Journal of Alzheimer's Disease - Volume 66, issue 3

Authors: Nasoohi, Sanaz | Parveen, Kehkashan | Ishrat, Tauheed

Article Type: Review Article

Abstract: Empirical evidence indicates a strong association between insulin resistance and pathological alterations related to Alzheimer’s disease (AD) in different cerebral regions. While cerebral insulin resistance is not essentially parallel with systemic metabolic derangements, type 2 diabetes mellitus (T2DM) has been established as a risk factor for AD. The circulating “toxic metabolites” emerging in metabolic syndrome may engage several biochemical pathways to promote oxidative stress and neuroinflammation leading to impair insulin function in the brain or “type 3 diabetes”. Thioredoxin-interacting protein (TXNIP) as an intracellular amplifier of oxidative stress and inflammasome activation may presumably mediate central insulin resistance. Emerging data including …those from our recent studies has demonstrated a sharp TXNIP upregulation in stroke, aging and AD and well underlining the significance of this hypothesis. With the main interest to illustrate TXNIP place in type 3 diabetes, the present review primarily briefs the potential mechanisms contributing to cerebral insulin resistance in a metabolically deranged environment. Then with a particular focus on plausible TXNIP functions to drive and associate with AD pathology, we present the most recent evidence supporting TXNIP as a promising therapeutic target in AD as an age-associated dementia. Show more

Keywords: Alzheimer’s disease, brain insulin resistance, inflammasomes, metabolic syndrome, oxidative stress, thioredoxin-interacting protein (TXNIP), type 3 diabetes

DOI: 10.3233/JAD-180735

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 857-885, 2018

Authors: Jiang, Lianying | Wang, Jiafeng | Wang, Zhigang | Huang, Wenhui | Yang, Yixia | Cai, Zhiyou | Li, Keshen

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is an insidious and progressive neurodegenerative disease. The main pathological features of AD are the formation of amyloid-β deposits in the anterior cerebral cortex and hippocampus as well as the formation of intracellular neurofibrillary tangles. Thus far, accumulating evidence shows that glycation is closely related to AD. As a final product resulting from the crosslinking of a reducing sugar or other reactive carbonyls and a protein, the advanced glycation end products have been found to be associated with the formation of amyloid-β and neurofibrillary tangles in AD. As a saccharification inhibitor, the glyoxalase system and its substrate …methylglyoxal (MG) were certified to be associated with AD onset and development. As an active substance of AGEs, MG could cause direct or indirect damage to nerve cells and tissues. MG is converted to D-lactic acid after decomposition by the glyoxalase system. Under normal circumstances, MG metabolism is in a dynamic equilibrium, whereas MG accumulates in cells in the case of aging or pathological states. Studies have shown that increasing glyoxalase activity and reducing the MG level can inhibit the generation of oxidative stress and AGEs, thereby alleviating the symptoms and signs of AD to some extent. This paper focuses on the relevant mechanisms of action of the glyoxalase system and MG in the pathogenesis of AD, as well as the potential of inhibiting the production of advanced glycation end products in the treatment of AD. Show more

Keywords: Advanced glycation end product, Alzheimer’s disease, glutathione, glyoxalase system, methylglyoxal

DOI: 10.3233/JAD-180413

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 887-899, 2018

Authors: Ramzaoui, Hanane | Faure, Sylvane | Spotorno, Sara

Article Type: Review Article

Abstract: Many instrumental activities of daily living (IADLs), like cooking and managing finances and medications, involve finding efficiently and in a timely manner one or several objects within complex environments. They may thus be disrupted by visual search deficits. These deficits, present in Alzheimer’s disease (AD) from its early stages, arise from impairments in multiple attentional and memory mechanisms. A growing body of research on visual search in AD has examined several factors underlying search impairments in simple arrays. Little is known about how AD patients search in real-world scenes and in real settings, and about how such impairments affect patients’ …functional autonomy. Here, we review studies on visuospatial attention and visual search in AD. We then consider why analysis of patients’ oculomotor behavior is promising to improve understanding of the specific search deficits in AD, and of their role in impairing IADL performance. We also highlight why paradigms developed in research on real-world scenes and real settings in healthy individuals are valuable to investigate visual search in AD. Finally, we indicate future research directions that may offer new insights to improve visual search abilities and autonomy in AD patients. Show more

Keywords: Alzheimer’s disease, eye movements, Instrumental Activities of Daily Living, memory, real-world settings, scene processing, visual search, visuospatial attention

DOI: 10.3233/JAD-180043

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 901-925, 2018

Authors: Madrid, Andy | Hogan, Kirk J. | Papale, Ligia A. | Clark, Lindsay R. | Asthana, Sanjay | Johnson, Sterling C. | Alisch, Reid S.

