Journal of Alzheimer's Disease - Volume 59, issue 1

Authors: Lin, Feng V. | Wang, Xixi | Wu, Rachel | Rebok, George W. | Chapman, Benjamin P. | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The present prospective observational study aimed to identify the existence of successful cognitive agers among a group of well-defined cognitively healthy older adults (n  = 354, mean age = 75 years), and to examine baseline individual-level predictors and associated health outcomes over time. Episodic memory (EM) and executive function (EF) composite scores and multiple health outcomes were obtained annually over 5 years. Potential individual-level predictors that were related to Alzheimer’s disease pathology or genetic risk, neurodegeneration, and vascular risks were collected at baseline. Three latent classes with matched age and education were identified using growth mixture modeling: a group of participants who exhibited …high, stable EM and EF (40.7% of the sample, “successful agers”); a group who had initial high cognitive performance that declined over time (21.2%, “declining agers”); and a group who had normal (EM) or poor (EF) but stable cognitive performance over time (38.1%, “low stable agers”). The group classification predicted significant differences in the incidence of global cognitive impairment, the development of at least one depressive symptom, and everyday functional impairment. Sex, apolipoprotein E allele 4, amyloid-β1-42 , and t-tau significantly contributed to the difference in cognitive trajectories between the successful agers and the other two groups. Characterizing successful cognitive agers who are relatively resistant to both tau and amyloid pathology provides potential pathways for promoting successful cognitive aging and preventing cognitive decline. Show more

Keywords: Amyloid-β, episodic memory, executive function, successful cognitive aging, tau

DOI: 10.3233/JAD-161278

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 101-111, 2017

Authors: Shaw, Marnie E. | Abhayaratna, Walter P. | Anstey, Kaarin J. | Cherbuin, Nicolas

Article Type: Research Article

Abstract: Higher body mass index (BMI) at midlife is associated with greater decreases in cognitive function at older age as well as increased Alzheimer’s disease (AD) risk, compared to those with normal BMI. Here, we tested whether BMI at midlife was associated with cortical thinning in brain regions known to be affected in early AD. We examined a large sample (n  = 404) of midlife individuals (44–49 years) from the PATH population-based study. Individuals were scanned with magnetic resonance imaging (1.5T) on up to three occasions over eight years. Change in cortical thickness was modeled as a linear function of BMI and …change in BMI longitudinally. Being obese was associated with thinner right frontal cortex at baseline (44–49 years). Across all individuals, increasing BMI over the 8-year study period was associated with increased cortical thinning in posterior cingulate bilaterally, as well as right lingual gyrus, anterior cingulate, and the peri-calcarine sulcus. Accelerated age-related cortical atrophy at midlife, particularly in posterior cingulate, is consistent with increased risk of AD in individuals with high BMI at this age. The findings suggest that management of body weight at midlife could reduce the risk of AD. Show more

Keywords: Body mass index, cortical thinning, magnetic resonance imaging, midlife, risk factor

DOI: 10.3233/JAD-170055

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 113-120, 2017

Authors: Tortelli, Rosanna | Lozupone, Madia | Guerra, Vito | Barulli, Maria Rosaria | Imbimbo, Bruno P. | Capozzo, Rosa | Grasso, Alessandra | Tursi, Marianna | Di Dio, Cristina | Sardone, Rodolfo | Giannelli, Gianluigi | Seripa, Davide | Misciagna, Giovanni | Panza, Francesco | Logroscino, Giancarlo

Article Type: Research Article

Abstract: Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) …score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08–1.59] and M2 (OR = 1.26; 95% CI: 1.01–1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia risk scores, diabetes mellitus, fasting glycemia, GreatAGE Study, insulin resistance, metabolic syndrome, nutrition

DOI: 10.3233/JAD-170153

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 121-130, 2017

Authors: Loewenstein, David A. | Curiel, Rosie E. | DeKosky, Steven | Rosselli, Monica | Bauer, Russell | Grieg-Custo, Maria | Penate, Ailyn | Li, Chunfei | Lizagarra, Gabriel | Golde, Todd | Adjouadi, Malek | Duara, Ranjan

