Journal of Alzheimer's Disease - Volume 63, issue 2

Authors: Pasinetti, Giulio Maria | Singh, Risham | Westfall, Susan | Herman, Francis | Faith, Jeremiah | Ho, Lap

Article Type: Review Article

Abstract: A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this …review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline. Show more

Keywords: Gnotobiotic mice, inflammation, microbiota, oxidative stress, polyphenol metabolism

DOI: 10.3233/JAD-171151

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 409-421, 2018

Authors: Kueper, Jacqueline K. | Speechley, Mark | Montero-Odasso, Manuel

Article Type: Review Article

Abstract: The Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) was developed in the 1980s to assess the level of cognitive dysfunction in Alzheimer’s disease. Advancements in the research field have shifted focus toward pre-dementia populations, and use of the ADAS-Cog has extended into these pre-dementia studies despite concerns about its ability to detect important changes at these milder stages of disease progression. If the ADAS-Cog cannot detect important changes, our understanding of pre-dementia disease progression may be compromised and trials may incorrectly conclude that a novel treatment approach is not beneficial. The purpose of this review was to assess the performance of …the ADAS-Cog in pre-dementia populations, and to review all modifications that have been made to the ADAS-Cog to improve its measurement performance in dementia or pre-dementia populations. The contents of this review are based on bibliographic searches of electronic databases to locate all studies using the ADAS-Cog in pre-dementia samples or subsamples, and to locate all modified versions. Citations from relevant articles were also consulted. Overall, our results suggest the original ADAS-Cog is not an optimal outcome measure for pre-dementia studies; however, given the prominence of the ADAS-Cog, care must be taken when considering the use of alternative outcome measures. Thirty-one modified versions of the ADAS-Cog were found. Modification approaches that appear most beneficial include altering scoring methodology or adding tests of memory, executive function, and/or daily functioning. Although modifications improve the performance of the ADAS-Cog, this is at the cost of introducing heterogeneity that may limit between-study comparison. Show more

Keywords: ADAS-Cog, literature review, mild cognitive impairment, outcome measures

DOI: 10.3233/JAD-170991

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 423-444, 2018

Authors: Chen, Chen | Zhang, Haifeng | Xu, Hongliang | Xue, Rui | Zheng, Yake | Wu, Tianwen | Lian, Yajun

Article Type: Research Article

Abstract: Vascular dementia (VaD) is the second most common dementia worldwide. Unlike Alzheimer’s disease, VaD does not yet have effective therapeutic drugs. Harpagoside is the most important component extracted from Harpagophytum procumbens , a traditional Chinese medicine that has been widely used. The neuroprotective effects of harpagoside have been studied in Aβ- and MPTP-induced neurotoxicity. However, whether harpagoside is protective against VaD is not clear. In this study, with the use of chronic cerebral hypoperfusion rats, a well-known VaD model, we demonstrated that chronic administration (two months) of harpagoside was able to restore both the spatial learning/memory and fear memory impairments. …Importantly, the protective effects of harpagoside were not due to alterations in the physiological conditions, metabolic parameters, or locomotor abilities of the rats. Meanwhile, we found that harpagoside suppressed the overactivation of PTEN induced by CCH by enhancing PTEN phosphorylation. Furthermore, harpagoside elevated the activity of Akt and inhibited the activity of GSK-3β, downstream effectors of PTEN. Overall, our study suggested that harpagoside treatment might be a potential therapeutic drug targeting the cognitive impairments of VaD. Show more

Keywords: Chronic cerebral hypoperfusion, GSK-3β, harpagoside, memory, PTEN

DOI: 10.3233/JAD-171170

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 445-455, 2018

Authors: Burns, Nicole C. | Watts, Amber | Perales, Jaime | Montgomery, Robert Neal | Morris, Jill K. | Mahnken, Jonathan D. | Lowther, Johnna | Vidoni, Eric D.

Article Type: Research Article

Abstract: Previous research involving dramatic performances about Alzheimer’s disease and dementia perception have targeted health care workers or caretakers. We examined the influence of a theater performance on the emotional affect of a general audience to determine the utility of this type of theater in large-scale public health education efforts. Our study included 147 participants that attended a self-revelatory theater performance based on the social/relationship experiences of those with dementia and those who care for them. This type of theater engages the audience and actors in a dual transformative process, supporting the emotional growth of all involved. Participants completed pre- and …post-performance questionnaires regarding their beliefs and feelings surrounding the topic of dementia and the importance of the Arts for educating on issues surrounding dementia care. We tested for change in emotional affect pre- and post-performance using sensitivity and center of gravity statistical analyses. We found a significant change in emotional affect from an initial strong negative affect to slightly more positive/relaxed view after viewing the performance. Findings support self-revelatory theater as a resource to destigmatize preconceived notions of dementia. Large-scale community health education efforts could benefit from using this style of theater to elicit a change in audience perception of disease realities. Show more

Keywords: Alzheimer’s disease, art therapy, awareness, dementia, neurodegenerative diseases, social stigma

DOI: 10.3233/JAD-180092

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 457-463, 2018

Authors: Urbanova, Barbora Soukupova | Schwabova, Jaroslava Paulasova | Magerova, Hana | Jansky, Petr | Markova, Hana | Vyhnalek, Martin | Laczo, Jan | Hort, Jakub | Tomek, Ales