Article Type: Short Communication

Abstract: Differentially methylated positions (DMPs) between persons with and without late-onset Alzheimer’s disease (LOAD) were observed at 477 of 769,190 loci in a plurality of genes. Of these, 17 were shared with DMPs identified using clinical LOAD markers analyzed independently as continuous variables comprising Rey Auditory Verbal Learning Test scores, cerebrospinal fluid total tau (t-tau) and phosphorylated tau 181 (p-tau181 ) levels, and t-tau/Aβ1–42 (Aβ42 ), p-tau181 /Aβ42 , and Aβ42 /Aβ1–40 (Aβ40 ) ratios. In patients with LOAD, 12 of the shared 17 DMPs were hypomethylated in B3GALT4 (Beta-1,3-galatcosyltransferase 4) (EC 2.4.1.62), and 5 were hypomethylated in ZADH2 …(Prostaglandin reductase 3) (EC 1.3.1.48). Show more

Keywords: Amyloid, DNA methylation, late-onset Alzheimer’s disease, tau proteins

DOI: 10.3233/JAD-180592

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 927-934, 2018

Authors: Kurlawala, Zimple | Roberts, Jeffrey A. | McMillan, Joseph D. | Friedland, Robert P.

Article Type: Short Communication

Abstract: The toxicity associated with long-standing benzodiazepine use in older persons is a critical issue. Several epidemiological reports have studied correlation between benzodiazepine use and risk of dementia development. In this manuscript, we used a case report to demonstrate how chronic diazepam use can cause cognitive deficits that resemble Alzheimer’s disease and related conditions. Benzodiazepine use is common in the geriatric population and is often taken for long periods of time in improper doses. In combination with age-related cortical atrophy on the MRI, our patient risked being misdiagnosed with Alzheimer’s disease or another dementing disorder if not for the systematic investigation …to resolve his symptoms. With elimination of the offending dispensable drug (diazepam), the patient’s cognition improved greatly. Show more

Keywords: Alzheimer’s disease, benzodiazepine, dementia, diazepam

DOI: 10.3233/JAD-180745

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 935-938, 2018

Authors: Tang, Ning | Kepp, Kasper P.

Article Type: Article Commentary

Abstract: Missense mutations in presenilin 1 cause early onset familial Alzheimer’s disease in a way that is not understood. Increased Aβ42 /Aβ40 ratios are the most consistent biochemical phenotype of such mutations in cultured cells and in vivo , and are thus considered central to the amyloid hypothesis. Previously, an inverse relation has been observed between the Aβ42 /Aβ40 ratio of such mutants and the clinical age of symptom onset in patients carrying the mutation. However, a recent extensive study by Sun et al. of assayed presenilin 1 mutants concluded that such a relationship is not evident. To reconcile …the disagreement, three different clinical datasets were compared directly with the data by Sun et al. After considering data noise and measurement uncertainty, we find a clear and highly significant inverse correlation between the Aβ42 /Aβ40 ratio and the clinical age of onset in all three datasets even without removing noisy single- and double-patient data. With these data removed, the correlation coefficients increase further. The probability that these relationships are coincidental are approximately 0.1%. Show more

Keywords: Aβ42/Aβ40 ratio, age of onset, Alzheimer’s disease, mutations, presenilin

DOI: 10.3233/JAD-180829

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 939-945, 2018

Authors: Innes, Kim E. | Selfe, Terry Kit | Brundage, Kathleen | Montgomery, Caitlin | Wen, Sijin | Kandati, Sahiti | Bowles, Hannah | Khalsa, Dharma Singh | Huysmans, Zenzi

Article Type: Research Article

Abstract: Background: Telomere length (TL), telomerase activity (TA), and plasma amyloid-β (Aβ) levels have emerged as possible predictors of cognitive decline and dementia. Objective: To assess the: 1) effects of two 12-week relaxation programs on TL, TA, and Aβ levels in adults with subjective cognitive decline; and 2) relationship of biomarker changes to those in cognitive function, psychosocial status, and quality of life (QOL). Methods: Participants were randomized to a 12-week Kirtan Kriya meditation (KK) or music listening (ML) program and asked to practice 12 minutes/day. Plasma Aβ(38/40/42) and peripheral blood mononuclear cell TL and TA were …measured at baseline and 3 months. Cognition, stress, sleep, mood, and QOL were assessed at baseline, 3 months, and 6 months. Results: Baseline blood samples were available for 53 participants (25 KK, 28 ML). The KK group showed significantly greater increases in Aβ40 than the ML group. TA rose in both groups, although increases were significant only among those with higher practice adherence and lower baseline TA. Changes in both TL and TA varied by their baseline values, with greater increases among participants with values ≤50th percentile (p s-interaction <0.006). Both groups improved in cognitive and psychosocial status (p s ≤0.05), with improvements in stress, mood, and QOL greater in the KK group. Rising Aβ levels were correlated with gains in cognitive function, mood, sleep, and QOL at both 3 and 6 months, associations that were particularly pronounced in the KK group. Increases in TL and TA were also correlated with improvements in certain cognitive and psychosocial measures. Conclusion: Practice of simple mind-body therapies may alter plasma Aβ levels, TL, and TA. Biomarker increases were associated with improvements in cognitive function, sleep, mood, and QOL, suggesting potential functional relationships. Show more