Article Type: Research Article

Abstract: Background: The rise in incidence of Alzheimer’s disease (AD) has led to efforts to advance early detection of the disease during its preclinical stages. To achieve this, the field needs to develop more sensitive cognitive tests that relate to biological markers of disease pathology. Failure to recover from proactive interference (frPSI) is one such cognitive marker that is associated with volumetric reductions in the hippocampus, precuneus, and other AD-prone regions, and to amyloid load in the brain. Objective: The current study attempted to replicate and extend our previous findings that frPSI is a sensitive marker of early …AD, and related to a unique pattern of volumetric loss in AD prone areas. Methods: Three different memory measures were examined relative to volumetric loss and cortical thickness among 45 participants with amnestic mild cognitive impairment. Results: frPSI was uniquely associated with reduced volumes in the hippocampus (r  = 0.50) precuneus (r  = 0.41), and other AD prone regions, replicating previous findings. Strong associations between frPSI and lower entorhinal cortex volumes and cortical thickness (r≥0.60) and precuneus (r  = 0.50) were also observed. Conclusion: Unique and strong associations between volumetric reductions and frPSI as observed by Loewenstein and colleagues were replicated. Together with cortical thickness findings, these results indicate that frPSI is worthy of further study as a sensitive and early cognitive marker of AD. Show more

Keywords: Cortical thickness, LASSI-L, mild cognitive impairment, MRI volume, proactive semantic interference

DOI: 10.3233/JAD-170276

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 131-139, 2017

Authors: Mortby, Moyra E. | Burns, Richard | Eramudugolla, Ranmalee | Ismail, Zahinoor | Anstey, Kaarin J.

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are common in older adults with cognitive impairment, yet little is known about population-based prevalence and clinical implications of co-morbid symptom presentation across the spectrum from normal cognition to dementia. Objective: To characterize the prevalence of NPS and explore the clinical implications of co-morbid symptom presentation. Methods: Cross-sectional study of 1,417 older adults (aged 73–79) with dementia (n  = 40); with mild cognitive impairment (MCI; n  = 133); who are ‘cognitively normal, but-at-risk’ (CN-AR; n  = 397); and who are cognitively normal (n  = 847). NPS were assessed by the Neuropsychiatric Inventory. Cluster analyses were …conducted using a latent class analysis (LCA). Results: NPS are highly prevalent across the cognitive function spectrum (30.8% –80%). NPS were associated with a 3-fold increased risk of dementia, a 2-fold increased risk of MCI, and a 1.5-times increased risk of CN-AR. Each additional co-morbid symptom was associated with an additional 1.5-times increased risk of dementia, but not MCI or CN-AR. LCA revealed four distinctive sub-populations: 1) frontal/low comorbidity; 2) high prevalence/high comorbidity; 3) affective/low comorbidity; and 4) sleep/low comorbidity. Conclusion: Our findings confirm previous reports on the prevalence of NPS in community-based samples and are consistent with the profiles of NPS domain characteristics of MCI and dementia. Number of co-morbid NPS and not symptom clusters are associated with increased risk of dementia. Understanding such patterns will help inform our understanding of mild behavioral disorders and assist with clinical assessment. Show more

Keywords: Cognitively normal, dementia, mild behavioral impairment, mild cognitive impairment, neuropsychiatricsymptoms

DOI: 10.3233/JAD-170050

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 141-153, 2017

Authors: Festa, Elena K. | Katz, Andrew P. | Ott, Brian R. | Tremont, Geoffrey | Heindel, William C.

Article Type: Research Article

Abstract: Effective audiovisual sensory integration involves dynamic changes in functional connectivity between superior temporal sulcus and primary sensory areas. This study examined whether disrupted connectivity in early Alzheimer’s disease (AD) produces impaired audiovisual integration under conditions requiring greater corticocortical interactions. Audiovisual speech integration was examined in healthy young adult controls (YC), healthy elderly controls (EC), and patients with amnestic mild cognitive impairment (MCI) using McGurk-type stimuli (providing either congruent or incongruent audiovisual speech information) under conditions differing in the strength of bottom-up support and the degree of top-down lexical asymmetry. All groups accurately identified auditory speech under congruent audiovisual conditions, and …displayed high levels of visual bias under strong bottom-up incongruent conditions. Under weak bottom-up incongruent conditions, however, EC and amnestic MCI groups displayed opposite patterns of performance, with enhanced visual bias in the EC group and reduced visual bias in the MCI group relative to the YC group. Moreover, there was no overlap between the EC and MCI groups in individual visual bias scores reflecting the change in audiovisual integration from the strong to the weak stimulus conditions. Top-down lexicality influences on visual biasing were observed only in the MCI patients under weaker bottom-up conditions. Results support a deficit in bottom-up audiovisual integration in early AD attributable to disruptions in corticocortical connectivity. Given that this deficit is not simply an exacerbation of changes associated with healthy aging, tests of audiovisual speech integration may serve as sensitive and specific markers of the earliest cognitive change associated with AD. Show more

