Journal of Alzheimer's Disease - Volume 74, issue 4

Authors: Ihara, Masafumi | Saito, Satoshi

Article Type: Review Article

Abstract: Although more than 100 years have passed since Alois Alzheimer reported a case of Alzheimer’s disease (AD), a definitive answer to the causes of cognitive impairment in the disease remains elusive. Despite significant enthusiasm and investment from the pharmaceutical industry, clinical trials of many disease-modifying drugs for AD have been largely unsuccessful. Drug repositioning (DR) or repurposing approaches are relatively inexpensive and more reliable compared to de novo drug development in AD. About 30% of clinical trials for AD in progress around the world use the DR method and hold potential in halting the current deadlock in treatment options. …By using drugs approved for other indications, these clinical trials target dysregulated pathways in AD with different or a combination of modes of action, including anti-amyloid, cardiovascular, anti-tau, anti-inflammatory, immunomodulatory, metabolic, neuroprotective, and neurotransmission-based approaches. For instance, anti-diabetic drugs, such as insulin, metformin, liraglutide, and dapagliflozin, and cardiovascular drugs, such as cilostazol, candesartan, telmisartan, prazosin, and dabigatran, could serendipitously provide previously unearthed benefits in AD. This is in line with recent thinking, which views AD as a complex multifactorial disorder, not dominated by one dominant biological factor, such as amyloid-β, and likely a confluence of many pathobiological mechanisms, including vascular dysregulation. Such increasingly available knowledge of phenotyping may be used to design ‘tailor-made’ DR and relatively homogeneous AD subpopulations specifically targeted with existing drugs based on known modes of action. It is thus expected that DR approaches will create a major paradigm shift in AD research and development. Show more

Keywords: Clinical trial, drug repositioning, drug reprofiling, drug repurposing, drug rescue

DOI: 10.3233/JAD-200049

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1013-1028, 2020

Authors: Counil, Hermine | Krantic, Slavica

Article Type: Review Article

Abstract: Nanosized extracellular vesicles, known as exosomes, are produced by all cell types in mammalian organisms and have been recently involved in neurodegeneration. In the brain, both glia and neurons give rise to exosomes, which contribute to their intercellular communication. In addition, brain-derived exosomes have a remarkable property to cross the blood-brain-barrier bi-directionally. In this line, exosomes of central origin have been identified in peripheral circulation and already considered as putative blood biomarkers of neurodegenerative diseases, including Alzheimer’s disease (AD). Moreover, tentative use of exosomes as vehicle for the clearance of brain-born toxic proteins or, conversely, neuroprotective drug delivery, was also …envisaged. However, little is known about the precise role of exosomes in the control and regulation of neuronal functions. Based on the presence of subunits of glutamate receptors in neuron-derived exosomes on one hand, and complement proteins in astrocyte-derived exosomes on the other hand, we hypothesize that exosomes may participate in the control of neuronal excitability via inflammatory-like mechanisms both at the central level and from the periphery. In this review, we will focus on AD and discuss the mechanisms by which exosomes of neuronal, glial, and/or peripheral origin could impact on neuronal excitability either directly or indirectly. Show more

Keywords: Alzheimer’s disease, exosomes, glial cells, neuronal excitability, synaptic activity

DOI: 10.3233/JAD-191237

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1029-1043, 2020

Authors: Babulal, Ganesh M. | Roe, Catherine M. | Stout, Sarah H. | Rajasekar, Ganesh | Wisch, Julie K. | Benzinger, Tammie L.S. | Morris, John C. | Ances, Beau M.

Article Type: Research Article

Abstract: Background: Depression is also common with older age. Alzheimer’s disease (AD) studies suggest that both cerebrospinal fluid and positron emission tomography (PET) amyloid biomarkers are associated with more depressive symptoms in cognitively normal older adults. The recent availability of tau radiotracers offers the ability to examine in vivo tauopathy. It is unclear if the tau biomarker is associated with depression diagnosis. Objective: We examined if tau and amyloid imaging were associated with a depression diagnosis among cognitively normal adults (Clinical Dementia Rating = 0) and whether antidepressants modified this relationship. Methods: Among 301 participants, logistic regression models …evaluated whether in vivo PET tau was associated with depression, while another model tested the interaction between PET tau and antidepressant use. A second set of models substituted PET amyloid for PET tau. A diagnosis of depression (yes/no) was made during an annual clinical assessment by a clinician. Antidepressant use (yes/no) was determined by comparing medications the participants used to a list of 30 commonly used antidepressants. All models adjusted for age, sex, education, race, and apolipoprotein ɛ 4. Similar models explored the association between the biomarkers and depressive symptoms. Results: Participants with elevated tau were twice as likely to be depressed. Antidepressant use modified this relationship where participants with elevated tau who were taking antidepressants had greater odds of being depressed. Relatedly, elevated amyloid was not associated with depression. Conclusions: Our results demonstrate that tau, not amyloid, was associated with a depression diagnosis. Additionally, antidepressant use interacts with tau to increase the odds of depression among cognitively normal adults. Show more

