Journal of Alzheimer's Disease - Volume 72, issue 3

Authors: Pepperberg, David R.

Article Type: Research Article

Abstract: Cerebral hypoperfusion-induced hypoxia, a condition that impairs oxygen utilization and thus ATP production by mitochondrial oxidative phosphorylation (oxphos), is thought to contribute to neural degeneration in Alzheimer’s disease. However, hypoxia upregulates the generation of amyloid-β (Aβ), a group of peptides known to impair/inhibit the electron transport chain (ETC) of reactions that support oxphos in the inner mitochondrial membrane (IMM). This is a hypothesis paper that reconciles the hypoxia-induced upregulation of Aβ with Aβ’s ETC-inhibiting action and, specifically, posits an oxphos-enhancing effect of this inhibition under conditions of newly developing or otherwise mild hypoxia. This effect is typically transient; that is, …under conditions of prolonged or severe hypoxia, the oxphos-enhancing activity is overwhelmed by Aβ’s well-known toxic actions on mitochondria and other cellular components. The hypothesis is motivated by evidence that the IMM transmembrane potential Ψ m , an important determinant of ETC activity, exhibits heterogeneity, i.e., a range of values, among a given local population of mitochondria. It specifically proposes that during oxygen limitation, Aβ selectively inactivates ETC complexes in mitochondria that exhibit relatively low absolute values of Ψ m , thereby suppressing oxygen binding and consumption by complex IV of the ETC in these mitochondria. This effect of Aβ on low-Ψ m mitochondria is hypothesized to spare hypoxia-limited oxygen for oxphos-enabling utilization by the ETC of the remaining active, higher-Ψ m local mitochondria, and thereby to increase overall ATP generated collectively by the local mitochondrial population, i.e., to ameliorate hypoxia-induced oxphos reduction. The protective action of Aβ hypothesized here may slow the early development of hypoxia-associated cellular deterioration/loss in Alzheimer’s disease and perhaps other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, amyloid-β, hypoxia, mitochondrial transmembrane potential, neurodegeneration, oxidative phosphorylation

DOI: 10.3233/JAD-190476

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 663-675, 2019

Authors: Bermejo-Guerrero, Laura | Sánchez-Tejerina, Daniel | Sánchez-Tornero, Mario | Sánchez-Sánchez, María del Carmen | Gómez-Grande, Adolfo | Villarejo-Galende, Alberto | Herrero-San Martín, Alejandro Octavio | González-Sánchez, Marta

Article Type: Short Communication

Abstract: Hereditary cerebral amyloid angiopathies (CAA) are rare disorders of early onset and severe course. We describe a 47-year-old patient with Iowa-type amyloid precursor protein (APP ) mutation-related hereditary CAA that manifested with concomitant lobar hemorrhage and venous sinus thrombosis. To analyze the cerebral amyloid-β burden, an amyloid-PET was performed, demonstrating low cortical retention except for the calcarine cortex. High amyloid retention was also found in the thalamus and pallidum. The co-occurrence of CAA and venous thrombosis has not been previously reported in Iowa CAA and its mechanism is yet to be elucidated. Low cortical florbetapir-PET uptake does not rule out …CAA in young patients, who may benefit from genetic testing to reach diagnosis when suspicion is strong. Show more

Keywords: Amyloid PET, cerebral amyloid angiopathy, cerebral hemorrhage, cerebral venous thrombosis, Iowa APP mutation

DOI: 10.3233/JAD-190800

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 677-681, 2019

Authors: Castellani, Rudy J. | Smith, Margaret | Bailey, Kristi | Perry, George | deJong, Joyce L.

Article Type: Research Article

Abstract: Traumatic brain injury (TBI) is widely assumed to be causal in neurodegenerative disease, based on epidemiological surveys demonstrating an increased risk of Alzheimer disease (AD) following TBI, and on recent theories surrounding repetitive head movement. We tested this assumption by evaluating 30 consecutive forensic examinations in which neuropathology consultation was sought, and in which a history of remote TBI was uncovered during the course of the investigation. In this series, there was a high frequency of psychiatric co-morbidities (100%), remote contusion (90%), and seizures (63%). Extent of proteinopathy showed no differences with age-matched controls. A subset of the cases showed …focal geographic tauopathy that correlated with older age at autopsy, but had no correlation with clinical signs, and was minimal in comparison with the encephalomalacia secondary to trauma. The results suggest that cerebral contusion and post-traumatic epilepsy may be over-represented in civilian TBI, while structural brain damage from trauma is the predominant cause of morbidity following TBI. We found no evidence that TBI initiates a progressive proteinopathy. Show more

