Journal of Alzheimer's Disease - Volume 73, issue 3

Authors: Santos-Mandujano, Rosalía A. | Ryan, Natalie S. | Chávez-Gutiérrez, Lucía | Sánchez-Torres, Carmen | Meraz-Ríos, Marco Antonio

Article Type: Research Article

Abstract: Presenilin 1 gene (PSEN1 ) mutations are the most common cause of familial Alzheimer’s disease (FAD). One of the most abundant FAD mutations, PSEN1 A431E, has been reported to be associated with spastic paraparesis in about half of its carriers, but the determining mechanisms of this phenotype are still unknown. In our study we characterized three A431E mutation carriers, one symptomatic and two asymptomatic, from a Mexican family with a history of spastic paraparesis in all of its affected members. At cognitive assessment and MRI, the symptomatic subject showed an atypical non-amnestic mild cognitive impairment with visuospatial deficits, olfactory …dysfunction and significant parieto-occipital brain atrophy. Furthermore, we found several periventricular white matter hyperintensities whose progression pattern and localization correlated with their motor impairment, cognitive profile, and non-motor symptoms. Together, our data suggests that in this family the A431E mutation leads to a divergent neurological disorder in which cognitive deterioration was clinically exceeded by motor impairment and that it involves early glial and vascular pathological changes. Show more

Keywords: A431E, familial Alzheimer’s disease, posterior cortical atrophy, Presenilin 1, spastic paraparesis, white matter hyperintensities

DOI: 10.3233/JAD-190978

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1075-1083, 2020

Authors: Chamberlain, Stanley | Gabriel, Hoda | Strittmatter, Warren | Didsbury, John

Article Type: Research Article

Abstract: Background: T3D-959 is a chemically unique, brain penetrant, dual PPAR delta/gamma agonist with 15-fold higher PPAR delta selectivity. Ubiquitous brain expression of PPAR delta, its critical role in regulating glucose and lipid metabolism, and the Alzheimer’s disease (AD)-like phenotype of PPAR delta null mice motivated this study. Objective: To determine safety and tolerability of multiple doses of T3D-959 in subjects with mild to moderate AD, examine systemic and central drug pharmacology and in an exploratory manner, perform cognitive assessments. Methods: Thirty-four subjects with mild-to-moderate AD were orally administered 3, 10, 30, or 90 mg of T3D-959 daily …for 14 days. There was no inclusion of a placebo arm. Safety and tolerability were monitored. Systemic drug pharmacology was examined via plasma metabolomics LC-MS-MS analysis, cerebral drug pharmacology via FDG-PET measures of changes in Relative CMRgl (R CMRgl, AD-effected regions relative to brain reference regions), and cognitive function assessed before and after drug treatment and again one week after completion of drug treatment, by ADAS-cog11 and the Digit Symbol Substitution Test (DSST). Results: T3D-959 was in general safe and well tolerated. Single point pharmacokinetics at the Tmax showed dose dependent exposure. Plasma metabolome profile changes showed dose-dependent systemic effects on lipid metabolism and metabolism related to insulin sensitization. Relative FDG-PET imaging demonstrated dose-dependent, regional, effects of T3D-959 on R CMRgl based on the use of multiple reference regions. ADAS-cog11 and DSST cognitive assessments showed improvements with possible ApoE genotype association and pharmacodynamics related to the mechanism of drug action. Conclusions: Exploratory data from this Phase IIa clinical trial supports further clinical investigation of T3D-959 in a larger placebo-controlled clinical study. Show more

Keywords: Alzheimer’s disease, clinical trials, FDG-PET, metabolism, metabolomics, PPAR

DOI: 10.3233/JAD-190864

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1085-1103, 2020

Authors: Xu, Cheng | Guo, Jing | Li, Li | Wang, Xin | Zhou, Qiuzhi | Sun, Dongsheng | Zhang, Shujuan | Li, Shihong | Ye, Jinwang | Liu, Yanchao | Liu, Enjie | Zeng, Peng | Wang, Xiaochuan | Yang, Ying | Wang, Jian-Zhi