Keywords: Alzheimer’s disease, antidepressants, biomarkers, depression, older adults

DOI: 10.3233/JAD-191078

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1045-1055, 2020

Authors: Tadayon, Ehsan | Moret, Beatrice | Sprugnoli, Giulia | Monti, Lucia | Pascual-Leone, Alvaro | Santarnecchi, Emiliano | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Recent studies have revealed the possible role of choroid plexus (ChP) in Alzheimer’s disease (AD). T1-weighted MRI is the modality of choice for the segmentation of ChP in humans. Manual segmentation is considered the gold-standard technique, but given its time-consuming nature, large-scale neuroimaging studies of ChP would be impossible. In this study, we introduce a lightweight segmentation algorithm based on the Gaussian Mixture Model (GMM). We compared its performance against manual segmentation as well as automated segmentation by Freesurfer in three separate datasets: 1) patients with structural MRIs enhanced with contrast (n  = 19), 2) young healthy subjects (n  = 20), and …3) patients with AD (n  = 20). GMM outperformed Freesurfer and showed high similarity with manual segmentation. To further assess the algorithm’s performance in large scale studies, we performed GMM segmentations in young healthy subjects from the Human Connectome Project (n  = 1,067), as well as healthy controls, mild cognitive impairment (MCI), and AD patients from the Alzheimer’s Disease Neuroimaging Initiative (n  = 509). In both datasets, GMM segmented ChP more accurately than Freesurfer. To show the clinical importance of accurate ChP segmentation, total AV1451 (tau) PET binding to ChP was measured in 108 MCI and 32 AD patients. GMM was able to reveal the higher AV1451 binding to ChP in AD compared with MCI. Our results provide evidence for the utility of the GMM in accurately segmenting ChP and show its clinical relevance in AD. Future structural and functional studies of ChP will benefit from GMM’s accurate segmentation. Show more

Keywords: Alzheimer’s disease, choroid plexus, magnetic resonance imaging, tau PET

DOI: 10.3233/JAD-190706

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1057-1068, 2020

Authors: Mehder, Rasha H. | Bennett, Brian M. | Andrew, R. David

Article Type: Research Article

Abstract: The study of late-onset (sporadic) Alzheimer’s disease (LOAD) has lacked animal models where impairments develop with aging. Oxidative stress promotes LOAD, so we have developed an oxidative stress-based model of age-related cognitive impairment based on gene deletion of aldehyde dehydrogenase 2 (ALDH2). This enzyme is important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit a progressive decline in recognition and spatial memory and AD-like pathologies. Here we performed morphometric analyses in the dorsal and ventral hippocampal CA1 regions (dCA1 and vCA1) as well as in overlying primary sensory …cortex to determine if altered neuronal structure can help account for the cognitive impairment in 12-month old KO mice. Dendritic morphology was quantitatively analyzed following Golgi-Cox staining using 9 WT mice (108 neurons) and 15 KO mice (180 neurons). Four pyramidal neurons were traced per mouse in each region, followed by branched structured analysis and Sholl analysis. Compared to WT controls, the morphology and complexity of dCA1 pyramidal neurons from KOs showed significant reductions in apical and basal dendritic length, dendrite intersections, ends, and nodes. As well, spine density along dorsal CA1 apical dendrites was significantly lower in KO versus WT. In contrast, pyramidal arborization in the vCA1 and primary sensory cortex were only minimally reduced in KO versus WT mice. These data suggest a region-specific vulnerability to oxidative stress-induced damage and/or a major and specific reduction in synaptic input to the pyramidal neurons of the dorsal hippocampus. This is in keeping with studies showing that lesions to the dorsal hippocampus impair primarily cognitive memory whereas ventral hippocampal lesions cause deficits in stress, emotion, and affect. Show more

Keywords: CA1, dendrite, hippocampus, morphometry, oxidative stress, pyramidal neurons, spatial memory, spines

DOI: 10.3233/JAD-191067

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1069-1083, 2020

Authors: Wisch, Julie K. | Roe, Catherine M. | Babulal, Ganesh M. | Schindler, Suzanne E. | Fagan, Anne M. | Benzinger, Tammie L. | Morris, John C. | Ances, Beau M.

