expressed in both ancestral groups. Joint analyses provided greater power to detect case-control differences and identified 1,102 differentially expressed genes between cases and controls (812 upregulated, 290 downregulated). Interaction analysis identified only 27 genes with different effects in AA compared to NHW. Pathway and gene-set enrichment analyses revealed differences in immune response-related pathways that were enriched across the analyses despite different underlying gene sets. Conclusion: These results support the hypothesis of converging underlying pathophysiological processes in AD across ancestral groups. Show more

Keywords: Gene expression profiling, population characteristics, RNA, transcriptome

DOI: 10.3233/JAD-190855

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1047-1060, 2020

Authors: Muurling, Marijn | Rhodius-Meester, Hanneke F.M. | Pärkkä, Juha | van Gils, Mark | Frederiksen, Kristian S. | Bruun, Marie | Hasselbalch, Steen G. | Soininen, Hilkka | Herukka, Sanna-Kaisa | Hallikainen, Merja | Teunissen, Charlotte E. | Visser, Pieter Jelle | Scheltens, Philip | van der Flier, Wiesje M. | Mattila, Jussi | Lötjönen, Jyrki | de Boer, Casper

Article Type: Research Article

Abstract: Background: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer’s disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer’s disease pathology. Objective: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer’s disease, and 3) predict cognitive decline. Methods: Gait was measured using tri-axial accelerometers attached …to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group. Results: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p  < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE. Conclusion: These findings suggest that gait — particularly measures related to pace and rhythm — are altered in dementia and have a direct link with measures of neurodegeneration. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, gait analysis, tau proteins

DOI: 10.3233/JAD-200225

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1061-1070, 2020

Authors: Liang, Yingxia | Raven, Frank | Ward, Joseph F. | Zhen, Sherri | Zhang, Siyi | Sun, Haoqi | Miller, Sean J. | Choi, Se Hoon | Tanzi, Rudolph E. | Zhang, Can

Article Type: Research Article

Abstract: Background: The amyloid cascade hypothesis of Alzheimer’s disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown. Objective: Here, we aimed to investigate astrocyte-related pathological changes of Aβ …and AβPP using immunohistochemistry and biochemical studies in both animal and cell models. Methods/Results: We utilized 5XFAD transgenic mice and found age-dependent upregulation of AβPP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that AβPP proteins presented well-defined punctate immuno reactivity in young animals, whereas AβPP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in downstream astrocyte autonomous changes, including up regulation in AβPP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1. Conclusion: Collectively, our results show that age-dependent AβPP up regulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD. Show more

Keywords: Alzheimer’s disease, amyloid pathology, amyloid-β , amyloid-β protein precursor, amyloidogenesis, astrocyte, autonomous

DOI: 10.3233/JAD-200128

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1071-1082, 2020

Authors: Kaur, Harpreet | Golovko, Svetlana | Golovko, Mikhail Y. | Singh, Surjeet | Darland, Diane C. | Combs, Colin K.

Article Type: Research Article

Abstract: Background: The intestinal microbiota and its metabolites, particularly short-chain fatty acids (SCFAs), have been implicated in immune function, host metabolism, and even behavior. Objective: This study was performed to investigate whether probiotic administration influences levels of intestinal microbiota and their metabolites in a fashion that may attenuate brain changes in a mouse model of Alzheimer’s disease (AD). Methods: C57BL/6 wild-type (WT) mice were compared to AppNL -G -F mice. The animals were treated with either vehicle or probiotic (VSL#3) for 8 weeks. Fecal microbiome analysis along with Aβ, GFAP, Iba-1, c-Fos, and Ki-67 immunohistochemistry …was done. SCFAs were analyzed in serum and brains using UPLC-MS/MS. Results: Probiotic (VSL#3) supplementation for 2 months resulted in altered microbiota in both WT and AppNL -G -F mice. An increase in serum SCFAs acetate, butyrate, and lactate were found in both genotypes following VSL#3 treatment. Propionate and isobutyrate were only increased in AppNL -G -F mice. Surprisingly, VSL#3 only increased lactate and acetate in brains of AppNL -G -F mice. No significant differences were observed between vehicle and VSL#3 fed AppNL -G -F hippocampal immunoreactivities of Aβ, GFAP, Iba-1, and Ki-67. However, hippocampal c-Fos staining increased in VSL#3 fed AppNL -G -F mice. Conclusion: These data demonstrate intestinal dysbiosis in the AppNL -G -F mouse model of AD. Probiotic VSL#3 feeding altered both serum and brain levels of lactate and acetate in AppNL -G -F mice correlating with increased expression of the neuronal activity marker, c-Fos. Show more

Keywords: Alzheimer’s disease, butyrate, gliosis, microbiota, plaques, probiotics, short chain fatty acids

DOI: 10.3233/JAD-200436

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1083-1102, 2020

Authors: Duan, Wenna | Sehrawat, Parshant | Balachandrasekaran, Arvind | Bhumkar, Ashish B. | Boraste, Paresh B. | Becker, James T. | Kuller, Lewis H. | Lopez, Oscar L. | Gach, H. Michael | Dai, Weiying