Article Type: Research Article

Abstract:  The three isoforms of 3R-tau are predominantly deposited in neurons bearing neurofibrillary tangles in Alzheimer’s disease (AD), while only 3R-tau accumulation has been detected in Pick’s disease (PiD), suggesting the involvement of 3R-tau in neurodegeneration. However, both the role and the molecular mechanism of 3R-tau in neurodegeneration are elusive. Here, we co-expressed three isoforms of human wild-type 3R-tau in adult mouse hippocampal to mimic the pathologic tau accumulating observed in PiD patients. We found that co-expressing three 3R-tau isoforms induced hyperphosphorylation and accumulation of tau proteins; simultaneously, the mice showed remarkable neuron death with synapse and memory deficits. Further in …vitro and in vivo studies demonstrated that co-expressing 3R-tau isoforms caused oxidative stress evidenced by an increased malondialdehyde, and the decreased superoxide dismutase and glutathione peroxidase; the 3R-tau accumulation also induced significant glial activation and DNA double-strand breaks (DSBs). Notably, the toxic effects of 3R-tau accumulation were efficiently reversed by administration of antioxidants Vitamin E (VitE) and Vitamin C (VitC), respectively. These data reveal that intracellular accumulation of 3R-tau isoforms in adult brain induces significant neuron death and memory deficits with the mechanism involving oxidation-mediated DSBs; and the antioxidants VitE and VitC can efficiently attenuate the toxicities of 3R-tau. Given that no significant cell death has been detected in the currently available wild-type tau-accumulating models, co-expressing 3R-tau isoforms could be a promising model for drug development of tauopathies, such as PiD. Show more

Keywords: 3R-tau, DNA double-strand breaks, oxidative stress, tauopathies

DOI: 10.3233/JAD-191132

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1105-1123, 2020

Authors: Liu, Hanxiang | Reynolds, Gavin P. | Wei, Xianwen

Article Type: Research Article

Abstract: Uric acid (UA) is a major contributor to naturally-occurring antioxidant activity and is thought to have protective effects against neurodegenerative processes. However, UA is also implicated as a risk factor in vascular, including cerebrovascular, disease. Its association with, and role in, dementia and its component diseases including Alzheimer’s disease (AD) and vascular dementia (VaD) remains unclear and inconsistently studied. Changes in blood lipids, particularly cholesterol measures, have also been implicated in dementias although the relationship or interactions with UA have been little studied. We have measured plasma UA and lipids taken from 187 subjects first attending a general hospital …neurology department for symptoms associated with dementia, and from a series of 79 healthy control subjects. Diagnoses of AD and VaD were made following neuroimaging; laboratory measures were compared between dementia and control groups and between AD and VaD subgroups. No overall change in UA was seen in dementia, although a substantial and highly significant reduction was found in the AD patients. Reduced values in total cholesterol, HDL, and LDL were found in dementia, independent of statin treatment. Further investigation found a significant reduction of HDL only in the VaD group, while total cholesterol was significantly reduced in both AD and VaD subjects. These findings indicate that in our Chinese sample, UA deficits are specifically associated with AD, while deficits in HDL cholesterol found in dementia tend to be greater in VaD. Show more

Keywords: Alzheimer’s disease, antioxidant, cerebrovascular disease, cholesterol, HDL, LDL, neurodegeneration, uric acid, vascular dementia

DOI: 10.3233/JAD-191111

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1125-1131, 2020

Authors: Benussi, Alberto | Dell’Era, Valentina | Cantoni, Valentina | Cotelli, Maria Sofia | Cosseddu, Maura | Spallazzi, Marco | Alberici, Antonella | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Background: The neural correlates of behavioral symptoms in frontotemporal dementia (FTD) are still to be elucidated. Neurotransmitter abnormalities could be correlated to the pathophysiology of negative and positive symptoms in FTD. Objective: To evaluate if the imbalance between inhibitory and excitatory cortical circuits, evaluated with transcranial magnetic stimulation (TMS), correlate with the magnitude of negative and positive symptoms, as measured by Frontal Behavioral Inventory (FBI) scores, in patients with FTD. Methods: Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 186 FTD patients (130 bvFTD, 35 avPPA, 21 svPPA). We applied short …interval intracortical inhibition (SICI – GABAA ergic transmission), intracortical facilitation (ICF – glutamatergic transmission), long interval intracortical inhibition (LICI – GABAB ergic transmission), and short latency afferent inhibition (SAI – cholinergic transmission). Linear and stepwise multiple regression analysis were used to determine the contribution of each neurophysiological measures to the total variance of FBI scores. Results: At the stepwise multivariate analysis, we observed a significant negative correlation between FBI-A scores (negative symptoms) and ICF (β = -0.57, p  < 0.001, adjusted R 2  = 0.32). For FBI-B scores (positive symptoms), we observed a significant positive correlation for SICI (β = 0.84, p  < 0.001, adjusted R 2  = 0.56). Significant correlations were observed for single items of the FBI-A score with ICF and FBI-B scores with SICI, with a medium-large size effect for several items. Conclusions: The present study shows that the imbalance between inhibitory and excitatory intracortical circuits, evaluated with TMS, correlated with the magnitude of negative and positive symptoms in FTD, respectively. Show more