Keywords: Alzheimer’s disease, Amyloid-β, contusion, epilepsy, neurodegenerative disease, phosphorylated tau, traumatic brain injury

DOI: 10.3233/JAD-190782

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 683-691, 2019

Authors: Seblova, Dominika | Brayne, Carol | Machů, Vendula | Kuklová, Marie | Kopecek, Miloslav | Cermakova, Pavla

Article Type: Research Article

Abstract: Background: Studies from North America and Western Europe suggest stable or declining trends in impaired cognition across birth cohorts. Objective: We aimed to examine changes in the age-specific prevalence of cognitive impairment in the Czech Republic. Methods: The study used two samples from the population-based Czech Survey on Health, Ageing and Retirement in Europe. Age-specific prevalence of cognitive impairment (defined based on scores in verbal fluency, immediate recall, delayed recall, and temporal orientation) was compared between participants in wave 2 (2006/2007; n  = 1,107) and wave 6 (2015; n  = 3,104). Logistic regression was used to estimate the …association between the wave and cognitive impairment, step-wise adjusting for sociodemographic and clinical characteristics. Multiple sensitivity analyses, focusing on alternative operationalizations of relative cognitive impairment, impact of missing cognitive data, and survival bias, were carried out. Results: The most conservative estimate suggested that the age-specific prevalence of cognitive impairment declined by one fifth, from 11% in 2006/2007 to 9% in 2015. Decline was observed in all sensitivity analyses. The change was associated with differences in physical inactivity, management of high blood cholesterol, and increases in length education. Conclusion: Older adults in the Czech Republic, a country situated in the Central and Eastern European region, have achieved positive developments in cognitive aging. Longer education, better management of cardiovascular factors, and reduced physical inactivity seem to be of key importance. Show more

Keywords: Alzheimer’s disease, cognitive impairment, Czech Republic, epidemiology, prevalence, trends

DOI: 10.3233/JAD-190688

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 693-701, 2019

Authors: Wong, Matthew Wai Kin | Braidy, Nady | Crawford, John | Pickford, Russell | Song, Fei | Mather, Karen A. | Attia, John | Brodaty, Henry | Sachdev, Perminder | Poljak, Anne

Article Type: Research Article

Abstract:  Apolipoprotein E (APOE ) genotype is an established genetic risk factor for sporadic Alzheimer’s disease (AD) but the extent to which APOE genotype influences the plasma lipidome is unknown, even though lipids are potential diagnostic or prognostic biomarkers for AD. We quantified plasma lipids using untargeted liquid chromatography coupled mass spectrometry in a total of 152 non-demented participants aged 65–100 years carrying at least one ɛ 2 or ɛ 4 allele (ɛ 2/ɛ 2 or ɛ 2/ɛ 3, n  = 38: ɛ 4/ɛ 3 or ɛ 4/ɛ 4, n  = 38), who were roughly matched to an ɛ 3/ɛ 3 control …by age, sex, and lipid-lowering medication (n  = 76). Low density lipoprotein cholesterol levels were genotype dependent (ɛ 4/ɛ 4> ɛ 4/ɛ 3> ɛ 3/ɛ 3> ɛ 2/ɛ 3> ɛ 2/ɛ 2). The greatest variation in lipids was related to the ɛ 2 isoform, where various lysophosphatidylcholines and all phosphatidylethanolamine (PE) subclasses were elevated relative to ɛ 3/ɛ 3 and ɛ 4 carriers. APOE ɛ 4 carriers had reduced phosphatidylinositol relative to ɛ 3/ɛ 3 and ɛ 2 carriers. Logistic regression revealed that ɛ 2 carriers were at least 4 times higher odds of being in the highest tertile of PE lipid level relative to ɛ 3/ɛ 3. The elevation in PE and other phospholipids in ɛ 2 carriers may indicate the protective effect of ɛ 2 is linked to these phospholipids. Additionally, high baseline PE in cognitively normal participants predicted protection against cognitive decline six years later. Our data suggest substantial modulation of plasma lipids by APOE genotype and therefore indicates possible lipid targets and pathomechanisms involved in AD risk. Show more

Keywords: Alzheimer’s disease, apolipoproteins, lipids, lipidomics, liquid chromatography-mass spectrometry, plasma

DOI: 10.3233/JAD-190524

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 703-716, 2019

Authors: Franchini, Flaminia | Musicco, Massimo | Ratto, Federica | Storti, Gabriele | Shofany, Jacob | Caltagirone, Carlo | Di Santo, Simona Gabriella