Keywords: Alzheimer’s disease, cognition, memory complaints, mind-body therapy, mood, plasma amyloid-β, quality of life, sleep, subjective cognitive impairment, telomerase, telomeres

DOI: 10.3233/JAD-180164

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 947-970, 2018

Authors: Winston, Charisse N. | Goetzl, Edward J. | Baker, Laura D. | Vitiello, Michael V. | Rissman, Robert A.

Article Type: Research Article

Abstract: Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted …protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ1-42 , neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients. Show more

Keywords: Amyloid, biomarker, GHRH, growth hormone, mild cognitive impairment, neuronal exosomes, synapse, tau

DOI: 10.3233/JAD-180302

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 971-981, 2018

Authors: Di Lorenzo, Francesco | Ponzo, Viviana | Motta, Caterina | Bonnì, Sonia | Picazio, Silvia | Caltagirone, Carlo | Bozzali, Marco | Martorana, Alessandro | Koch, Giacomo

Article Type: Research Article

Abstract: Background: Mechanisms of cortical plasticity have been recently investigated in Alzheimer’s disease (AD) patients with transcranial magnetic stimulation protocols showing a clear impairment of long-term potentiation (LTP) cortical-like plasticity mechanisms. Objective: We aimed to investigate mechanisms of cortico-cortical spike-timing dependent plasticity (STDP) in AD patients investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1). Methods: We used a cortico-cortical paired associative stimulation (cc-PAS) protocol to repeatedly activate the connection between PPC and M1 of the left-dominant hemisphere in a sample of fifteen AD patients and ten age-matched healthy subjects. PPC transcranial magnetic …stimulation preceded (ccPAS +5) or followed M1 stimulation (ccPAS – 5) by 5 ms. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity. Results: In healthy subjects, ccPAS – 5 protocol induced the expected long-lasting increase of MEP amplitude compatible with LTP-like cortical plasticity while PAS +5 protocol induced the opposite effect. AD patients did not show any significant modification of the amplitude of MEP after both ccPAS protocols. Conclusions: Our study shows that in AD patients the time-locked activation of human cortico-cortical connections is not able to form STDP, reflecting an impairment of a multi-factor plasticity process. Show more

Keywords: Alzheimer’s disease, connectivity, long-term potentiation, motor cortex, parietal cortex, plasticity, spike-timing dependent plasticity

DOI: 10.3233/JAD-180503

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 983-991, 2018

Authors: Liguori, Claudio | Mercuri, Nicola Biagio | Nuccetelli, Marzia | Izzi, Francesca | Bernardini, Sergio | Placidi, Fabio

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia. It is characterized by a progressive deterioration of cognition, frequently associated with neuropsychiatric symptoms (NPS). Among NPS, sleep disturbances often affect AD patients. Orexinergic system dysregulation has been associated with sleep impairment in AD patients. Objective: The present study investigated CSF orexin levels in AD patients and their relationship with both NPS, measured by the neuropsychiatric inventory (NPI), and sleep, measured via polysomnography. Methods: This is a secondary analysis of a previous study investigating CSF biomarkers, sleep impairment and cognitive decline in AD patients. AD …patients completing the NPI were included in this analysis and distributed in two groups based on the presence (NPI score ≥4, AD/NPS+) or absence (NPI score <4, AD/NPS–) of NPS. Results: Twenty-two AD patients constituted the AD/NPS+ group and 20 patients constituted the AD/NPS–group. We observed higher CSF orexin levels in AD/NPS+ than AD/NPS–patients. Moreover, AD/NPS+ showed a more fragmented and the reduction of REM sleep compared to AD/NPS–patients. Notably, higher NPI scores correlated with a more altered sleep structure, higher CSF orexin levels and lower MMSE scores. Conclusion: This study documented that AD patients showing NPS present a more fragmented sleep coupled with higher CSF orexin levels compared to AD patients not affected by NPS. This finding showing the increased orexinergic tone in AD patients affected by NPS suggests the possible influence of the orexinergic system dysregulation not only on sleep impairment but also on neurobehavioral disturbances. Show more

Keywords: Alzheimer’s disease, neuropsychiatric symptoms, orexin, sleep

DOI: 10.3233/JAD-180769

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 993-999, 2018