Article Type: Research Article

Abstract: Background: Reliable cerebral blood flow (CBF) biomarkers using a noninvasive imaging technique are sought to facilitate early diagnosis and intervention in early Alzheimer’s disease (AD). Objective: We aim to identify brain regions in which CBF values are affected and related to cognitive decline in early AD using a large cohort. Methods: Perfusion MRIs using continuous arterial spin labeling were acquired at 1.5 T in 58 normal controls (NC), 50 mild cognitive impairments (MCI), and 40 AD subjects from the Cardiovascular Health Study Cognition Study. Regional absolute CBF and normalized CBF (nCBF) values, without and with correction …of partial volume effects, were compared across three groups. Association between regional CBF values and Modified Mini-Mental State Examination (3MSE) were investigated by multiple linear regression analyses adjusted for cardiovascular risk factors. Results: After correcting for partial volume effects and cardiovascular risk factors, ADs exhibited decreased nCBF with the strongest reduction in the bilateral posterior cingulate & precuneus region (p  < 0.001) compared to NCs, and the strongest reduction in the bilateral superior medial frontal region (p  < 0.001) compared to MCIs. MCIs exhibited the strongest nCBF decrease in the left hippocampus and nCBF increase in the right inferior frontal and insular region. The 3MSE scores within the symptomatic subjects were significantly associated with nCBF in the bilateral posterior and middle cingulate and parietal (p  < 0.001), bilateral superior medial frontal (p  < 0.001), bilateral temporoparietal (p  < 0.02), and right hippocampus (p  = 0.02) regions. Conclusion: Noninvasive perfusion MRI can detect functional changes across diagnostic class and serve as a staging biomarker of cognitive status. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, cerebral blood flow, cognition

DOI: 10.3233/JAD-200034

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1103-1120, 2020

Authors: Chatzistavraki, Maria | Papazafiri, Panagiota | Efthimiopoulos, Spiros

Article Type: Research Article

Abstract: Background: Coordinated calcium influx upon neuronal depolarization activates pathways that phosphorylate CaMKII, ERKs, and the transcription factor CREB and, therefore, expression of pro-survival and neuroprotective genes. Recent evidence indicates that amyloid-β protein precursor (AβPP) is trafficked to synapses and promotes their formation. At the synapse, AβPP interacts with synaptic proteins involved in vesicle exocytosis and affects calcium channel function. Objective: Herein, we examined the role of AβPP in depolarization-induced calcium-mediated signaling using acute cerebral slices from wild-type C57bl/6 mice and AβPP–/– C57bl/6 mice. Methods: Depolarization of acute cerebral slices from wild-type C57bl/6 and AβPP–/– C57bl/6 mice …was used to induce synaptic signaling. Protein levels were examined by western blot and calcium dynamics were assessed using primary neuronal cultures. Results: In the absence of AβPP, decreased pCaMKII and pERKs levels were observed. This decrease was sensitive to the inhibition of N- and P/Q-type Voltage Gated Calcium Channels (N- and P/Q-VGCCs) by ω -conotoxin GVIA and ω -conotoxin MVIIC, respectively, but not to inhibition of L-type VGCCs by nifedipine. However, the absence of AβPP did not result in a statistically significant decrease of pCREB, which is a known substrate of pERKs. Finally, using calcium imaging, we found that down regulation of AβPP in cortical neurons results in a decreased response to depolarization and altered kinetics of calcium response. Conclusion: AβPP regulates synaptic activity-mediated neuronal signaling by affecting N- and P/Q-VGCCs. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, AβPP, calcium, neuronal signaling, synapse

DOI: 10.3233/JAD-200290

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1121-1133, 2020

Authors: Habiba, Umma | Merlin, Sam | Lim, Jeremiah K.H. | Wong, Vickie H.Y. | Nguyen, Christine T.O. | Morley, John W. | Bui, Bang V. | Tayebi, Mourad

Article Type: Research Article

Abstract: Background: Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer’s disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature. Objective: This study’s aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in …the retina of a rodent model of AD. Methods: Retinas and brain tissue from 5×FAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aβ plaque-specific and Aβo-specific antibodies. Results: We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aβ antibody confirmed the presence of the Aβ plaques in all 5×FAD retinas tested. In contrast, staining with anti-Aβo antibody showed an age-dependent decrease of retinal Aβo. Of note, Aβo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aβo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway. Conclusion: Our results demonstrate the presence of intraneuronal Aβo in the retina and its accumulation inversely correlated with retinal Aβ plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aβo in the eye. Show more

Keywords: Anti-oligomer antibody, Alzheimer’s disease, amyloid-β oligomers, retina, retinal immunodetection, 5×FAD mice

DOI: 10.3233/JAD-191346

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1135-1150, 2020

Authors: Sy, Marie Charmaine C. | Espiritu, Adrian I. | Sy, Matthew Samuel C. | Jamora, Roland Dominic G. | Anlacan, Veeda Michelle M.