Article Type: Research Article

Abstract: Background: Alzheimer’s disease is the principal cause of dementia and is determined, in at least one third cases, by modifiable risk factors (MRF). The “Lifestyle for Brain Health (LIBRA)” index was recently developed to quantify the individual risk of progression to dementia ascribable to MRF. Objective: The aim of this study was to investigate the association between LIBRA scores and markers of cognitive performance, functional independence, and psycho-behavioral symptoms in a community-based sample of Italian elders. Methods: 308 senior participants with mild cognitive impairment (MCI) or subjective cognitive decline (SCD) were evaluated with a complete neuropsychological …battery and semi-structured interviews for the assessment of depression, apathy, and functional autonomy. All the 12 LIBRA MRF were available for the calculation of LIBRA scores. A modified version of the index (LIBRA-2) was calculated by removing depression weight from the LIBRA index. Partial correlation analyses, controlling for age and education, assessed the association between LIBRA indices and cognitive, functional, and behavioral outcomes. Separate analyses were repeated in the MCI and SCD subgroups. Results: In participants with SCD (SCDp), significant correlations existed between LIBRA and markers of impairment in global cognition, visuo-spatial attention, and semantic fluency. LIBRA-2 associated with psycho-behavioral symptoms in the whole sample and in SCDp. LIBRA-2 only associated with apathy in the MCI subgroup. Conclusions: The LIBRA index might be useful to determine the lifestyle-attributable risk of cognitive and psycho-behavioral decline in Italian seniors at risk, while in those with overt cognitive impairment, these outcomes are presumably mainly associated with non-modifiable factors. Show more

Keywords: Alzheimer’s disease, apathy, depression, LIBRA Index, modifiable risk factors, mild cognitive impairment, neuropsychological tests, subjective cognitive decline

DOI: 10.3233/JAD-190495

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 717-731, 2019

Authors: Pathak, Gita A. | Silzer, Talisa K. | Sun, Jie | Zhou, Zhengyang | Daniel, Ann A. | Johnson, Leigh | O’Bryant, Sid | Phillips, Nicole R. | Barber, Robert C.

Article Type: Research Article

Abstract: The Mexican American population is among the fastest growing aging population and has a younger onset of cognitive decline. This group is also heavily burdened with metabolic conditions such as hypertension, diabetes, and obesity. Unfortunately, limited research has been conducted in this group. Understanding methylation alterations, which are influenced by both genetic and lifestyle factors, is key to identifying and addressing the root cause for mild cognitive impairment, a clinical precursor for dementia. We conducted an epigenome-wide association study on a community-based Mexican American population using the Illumina EPIC array. Following rigorous quality control measures, we identified 10 CpG sites …to be differentially methylated between normal controls and individuals with mild cognitive impairment annotated to PKIB, KLHL29, SEPT9, OR2C3, CPLX3, BCL2L2-PABPN1 , and CCNY . We found four regions to be differentially methylated in TMEM232, SLC17A8, ALOX12 , and SEPT8 . Functional gene-set analysis identified four gene-sets, RIN3, SPEG, CTSG , and UBE2L3 , as significant. The gene ontology and pathway analyses point to neuronal cell death, metabolic dysfunction, and inflammatory processes. We found 1,450 processes to be enriched using empirical Bayes gene-set enrichment. In conclusion, the functional overlap of differentially methylated genes associated with cognitive impairment in Mexican Americans implies cross-talk between metabolically-instigated systemic inflammation and disruption of synaptic vesicular transport. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, epigenetics, Mexican Americans, SEPT8 protein

DOI: 10.3233/JAD-190634

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 733-749, 2019

Authors: Trumbore, Conrad N. | Paik, Jennie | Fay, David | Vachet, Richard W.

Article Type: Research Article

Abstract:  Amyloid-β (Aβ) solution injections into an aqueous mobile phase moving through narrow bore stainless-steel capillary tubing results in adsorption of at least 99% Aβ within the tubing or injection valve. However, if flow is stopped for a period of 5–10 minutes, then started, wall desorption yields Aβ-containing molecules in the new effluent. The amount of desorbed Aβ-containing effluent depends on flow rate, period of flow cessation, and number of successive Aβ injections into the same tube without cleaning between injections. Unexpected multiple chromatographic peaks in these experiments seem to imply “separation” of released, previously adsorbed Aβ-containing products in the empty …capillary tubing. These preliminary experiments raise questions about possible errors in Alzheimer’s disease (AD) spinal tap analyses, which use stainless-steel needles of approximately the same inner diameter and encounter similar flow rates as those in our capillary experiments. Microliter syringes and HPLC connectors also contain stainless-steel tubing that have similar inner diameter dimensions and similar flow rates. The capillary system involved in these experiments has previously been proposed as a model system for studying the effects of shear on Aβ within the brain because it offers a research environment that provides highly restrictive flow through very small dimension channels. A suggestion is made for the use of this system in exploratory anti-amyloid drug studies in which both the drug and Aβ are injected in the same solution so that both drug and Aβ are subjected to the same shear environment. Reduction in adsorbed Aβ is suggested as an indicator of effective anti-Aβ drugs. Show more