Keywords: Frontal Behavior Inventory, frontotemporal dementia, long interval intracortical inhibition, short interval intracortical inhibition-intracortical facilitation, transcranial magnetic stimulation

DOI: 10.3233/JAD-190986

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1133-1142, 2020

Authors: Fischer, Corinne E. | Ismail, Zahinoor | Youakim, James M. | Creese, Byron | Kumar, Sanjeev | Nuñez, Nicolas | Ryan Darby, R. | Di Vita, Antonella | D’Antonio, Fabrizia | de Lena, Carlo | McGeown, William J. | Ramit, Ravona | Rasmussen, Jill | Bell, Joanne | Wang, Huali | Bruneau, Marie-Andrée | Panegyres, Peter K. | Lanctôt, Krista L. | Agüera-Ortiz, Luis | Lyketsos, Constantine | Cummings, Jeffrey | Jeste, Dilip V. | Sano, Mary | Devanand, D.P. | Sweet, Robert A. | Ballard, Clive

Article Type: Research Article

Abstract: Background: Psychotic symptoms are common in Alzheimer’s disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to …capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders , 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders. Show more

Keywords: Alzheimer’s disease, criteria, delusions, hallucinations, mild cognitive impairment, psychosis

DOI: 10.3233/JAD-190828

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1143-1156, 2020

Authors: Cao, Qing | Tan, Chen-Chen | Xu, Wei | Hu, Hao | Cao, Xi-Peng | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Dementia is a severe neurodegenerative disorder and it can be categorized into several subtypes by different pathogenic causes. We sought to comprehensively analyzed the prevalence of dementia from perspectives of geographic region (Asia, Africa, South America, and Europe/North America), age, and gender. We searched PubMed and EMBASE for relevant articles on dementia published from January 1985 to August 2019. In these studies, analyses were stratified by geographic region, age, and gender. Meta-regression was conducted to identify if there were significant differences between groups. We included forty-seven studies. Among the individuals aged 50 and over in the community, the pooled prevalence …for all-cause dementia, Alzheimer’s disease, and vascular dementia were 697 (CI95%: 546–864) per 10,000 persons, 324 (CI95%: 228–460) per 10,000 persons, and 116 (CI95%: 86–157) per 10,000 persons, respectively. In our study, the prevalence of all-type dementia in individuals aged 100 years and older (6,592 per 10,000 cases) is 244 times higher than in those aged 50–59 (27 per 10,000 cases). The number of people living with dementia approximately doubles every five years. The prevalence was greater in women than in men (788 cases versus 561 cases per 10,000 persons) in overall analysis. In individuals aged 60 to 69 years, AD prevalence in females was 1.9 times greater than that in males (108 cases versus 56 cases per 10,000 persons), while the prevalence of VaD was 1.8 times greater in males than in females (56 cases versus 32 cases per 10,000 persons). Prevalence rate was higher in Europe and North America than in Asia, Africa, and South America. Show more

Keywords: Alzheimer’s disease, dementia, prevalence, vascular dementia

DOI: 10.3233/JAD-191092

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1157-1166, 2020

Authors: Devyatkin, Vasiliy A. | Redina, Olga E. | Kolosova, Nataliya G. | Muraleva, Natalia A.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and age-related macular degeneration (AMD) are two complex incurable neurodegenerative disorders the common pathogenesis of which is actively discussed. There are overlapping risk factors and molecular mechanisms of the two diseases; at the same time, there are arguments in favor of the notion that susceptibility to each of these diseases is associated with a distinct genetic background. Here we identified single-nucleotide polymorphisms (SNPs) that are specific for senescence-accelerated OXYS rats, which simulate key characteristics of both sporadic AD and AMD. Transcriptomes of the hippocampus, prefrontal cortex, and retina (data of RNA-Seq) were analyzed. We detected SNPs in …genes Rims2 , AABR07072639.2 , Lemd2 , and AABR07045405.1 , which thus can express significantly truncated proteins lacking functionally important domains. Additionally, 33 mutations in genes—which are related to various metabolic and signaling pathways—cause nonsynonymous amino acid substitutions presumably leading to disturbances in protein structure or functions. Some of the genes carrying these SNPs are associated with aging, neurodegenerative, and mental diseases. Thus, we revealed the SNPs can lead to abnormalities in protein structure or functions and affect the development of the senescence-accelerated phenotype of OXYS rats. Our data are consistent with the latest results of genome-wide association studies that highlight the importance of multiple pathways for the pathogenesis of AD and AMD. Identified SNPs can serve as promising research objects for further studies on the molecular mechanisms underlying this particular rat model as well as for the prediction of potential biomarkers of AD and AMD. Show more