Keywords: Early Alzheimer’s disease, lexical influence, McGurk effect, multisensory integration, sensory binding

DOI: 10.3233/JAD-161062

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 155-167, 2017

Authors: Dillen, Kim N.H. | Jacobs, Heidi I.L. | Kukolja, Juraj | Richter, Nils | von Reutern, Boris | Onur, Özgür A. | Langen, Karl-Josef | Fink, Gereon R.

Article Type: Research Article

Abstract: Neurodegenerative brain changes can affect the functional connectivity strength between nodes of the default-mode network (DMN), which may underlie changes in cognitive performance. It remains unclear how the functional connectivity strength of DMN nodes differs from healthy to pathological aging and whether these changes are cognitively relevant. We used resting-state functional magnetic resonance imaging to investigate the functional connectivity strength across five DMN nodes in 25 healthy controls (HC), 28 subjective cognitive decline (SCD) participants, and 25 prodromal Alzheimer’s disease (AD) patients. After identifying the ventral medial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), retrosplenial cortex (RSC), inferior parietal lobule, …and the hippocampus we investigated the functional strength between DMN nodes using temporal network modeling. Functional coupling of the vmPFC and PCC in prodromal AD patients was disrupted. This vmPFC-PCC coupling correlated positively with memory performance in prodromal AD. Furthermore, the hippocampus de-coupled from posterior DMN nodes in SCD and prodromal AD patients. There was no coupling between the hippocampus and the anterior DMN. Additional mediation analyses indicated that the RSC enables communication between the hippocampus and DMN regions in HC but none of the other two groups. These results suggest an anterior-posterior disconnection and a hippocampal de-coupling from posterior DMN nodes with disease progression. Hippocampal de-coupling already occurring in SCD may provide valuable information for the development of a functional biomarker. Show more

Keywords: Dementia, functional MRI, hippocampus, memory

DOI: 10.3233/JAD-161120

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 169-187, 2017

Authors: González-Maciel, Angélica | Reynoso-Robles, Rafael | Torres-Jardón, Ricardo | Mukherjee, Partha S. | Calderón-Garcidueñas, Lilian

Article Type: Research Article

Abstract: Millions of children and young adults are exposed to fine particulate matter (PM2.5 ) and ozone, associated with Alzheimer’s disease (AD) risk. Mexico City (MC) children exhibit systemic and brain inflammation, low cerebrospinal fluid (CSF) Aβ1 -42, breakdown of nasal, olfactory, alveolar-capillary, duodenal, and blood-brain barriers, volumetric and metabolic brain changes, attention and short-term memory deficits, and hallmarks of AD and Parkinson’s disease. Airborne iron-rich strongly magnetic combustion-derived nanoparticles (CDNPs) are present in young urbanites’ brains. Using transmission electron microscopy, we documented CDNPs in neurons, glia, choroid plexus, and neurovascular units of young MC residents versus matched clean air …controls. CDNPs are associated with pathology in mitochondria, endoplasmic reticulum (ER), mitochondria-ER contacts (MERCs), axons,and dendrites. There is a significant difference in size and numbers between spherical CDNPs (>85%) and the angular, euhedral endogenous NPs (<15%). Spherical CDNPs (dogs 21.2±7.1 nm in diameter versus humans 29.1±11.2 nm, p  = 0.002) are present in neurons, glia, choroid plexus, endothelium, nasal and olfactory epithelium, and in CSF at significantly higher in numbers in MC residents (p  < 0.0001). Degenerated MERCs, abnormal mitochondria, and dilated ER are widespread, and CDNPs in close contact with neurofilaments, glial fibers, and chromatin are a potential source for altered microtubule dynamics, mitochondrial dysfunction, accumulation and aggregation of unfolded proteins, abnormal endosomal systems, altered insulin signaling, calcium homeostasis, apoptotic signaling, autophagy, and epigenetic changes. Highly oxidative, ubiquitous CDNPs constitute a novel path into AD pathogenesis. Exposed children and young adults need early neuroprotection and multidisciplinary prevention efforts to modify the course of AD at early stages. Show more