Article Type: Research Article

Abstract: Background: Changes in resting state functional connectivity (rs-fc) occur in Alzheimer’s disease (AD), but few longitudinal rs-fc studies have been performed. Most studies focus on single networks and not a global measure of rs-fc. Although the amyloid tau neurodegeneration (AT(N)) framework is increasingly utilized by the AD community, few studies investigated when global rs-fc signature changes occur within this model. Objective: 1) Identify a global rs-fc signature that differentiates cognitively normal (CN) individuals from symptomatic AD. 2) Assess when longitudinal changes in rs-fc occur relative to conversion to symptomatic AD. 3) Compare rs-fc with amyloid, tau, and neurodegeneration …biomarkers. Methods: A global rs-fc signature composed of intra-network connections was longitudinally evaluated in a cohort of cognitively normal participants at baseline (n  = 335). Biomarkers, including cerebrospinal fluid (Aβ42 and tau), structural magnetic resonance imaging, and positron emission tomography were obtained. Results: Global rs-fc signature distinguished CN individuals from individuals who developed symptomatic AD. Changes occurred nearly four years before conversion to symptomatic AD. The global rs-fc signature most strongly correlated with markers of neurodegeneration. Conclusion: The global rs-fc signature changes near symptomatic onset and is likely a neurodegenerative biomarker. Rs-fc changes could serve as a biomarker for evaluating potential therapies for symptomatic conversion to AD. Show more

Keywords: Alzheimer’s disease, biomarkers, neuroimaging, observational studies

DOI: 10.3233/JAD-191039

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1085-1095, 2020

Authors: Zhang, Jingtian | Zhao, Zhizhuang Joe | Fu, Xueqi | Niu, Han | Hu, Chen | Dong, Yunzhou | Cui, Mei-Zhen | Zhang, Fuqiang | Zeng, Linlin | Xu, Xuemin

Article Type: Research Article

Abstract: Presenilin-associated protein (PSAP) was originally identified as a mitochondrial proapoptotic protein. To further explore the apoptotic pathway that involves PSAP, our yeast two-hybrid screen revealed that PSAP interacts with a death receptor, DR6. DR6 is a relatively less common member of the death receptor family and has been shown to mediate the neurotoxicity of amyloid-β, mutant SOD1, and prion proteins and has also been implicated in the regulation of immune cell proliferation and differentiation. Our previous study showed that DR6 induces apoptosis via a unique mitochondria-dependent pathway different from the conventional death receptor-mediated extrinsic apoptotic pathways. Thus, the interaction of …DR6 with PSAP established a direct molecular link between DR6 and mitochondrial apoptotic pathway. We investigated the possible role of PSAP in DR6-induced apoptosis. Interestingly, it was discovered that knockdown of PSAP strongly inhibited DR6-induced apoptosis. To further elucidate the mechanism by which PSAP mediates DR6-induced mitochondria-dependent apoptosis, our data demonstrated that knockdown of PSAP blocked DR6-induced Bax translocation and cytochrome c release from the mitochondria. Moreover, it was found that both PSAP and DR6 form complexes with Bax, but at different subcellular locations. The DR6-Bax complex was detected in the cytosolic fraction while the PSAP-Bax complex was detected in the mitochondrial fraction. The observation that knockdown of DR6 significantly reduced the amount of PSAP-Bax complex detected in mitochondria suggests a possibility that DR6-bound Bax is transferred to PSAP upon interaction with PSAP at the mitochondria, leading to cytochrome c release and eventually apoptosis. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, apoptosis, DR6, mitochondria, neurodegenerative disease, PSAP

DOI: 10.3233/JAD-191086

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1097-1106, 2020

Authors: Gallucci, Maurizio | Pallucca, Claudia | Di Battista, Maria Elena | Bergamelli, Cristina | Fiore, Vittorio | Boccaletto, Franco | Fiorini, Michele | Perra, Daniela | Zanusso, Gianluigi | Fenoglio, Chiara | Serpente, Maria | Galimberti, Daniela | Bonanni, Laura