Article Type: Research Article

Abstract: Background: Scientific output in Southeast Asia (SEA) on the topic of dementia is postulated to be low in quality and quantity. It is also speculated that certain socioeconomic variables and measures of disease burden for dementia may play a significant role in driving the research output of a particular country. Objective: This study aimed to determine the research impact of published journal articles on dementia in SEA and its association with country-level socioeconomic factors and measures of disease burden for dementia. Methods: A systematic search was conducted using electronic healthcare databases. We included articles published on …dementia until August 2019 with at least 1 author affiliated with any SEA institution. We obtained bibliometric indices, relevant socioeconomic factors, and measures of disease burden for dementia from published sources. Results: One thousand six articles fulfilled the inclusion criteria. The majority of publications were related to Alzheimer’s disease (n  = 775, 77.0%). Singapore contributed the highest number of publications (n  = 457, 45.4%). Gross domestic product (GDP) per capita, % GDP for research and development, and total neurologists significantly correlated with several bibliometric indices. On the other hand, the measures of disease burden for dementia in SEA countries were not significantly associated with research productivity. Conclusion: Research productivity in SEA on dementia has substantially increased in recent years. Augmenting GDP per capita and expanding the apportionment of resources to research and development (R&D) may have a significant role in the advancement of dementia research in SEA. Show more

Keywords: Bibliometric analysis, burden of disease, dementia, scientometrics, socioeconomic factors, Southeast Asia

DOI: 10.3233/JAD-200355

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1151-1160, 2020

Authors: Vergouw, Leonie J. M. | Geut, Hanneke | Breedveld, Guido | Kuipers, Demy J. S. | Quadri, Marialuisa | Netherlands Brain Bank | Rozemuller, Annemieke J. M. | van Swieten, John C. | de Jong, Frank Jan | van de Berg, Wilma D. J. | Bonifati, Vincenzo

Article Type: Research Article

Abstract: Background: Rare variants in the low-density lipoprotein receptor related protein 10 gene (LRP10 ) have recently been implicated in the etiology of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Objective: We searched for LRP10 variants in a new series of brain donors with dementia and Lewy pathology (LP) at autopsy, or dementia and parkinsonism without LP but with various other neurodegenerative pathologies. Methods: Sanger sequencing of LRP10 was performed in 233 donors collected by the Netherlands Brain Bank. Results: Rare, possibly pathogenic heterozygous LRP10 variants were present in …three patients: p.Gly453Ser in a patient with mixed Alzheimer’s disease (AD)/Lewy body disease (LBD), p.Arg151Cys in a DLB patient, and p.Gly326Asp in an AD patient without LP. All three patients had a positive family history for dementia or PD. Conclusion: Rare LRP10 variants are present in some patients with dementia and different brain pathologies including DLB, mixed AD/LBD, and AD. These findings suggest a role for LRP10 across a broad neurodegenerative spectrum. Show more

Keywords: Genetic predisposition to disease, genotype, LRP10, neuropathology, phenotype

DOI: 10.3233/JAD-200318

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1161-1170, 2020

Authors: Sancesario, Giulia Maria | Di Lazzaro, Giulia | Alwardat, Mohammad | Biticchi, Benedetta | Basile, Valerio | Salimei, Chiara | Colona, Vito Luigi | Sinibaldi Salimei, Paola | Bernardini, Sergio | Mercuri, Nicola Biagio | Pisani, Antonio | Schirinzi, Tommaso

Article Type: Research Article

Abstract: Background: Synaptopathy is critical in pathophysiology of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) levels of neurogranin (NG) and amyloid-β42 (Aβ42 ) are considered markers of synaptic dysfunction in neurodegenerative diseases. Objective: To evaluate the CSF synaptopathy-related biomarkers, especially the novel Aβ42 /NG ratio, in PD, establishing possible associations with cognitive level and other clinical parameters. Methods: Levels of NG, Aβ42 , amyloid-β40 , total and phosphorylated tau, and Aβ42 /NG ratio were measured in 30 PD patients and 30 controls and correlated with cognitive and motor parameters. The accuracy in distinguishing the cognitive status was …determined. Results: NG and Aβ42 were significantly reduced in PD, with higher NG levels in patients with worse cognition. The Aβ42 /NG ratio showed a direct correlation with Mini-Mental State Examination, independently from age and sex, and differentiated cognitively impaired patients with 92% sensitivity and 71.4% specificity, accuracy higher than NG alone. No correlations resulted with motor disturbances or therapy. Conclusions: The novel Aβ42 /NG ratio couples either presynaptic or postsynaptic markers of synaptic dysfunction, representing a potential global index of synaptopathy, useful to track cognitive functions in PD. Show more

Keywords: Cerebrospinal fluid biomarkers, cognitive, neurogranin, Parkinson’s disease

DOI: 10.3233/JAD-200344

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1171-1178, 2020