Keywords: Age-related macular degeneration, aging, Alzheimer’s disease, senescence-accelerated OXYS rats, SNP

DOI: 10.3233/JAD-190956

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1167-1183, 2020

Authors: Palmer, Jennifer C. | Tayler, Hannah M. | Dyer, Laurence | Kehoe, Patrick G. | Paton, Julian F.R. | Love, Seth

Article Type: Research Article

Abstract: Cerebral blood flow is reduced in Alzheimer’s disease (AD), which is associated with mid-life hypertension. In people with increased cerebral vascular resistance due to vertebral artery or posterior communicating artery hypoplasia, there is evidence that hypertension develops as a protective mechanism to maintain cerebral perfusion. In AD, amyloid-β (Aβ) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system. The level of endothelin-1 in brain tissue correlates positively with Aβ load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of Aβ40 exacerbated pre-existing …hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of Aβ40 on blood pressure and heart rate and their variability; carotid flow; endothelin-1; and markers of cerebral oxygenation, in the (normotensive) Wistar rat, and the modulatory influence of the endothelin A receptor antagonist Zibotentan (ZD4054). Cerebral infusion of Aβ caused progressive rise in blood pressure (p  < 0.0001) (paired t -test: increase of 3 (0.1–5.6) mmHg (p  = 0.040)), with evidence of reduced baroreflex responsiveness, and accumulation of Aβ and elevated endothelin-1 in the vicinity of the infusion. Oral Zibotentan (3 mg/kg/d, administered for 31 d) abrogated the effects of Aβ40 infusion on baroreflex responsiveness and blood pressure, which declined, although without reduction in carotid blood flow, and Zibotentan caused uncoupling of the positive linear relationship between endothelin-1 and vascular endothelial growth factor, which as a sensor of tissue oxygenation would be expected to increase if there were hypoperfusion. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, endothelin, hypertension, Zibotentan

DOI: 10.3233/JAD-190630

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1185-1199, 2020

Authors: Schultz, Nina | Byman, Elin | the Netherlands Brain Bank | Wennström, Malin

Article Type: Research Article

Abstract: Background: Previous studies have used immunohistology to demonstrate Alzheimer’s disease (AD) characteristic accumulation of amyloid-β (Aβ) in the retina of AD patients, a finding indicating retina examination as a potential diagnostic tool for AD pathology. Objective: To further explore this idea by investigating whether levels of Aβ42 and Aβ40 in retina are associated with corresponding levels in hippocampus, neuropathological assessments, apolipoprotein E (APOE ) genotype, and levels of islet amyloid polypeptide (IAPP). Methods: Levels of high molecular weight (HMW) Aβ42 , Aβ40 , and IAPP in ultra-centrifuged homogenates of retina and hippocampus from patients …with AD, multiple sclerosis, AD with Lewy bodies, and non-demented controls were analyzed using Mesoscale Discovery electrochemiluminescence technology employing immunoassay and enzyme-linked immunosorbent assay. Results: Higher levels of retinal and hippocampal Aβ42-HMW , Aβ40-HMW , and IAPP-HMW were found in individuals with high neuropathological scores of Aβ plaques and in individuals carrying the APOE ɛ 4 allele. The retinal levels of Aβ42-HMW and Aβ40-HMW correlated with corresponding levels in hippocampus as well as with neurofibrillary tangles (NFT) and Aβ scores. Retinal IAPP-HMW correlated with retinal levels of Aβ42-HMW and with NFT and Aβ scores. Conclusion: These results show that different isoforms of Aβ can be detected in the human retina and moreover support the growing number of studies indicating that AD-related pathological changes occurring in the brain could be reflected in the retina. Show more

Keywords: Alzheimer’s disease, amyloid-β, hippocampus, IAPP, retina

DOI: 10.3233/JAD-190868

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1201-1209, 2020