Keywords: Air pollution, Alzheimer’s disease, brain damage, children, electron microscopy, epigenetics, magnetite, Mexico City, mitochondria–ER contacts, nanoparticles, oxidative damage, ultrafine particulate matter

DOI: 10.3233/JAD-170012

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 189-208, 2017

Authors: Andreadou, Eleni | Pantazaki, Anastasia A. | Daniilidou, Makrina | Tsolaki, Magda

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) has been attributed to chronic bacterial infections. The recognition of human microbiota as a substantial contributor to health and disease is relatively recent and growing. During evolution, mammals live in a symbiotic state with myriads of microorganisms that survive at a diversity of tissue micro-surroundings. Microbes produce a plethora of secretory products [amyloids, lipopolysaccharides, virulence factors rhamnolipids (RLs), toxins, and a great number of neuroactive compounds]. The contribution of infectious microbial components to the pathophysiology of the human central nervous system including AD is considered potentially substantial, but the involvement of the RLs has never been reported. …Here, RLs were isolated from serum and identified through various conventional methods including the colorimetric orcinol method, thin-layer chromatography, attenuated total reflection Fourier transform infrared (ATR-FTIR), and dot blot using antibodies against RLs. Dot blot demonstrated elevated RL levels in sera of AD patients compared to controls (p  = 0.014). Moreover, ELISA showed similarly elevated RL levels in cerebrospinal fluid of both AD (0.188 versus 0.080) (p  = 0.04) and mild cognitive impairment (0.188 versus 0.129) (p  = 0.088) patients compared to healthy, and are well-correlated with the AD stages severity assessed using the Mini-Mental State Examination. These results provide conclusive evidence for the newly-reported implication of RLs in AD, adding it to the list of bacterial components, opening new avenues for AD investigation. Moreover, they strengthen and vindicate the divergence of research toward the exploration of bacterial involvement in AD generation and progression. Show more

Keywords: Alzheimer’s disease, bacteria, blood serum, cerebrospinal fluid, rhamnolipids

DOI: 10.3233/JAD-161020

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 209-222, 2017

Authors: Yu, Qing | Du, Fang | Douglas, Justin T. | Yu, Haiyang | Yan, Shirley ShiDu | Yan, Shi Fang

Article Type: Research Article

Abstract: Loss of synapse and synaptic dysfunction contribute importantly to cognitive impairment in Alzheimer’s disease (AD). Mitochondrial dysfunction and oxidative stress are early pathological features in AD-affected brain. However, the effect of AD mitochondria on synaptogenesis remains to be determined. Using human trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells whose mitochondria were transferred from platelets of patients with sporadic AD or age-matched non-AD subjects with relatively normal cognition, we provide the first evidence of mitochondrial dysfunction compromises synaptic development and formation of synapse in AD cybrid cells in response to chemical-induced neuronal differentiation. Compared to non-AD control cybrids, AD cybrid cells showed …synaptic loss which was evidenced by a significant reduction in expression of two synaptic marker proteins: synaptophysin (presynaptic marker) and postsynaptic density protein-95, and neuronal proteins (MAP-2 and NeuN) upon neuronal differentiation. In parallel, AD-mediated synaptic deficits correlate to mitochondrial dysfunction and oxidative stress as well as activation of p38 MAP kinase. Notably, inhibition of p38 MAP kinase by pharmacological specific p38 inhibitor significantly increased synaptic density, improved mitochondrial function, and reduced oxidative stress. These results suggest that activation of p38 MAP kinase signaling pathway contributes to AD-mediated impairment in neurogenesis, possibly by inhibiting the neuronal differentiation. Our results provide new insight into the crosstalk of dysfunctional AD mitochondria to synaptic formation and maturation via activation of p38 MAP kinase. Therefore, blockade of p38 MAP kinase signal transduction could be a potential therapeutic strategy for AD by alleviating loss of synapses. Show more

Keywords: Alzheimer’s disease, cybrid cells, mitochondrial dysfunction, synaptic deficits

DOI: 10.3233/JAD-170283

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 223-239, 2017