Journal of Alzheimer's Disease - Volume 77, issue 3

Authors: Shi, Jian-Quan | Wang, Bian-Rong | Jiang, Teng | Gao, Li | Zhang, Ying-Dong | Xu, Jun

Article Type: Review Article

Abstract: As one of the most harmful air pollutants, fine particulate matter (PM2.5) has been implicated as a risk factor for multiple diseases, which has generated widespread public concern. Accordingly, a growing literature links PM2.5 exposure with Alzheimer’s disease (AD). A critical gap in our understanding of the adverse effects of PM2.5 on AD is the mechanism triggered by PM2.5 that contributes to disease progression. Recent evidence has demonstrated that PM2.5 can activate NLRP3 inflammasome-mediated neuroinflammation. In this review, we highlight the novel evidence between PM2.5 exposure and AD incidence, which is collected and summarized from neuropathological, epidemiological, and neuroimaging studies …to in-depth deciphering molecular mechanisms. First, neuropathological, epidemiological, and neuroimaging studies will be summarized. Then, the transport pathway for central nervous system delivery of PM2.5 will be presented. Finally, the role of NLRP3 inflammasome-mediated neuroinflammation in PM2.5 induced-effects on AD will be recapitulated. Show more

Keywords: Alzheimer’s disease, fine particulate matter, microglia, neuroinflammation, NLRP3 inflammasome

DOI: 10.3233/JAD-200359

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 923-934, 2020

Authors: Raji, Cyrus A. | Torosyan, Nare | Silverman, Daniel H. S.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by preclinical, pre-dementia, and dementia phases. Progression of the disease leads to cognitive decline and is associated with loss of functional independence, personality changes, and behavioral disturbances. Current guidelines for AD diagnosis include the use of neuroimaging tools as biomarkers for identifying and monitoring pathological changes. Various imaging modalities, namely magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET) and PET with amyloid-beta tracers are available to facilitate early accurate diagnoses. Enhancing diagnosis in the early stages of the disease can allow for timely interventions that can delay progression …of the disease. This paper will discuss the characteristic findings associated with each of the imaging tools for patients with AD, with a focus on FDG-PET due to its established accuracy in assisting with the differential diagnosis of dementia and discussion of other methods including MRI. Diagnostically-relevant features to aid clinicians in making a differential diagnosis will also be pointed out and multimodal imaging will be reviewed. We also discuss the role of quantification software in interpretation of brain imaging. Lastly, to guide evaluation of patients presenting with cognitive deficits, an algorithm for optimal integration of these imaging tools will be shared. Molecular imaging modalities used in dementia evaluations hold promise toward identifying AD-related pathology before symptoms are fully in evidence. The work describes state of the art functional and molecular imaging methods for AD. It will also overview a clinically applicable quantitative method for reproducible assessments of such scans in the early identification of AD. Show more

Keywords: Alzheimer’s disease, brain imaging, FDG-PET

DOI: 10.3233/JAD-200487

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 935-947, 2020

Authors: Quach, Tam T. | Moutal, Aubin | Khanna, Rajesh | Deems, Nicholas P. | Duchemin, Anne-Marie | Barrientos, Ruth M.

Article Type: Review Article

Abstract: Numerous experimental and postmortem studies have increasingly reported dystrophic axons and dendrites, and alterations of dendritic spine morphology and density in the hippocampus as prominent changes in the early stages of Alzheimer’s disease (AD). Furthermore, these alterations tend to correlate well with the progressive cognitive decline observed in AD. For these reasons, and because these neurite structures have a capacity to re-grow, re-establish lost connections, and are critical for learning and memory, there is compelling evidence to suggest that therapeutic interventions aimed at preventing their degradation or promoting their regrowth may hold tremendous promise in preventing the progression of AD. …In this regard, collapsin response mediator proteins (CRMPs), a family of phosphoproteins playing a major role in axon guidance and dendritic growth, are especially interesting. The roles these proteins play in neurons and immune cells are reviewed here. Show more

Keywords: Axon guidance, dendrite regeneration, hippocampus, memory

DOI: 10.3233/JAD-200721

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 949-960, 2020

Authors: Deaton, Carol A. | Johnson, Gail V.W.