Keywords: Amyloid aggregation, amyloid-β, cerebrospinal fluid, chromatography, glymphatic pathway, HPLC, interstitial fluid, shear energy

DOI: 10.3233/JAD-190522

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 751-760, 2019

Authors: Wan, Yu | Liang, Yingxia | Liang, Feng | Shen, Nolan | Shinozuka, Kenneth | Yu, Jin-Tai | Ran, Chongzhao | Quan, Qimin | Tanzi, Rudolph E. | Zhang, Can

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disease with no cure currently available. A pathological hallmark of AD is accumulation and deposition of amyloid-β protein (Aβ), a ∼4 kDa peptide generated through serial cleavage of the amyloid-β protein precursor (AβPP) by β- and γ -secretases. Curcumin is a natural compound primarily found in the widely used culinary spice, turmeric, which displays therapeutic potential for AD. Recently, we reported the development of curcumin analogs and identified a lead compound, curcumin-like compound-R17 (CLC-R17), that significantly attenuates Aβ deposition in an AD transgenic mouse model. Here, we elucidated the mechanisms of this analog …on Aβ levels and AβPP processing using cell models of AD. Using biochemical methods and our recently developed nanoplasmonic fiber tip probe technology, we showed that the lead compound potently lowers Aβ levels in conditioned media and reduces oligomeric amyloid levels in the cells. Furthermore, like curcumin, the lead compound attenuates the maturation of AβPP in the secretory pathway. Interestingly, it upregulated α -secretase processing of AβPP and inhibited β-secretase processing of AβPP by decreasing BACE1 protein levels. Collectively, our data reveal mechanisms of a promising curcumin analog in reducing Aβ levels, which strongly support its development as a potential therapeutic for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, autophagy, curcumin, curcumin analog, oligomerization

DOI: 10.3233/JAD-190562

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 761-771, 2019

Authors: Matías-Guiu, Jordi A. | Gómez-Pinedo, Ulises | Forero, Lucía | Pytel, Vanesa | Cano, Fátima | Moreno-Ramos, Teresa | Cabrera-Martín, María Nieves | Matías-Guiu, Jorge | González-Rosa, Javier J.

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) is a heterogeneous syndrome that is difficult to diagnose at early stages. Plasma neurofilament light chain (NFL) has been proposed as a potential biomarker for PPA. Objective: To examine the diagnostic properties of plasma NFL in PPA and to evaluate its association with clinical stages of the disease and brain metabolism. Methods: Our study included 80 participants (13 with non-fluent, 12 with semantic, and 16 with logopenic variant PPA; 13 with amnestic Alzheimer’s disease [AD]; 13 with behavioral variant frontotemporal dementia; and 13 healthy controls). Plasma NFL concentration was measured using …a high-sensitivity enzyme-linked immunosorbent assay (ELISA) kit. PET imaging was performed in a subgroup of patients. Results: NFL discriminated patients from controls with an area under the curve of 0.914 (95% CI, 0.843–0.984; p  < 0.001) (cut-off: 76.46 pg/mL; 94% sensitivity, 76.9% specificity). There were no significant differences between clinical syndromes (PPA subtypes), the main clinical forms of dementia (frontotemporal dementia and AD), or the expected pathological groups (frontotemporal lobar degeneration-tau [FTLD-tau], FTLD-TDP43, and AD). NFL levels showed weak to moderate correlations with age and functional scale score. We found no significant correlation with the extent of hypometabolism observed on FDG-PET images. Conclusion: Plasma NFL is a non-specific marker of neurodegeneration, and may be helpful in the diagnosis of PPA. However, NFL does not permit differential diagnosis between PPA subtypes and is not correlated with the extent of neurodegeneration. Show more

Keywords: Alzheimer’s disease, biomarkers, frontotemporal dementia, neurofilament, positron emission tomography, primary progressive aphasia

DOI: 10.3233/JAD-190838

Citation: Journal of Alzheimer's Disease, vol. 72, no. 3, pp. 773-782, 2019