Article Type: Research Article

Abstract: We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old patient, followed by psychiatrists for depression and behavioral disorders, received a diagnosis of dementia with Lewy bodies (DLB) at another Center due to auditory hallucinations, gait impairment, and tendency to fall. He was then admitted to our Memory Clinic Unit for behavioral disturbances, such as delusional thinking, auditory hallucinations, and memory complaints. At that time, the patient’s therapy included Lorazepam, Quetiapine, Promazine, and Biperiden. The latter was immediately suspended for the absence of extrapyramidal …signs and to avoid the anticholinergic cognitive side effects. A 18 F-FDG PET showed a derangement of cortical metabolism with diffusely reduced activity, and limited areas of hyperactivity involving lateral frontal and lateral temporal inferior regions bilaterally. The patient underwent a series of exams, including neuropsychological tests, 123 I-MIBG scintigraphy, cerebrospinal fluid examination, and genetic analysis. A second 18 F-FDG PET showed an extensive remodulation of metabolic activity: relative higher concentration of the tracer in the prefrontal and inferior temporal cortex was no more detectable. Similarly, the diffuse reduced metabolic activity could not be traced anymore. Nonetheless, the metabolic activity still appeared reduced in the frontal lobe, in the anterior cingulate bilaterally, and in the anterior part of the hemispheric fissure. Taken together, clinical and neuroimaging features would point to a FTLD-like form. Furthermore, the diagnostic work-up was likely confounded by the anticholinergic drug on 18 F-FDG PET, highlighting the importance of carefully checking the patient’s pharmacology during the diagnostic process. Show more

Keywords: Anti-cholinergics, cerebral cortex, frontotemporal dementia, PET scan, TREDEM

DOI: 10.3233/JAD-191290

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1107-1117, 2020

Authors: Aschenbrenner, Andrew J. | Gordon, Brian A. | Fagan, Anne M. | Schindler, Suzanne E. | Balota, David A. | Morris, John C. | Hassenstab, Jason J.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid tau and neurofilament light (NfL) are two biomarkers of neurodegeneration in Alzheimer’s disease. Previous reports have shown that the influence of tau on cognitive decline depends on levels of amyloid burden whereas NfL predicts decline independently of amyloid. Most studies use a global cognitive composite as the primary outcome, and it is unknown if critical cognitive domain scores are similarly sensitive to rates of decline due to neurodegeneration. Objective: To examine the unique contribution of amyloid, tau, and NfL to rates of cognitive decline in multiple cognitive composites in a cognitively healthy, middle-aged to older …adult cohort. Methods: A total of 255 participants (55% female; mean age = 66.2 years, range = 42.5–86.7 years) completed CSF studies and serial cognitive assessments to measure global cognition, episodic memory, and attentional control. Linear mixed effects models were used to examine rates of change on each composite score as a function of baseline biomarker levels. Results: Total tau predicted decline in attention regardless of amyloid status, but the relationship to global cognition and episodic memory was dependent on amyloid, replicating prior literature. NfL predicted decline in attention and global cognition, but not memory, and this effect was independent of amyloid status. Conclusions: These findings suggest that NfL can be used to monitor cognitive decline in aging and Alzheimer’s disease and that an attentional control composite may be a better outcome for tracking general neurodegenerative effects on cognition. Show more

Keywords: Alzheimer’s disease, attention, cerebrospinal fluid, memory, neurofilament light

DOI: 10.3233/JAD-200018

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1119-1129, 2020

Authors: Dominguez, Sky | Rodriguez, Guadalupe | Fazelinia, Hossein | Ding, Hua | Spruce, Lynn | Seeholzer, Steven H. | Dong, Hongxin

Article Type: Research Article

Abstract: Approximately two-thirds of those suffering with Alzheimer’s disease (AD) are women, however, the biological mechanisms underlying this sex divergence of AD prevalence remain unknown. Previous research has shown sex-specific biochemical differences that bias female mice toward pro-AD signaling on the phosphoproteomic level via corticotropin releasing factor (CRF) receptor 1 activation after CRF overexpression. Here we aimed to determine if chronic stress would induce a similar response in AD mouse models. We stressed 4-month-old APP/PS1 mice using a chronic unpredictable mild stress (CUMS) paradigm for up to 1 month. Following CUMS and behavioral assessments, we quantified whole protein and phosphoprotein levels …in the cortex of stressed and non-stressed APP/PS1 mice using mass spectrometry-based proteomics. While there were no statistically significant differences at the total protein and peptide abundance levels, we found 909 and 841 statistically significant phosphopeptides between stressed and unstressed females and males, respectively, using a false discovery rate of 5%. Of these significant phosphopeptides, only 301 were the same in males and females. These results indicate that while both males and females undergo protein phosphorylation changes following stress, the peptides that are phosphorylated differ between sexes. We then used Metacore analysis to determine which biological pathways were affected. We found that several pathways were changed differently between male and female mice including NMDA receptor trafficking, cytoskeleton organization, and tau pathology. The differing biological pathways affected between males and females in response to chronic stress may help us to better understand why women are at a higher risk of AD. Show more

Keywords: Alzheimer’s disease, APP/PS1 mice, chronic stress, phosphoproteomics, sex differences

DOI: 10.3233/JAD-191009

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1131-1142, 2020