Article Type: Review Article

Abstract: Mutations in the PSEN1 gene, encoding presenilin 1 (PS1), are the most common cause of familial Alzheimer’s disease (fAD). Since the first mutations in the PSEN1 gene were discovered more than 25 years ago, many postulated functions of PS1 have been investigated. The majority of earlier studies focused on its role as the catalytic component of the γ -secretase complex, which in concert with β site amyloid precursor protein cleaving enzyme 1 (BACE1), mediates the formation of Aβ from amyloid-β protein precursor (AβPP). Though mutant PS1 was originally considered to cause AD by promoting Aβ pathology through its …protease function, it is now becoming clear that PS1 is a multifunctional protein involved in regulating membrane dynamics and protein trafficking. Therefore, through loss of these abilities, mutant PS1 has the potential to impair numerous cellular functions such as calcium flux, organization of proteins in different compartments, and protein turnover via vacuolar metabolism. Impaired calcium signaling, vacuolar dysfunction, mitochondrial dysfunction, and increased ER stress, among other related membrane-dependent disturbances, have been considered critical to the development and progression of AD. Given that PS1 plays a key regulatory role in all these processes, this review will describe the role of PS1 in different cellular compartments and provide an integrated view of how PS1 dysregulation (due to mutations or other causes) could result in impairment of various cellular processes and result in a “multi-hit”, integrated pathological outcome that could contribute to the etiology of AD. Show more

Keywords: Calcium, endoplasmic reticulum, endosomal pathways, presenilin-1, vacuolar processes

DOI: 10.3233/JAD-200598

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 961-977, 2020

Authors: Marano, Massimo | Pompucci, Angelo | Motolese, Francesco | Rossi, Mariagrazia | Coletta, Ernesto | Di Lazzaro, Vincenzo | Fasano, Alfonso | Petrella, Gianpaolo

Article Type: Short Communication

Abstract: Down syndrome (DS) is the most common cause of intellectual disability in infants and has a well-known relationship with the Alzheimer’s disease. The association between DS and the other pathologies of senescence, such as normal pressure hydrocephalus (NPH), has been poorly investigated. This series included two DS patients with NPH. In both cases, NPH symptoms were initially misdiagnosed as DS associated senescence. Patients were treated with ventricular-peritoneal shunt, showing a sustained improvement (1 and 4 years of follow-up). To our knowledge, this is the first description of the occurrence of NPH in adult patients with DS and surgical outcomes.

Keywords: Cerebrospinal fluid, down syndrome, normal pressure hydrocephalus, trisomy 21, ventricular-peritoneal shunt

DOI: 10.3233/JAD-200409

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 979-984, 2020

Authors: Valls-Carbó, Adrián | Gajate, Vicente | Romeral, María | Gutiérrez-Viedma, Álvaro | Parejo-Carbonell, Beatriz | Cabrera-Martín, María Nieves | Matías-Guiu, Jorge | Matías-Guiu, Jordi A. | García-Morales, Irene

Article Type: Short Communication

Abstract: Epilepsy in frontotemporal dementia is considered to be less frequent than in Alzheimer’s disease. We report two cases of patients with non-convulsive status epilepticus associated with behavioral variant frontotemporal dementia. In the first case, status epilepticus was the first symptom of the disease, and consisted of loss of consciousness and mutism. In the second case, status epilepticus led to a clinical worsening one year after the diagnosis. Our study highlights the importance of suspecting non-convulsive status epilepticus in patients with frontotemporal dementia, and including frontotemporal dementia within the differential diagnosis of new-onset seizures.

Keywords: Dementia, epilepsy, frontotemporal dementia

DOI: 10.3233/JAD-200512

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 985-991, 2020

Authors: Surinkaew, Poomarin | Apaijai, Nattayaporn | Sawaddiruk, Passakorn | Jaiwongkam, Thidarat | Kerdphoo, Sasiwan | Chattipakorn, Nipon | Chattipakorn, Siriporn C.

Article Type: Research Article

Abstract: Background: Cardiac ischemia/reperfusion (I/R) injury induces brain damage through increased blood-brain barrier (BBB) breakdown, microglial hyperactivity, pro-inflammatory cytokines, amyloid-β deposition, loss of dendritic spines, brain mitochondrial dysfunction, and imbalanced mitochondrial dynamics. Previous studies demonstrated that mitochondrial fusion promoter reduced cardiac damage from cardiac I/R injury; however, following cardiac I/R injury, the roles of mitochondrial dynamics on the brain have not been investigated. Objective: To investigate the effects of pharmacological modulation using mitochondrial fusion promoter (M1) in the brain of rats following cardiac I/R injury. Methods: Twenty-four male Wistar rats were separated into two groups; 1) sham-operation …(n  = 8) and 2) cardiac I/R injury (n  = 16). Rats in the cardiac I/R injury group were randomly received either normal saline solution as a vehicle or a mitochondrial fusion promoter (M1, 2 mg/kg) intravenously. Both treatments were given to the rats 15 minutes before cardiac I/R injury. At the end of the reperfusion protocol, the brain was rapidly removed to investigate brain mitochondrial function, mitochondrial dynamics proteins, microglial activity, and Alzheimer’s disease (AD) related proteins. Results: Cardiac I/R injury induced brain mitochondrial dynamics imbalance as indicated by reduced mitochondrial fusion proteins expression without alteration in mitochondrial fission, brain mitochondrial dysfunction, BBB breakdown, increased macrophage infiltration, apoptosis, and AD-related proteins. Pretreatment with M1 effectively increased the expression of mitofusin 2, a mitochondrial outer membrane fusion protein, reduced brain mitochondrial dysfunction, BBB breakdown, macrophage infiltration, apoptosis, and AD-related proteins in rats following cardiac I/R injury. Conclusion: This mitochondrial fusion promoter significantly protected rats with cardiac I/R injury against brain damage. Show more

Keywords: Amyloid plaque, brain, heart, ischemia-reperfusion injury, microglia, mitochondrial fusion

DOI: 10.3233/JAD-200495

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 993-1003, 2020

Authors: Robinson, Andrew C. | Roncaroli, Federico | Chew-Graham, Stephen | Davidson, Yvonne S. | Minshull, James | Horan, Michael A. | Payton, Antony | Pendleton, Neil | Mann, David M.A.

Article Type: Research Article

Abstract: Background: The pathological features of Alzheimer’s disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment. Objective: The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages. Methods: We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The …University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment. Results: We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia. Conclusion: Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer’s type pathology. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, cognition, dementia, neuropathology

DOI: 10.3233/JAD-200339

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1005-1015, 2020

Authors: Ho, Seong Hee | Yang, Dong-Won

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) ɛ 4 allele is a well-known risk factor for AD and is associated with higher amyloid deposition and earlier dementia onset. However, the relationship between amyloid pathology and the most common APOE allele, ɛ 3, has not been well studied. Objective: In this study, we aimed to identify the risk factors predicting amyloid PET positivity in patients with mild cognitive impairment (MCI) and APOE ɛ 3/ɛ 3 genotypes. Methods: We retrospectively reviewed the medical records of MCI patients with APOE ɛ 3/ɛ 3 genotypes who underwent amyloid …PET scanning. Demographics, neuropsychological tests, and brain MRI were obtained. We analyzed which risk factors could affect amyloid PET positivity in MCI patients with APOE ɛ 3/ɛ 3 genotypes using logistic regression models. Results: We recruited 171 MCI patients with APOE ɛ 3/ɛ 3 genotypes in this study. Out of 171 patients, 49 patients (28.65%) showed positive results in the amyloid PET scans. In a multivariate logistic regression model, amyloid positivity was associated with frontal atrophy (OR = 2.63, p  = 0.009), and CDR-SOB scores (OR = 2.46, p  = 0.013). The odds ratio for amyloid PET positivity in patients older than and equal to 75 years with both frontal atrophy and CDR-SOB scores >1.0 was 3.63. Conclusion: Our study demonstrated that frontal atrophy, high CDR-SOB scores, and old age were risk factors associated with amyloid PET positivity in MCI with APOE ɛ 3/ɛ 3 genotypes. Show more

Keywords: Amyloid, apolipoproteins, cognitive dysfunction, plaque, risk factors

DOI: 10.3233/JAD-200439

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1017-1024, 2020

Authors: Huang, Jie | Beach, Paul | Bozoki, Andrea | Zhu, David C.

Article Type: Research Article

Abstract: Background: Postmortem studies of Alzheimer’s disease (AD) brains not only find amyloid-β (Aβ) and neurofibrillary tangles (NFT) in the primary and associative visual cortical areas, but also reveal a temporally successive sequence of AD pathology beginning in higher-order visual association areas, followed by involvement of lower-order visual processing regions with disease progression, and extending to primary visual cortex in late-stage disease. These findings suggest that neuronal loss associated with Aβ and NFT aggregation in these areas may alter not only the local neuronal activation but also visual neural network activity. Objective: Applying a novel method to identify the …visual functional network and investigate the association of the network changes with disease progression. Methods: To investigate the effect of AD on the face-evoked visual-processing network, 8 severe AD (SAD) patients, 11 mild/moderate AD (MAD), and 26 healthy senior (HS) controls undertook a task-fMRI study of viewing face photos. Results: For the HS, the identified group-mean visual-processing network in the ventral pathway started from V1 and ended within the fusiform gyrus. In contrast, this network was disrupted and reduced in the AD patients in a disease-severity dependent manner: for the MAD patients, the network was disrupted and reduced mainly in the higher-order visual association areas; for the SAD patients, the network was nearly absent in the higher-order association areas, and disrupted and reduced in the lower-order areas. Conclusion: This finding is consistent with the current canonical view of the temporally successive sequence of AD pathology through visual cortical areas. Show more

Keywords: Alzheimer’s disease, FAUPA, functional areas of unitary pooled activity, task-fMRI, visual functional network

DOI: 10.3233/JAD-200173

Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1025-1042, 2020