Article Type: Research Article

Abstract: Background: Cerebral microangiopathy in Alzheimer’s disease (AD) causes chronic hypoperfusion and probably accelerates neurodegenerative changes. Objective: We hypothesize microvascular impairment could be present already in mild cognitive impairment (MCI) and can be revealed using transcranial color-coded sonography (TCCS) and the breath-holding maneuver. Methods: Three groups of subjects (AD in the stage of dementia, MCI, and cognitively normal controls) with detailed neuropsychological testing and low cerebrovascular burden (no history of stroke, no intra- or extracranial artery stenoses, and no severe vascular lesions on brain MRI), underwent a TCCS assessment of peak systolic (PSV), mean flow (MFV), and …end diastolic velocities (EDV) and resistance and pulsatility indices (RI, PI) in large intracranial vessels bilaterally. Cerebrovascular reserve capacity was assessed using the breath-holding index (BHI) in middle cerebral artery (MCA) bilaterally. The ultrasound parameters were compared between the groups, correlated with neuropsychological tests, and compared between amnestic and non-amnestic MCI subtypes. Results: Fourteen AD (3 males, 67.9±11.1 years, MMSE 18.0±4.6), 24 MCI (13 males, 71.9±7.3 years, MMSE 28.0±1.6), and 24 risk factor-matched controls (14 males, 67.8±6.4 years, MMSE 29.1±1.2) were enrolled. Significant differences were found between AD and controls in MFV, EDV, RI, PI in right MCA after breath holding, in PSV, MFV, EDV in left MCA after breath holding, and in BHI on the left side. The left BHI correlated positively with verbal memory test. Conclusion: Results show decreased cerebrovascular reserve capacity in AD as a sign of impaired cerebral hemodynamic status without severe underlying atherosclerosis. This can be identified using TCCS and BHI. Show more

Keywords: Alzheimer’s disease, breath-holding index, cerebrovascular reserve capacity, microangiopathy, mild cognitive impairment, transcranial color-coded sonography, transcranial Doppler

DOI: 10.3233/JAD-170815

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 465-477, 2018

Authors: Chatterjee, Pratishtha | Goozee, Kathryn | Sohrabi, Hamid R. | Shen, Kaikai | Shah, Tejal | Asih, Prita R. | Dave, Preeti | ManYan, Candice | Taddei, Kevin | Chung, Roger | Zetterberg, Henrik | Blennow, Kaj | Martins, Ralph N.

Article Type: Research Article

Abstract: Background: The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer’s disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood. Objective: Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-β load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults. Methods: Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in …Ageing Health cohort, aged 65– 90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n  = 65) and high NAL (NAL+, n  = 35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51, nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment Clinic– Questionnaire. Results: Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOE ɛ 4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC. Conclusion: Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, blood, neurofilaments, positron emission tomography, cognitive function, episodic memory, executive function, verbal memory, visual memory

DOI: 10.3233/JAD-180025

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 479-487, 2018

Authors: Fodor, Zsuzsanna | Sirály, Enikő | Horváth, András | Salacz, Pál | Hidasi, Zoltán | Csibri, Éva | Szabó, Ádám | Csukly, Gábor

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) refers to a measurable deficit in cognition in the absence of dementia or impairment in activities of daily living. Working memory impairment is among the earliest signs of MCI. Oscillatory analysis of working memory might be a potential tool for identifying patients at increased risk of developing dementia. Our study aimed to assess the temporospatial pattern of spectral differences during working memory maintenance between MCI patients and healthy controls and to compare the sources of oscillatory activity between the two groups. Event-related spectral perturbation of 17 MCI patients and 21 healthy control participants was studied with …128-channel EEG during the Sternberg working memory task. Source localization was performed by using the eLORETA software. Among the participants, 13 MCI and 15 control participants underwent a structural brain MRI examination. Event-related synchronization (ERS) in the alpha and beta frequency band was significantly lower in MCI patients compared to healthy control participants during retention. Both study groups showed significant memory load-related enhancement in both frequency band. In the MCI group, source localization revealed significantly attenuated beta oscillatory activity in the inferior and middle temporal gyrus, in the fusiform gyrus, and in the cuneus. Beta ERS correlated significantly with the size of the hippocampus, entorhinal cortex, and parahippocampal gyrus. During the retention period, MCI is characterized by decreased alpha and beta ERS compared to controls indicating early impairment in neural networks serving working memory maintenance. The assessment of electrophysiological changes in the beta frequency range may provide a useful diagnostic tool for the early detection of cognitive impairment. Show more

Keywords: Alpha rhythm, beta rhythm, electroencephalography, memory, mild cognitive impairment, short-term

DOI: 10.3233/JAD-171079

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 489-502, 2018

Authors: Couttas, Timothy A. | Kain, Nupur | Tran, Collin | Chatterton, Zac | Kwok, John B. | Don, Anthony S.

Article Type: Research Article

Abstract: The greatest risk factor for developing Alzheimer’s disease (AD) is aging. The major genetic risk factor for AD is the ɛ4 allele of the APOE gene, encoding the brain’s major lipid transport protein, apolipoprotein E (ApoE). The research community is yet to decipher why the ApoE4 variant pre-disposes to AD, and how aging causes the disease. Studies have shown deregulated levels of sphingolipids, including decreased levels of the neuroprotective signaling lipid sphingosine 1-phosphate (S1P), and increased ceramide content, in brain tissue and serum of people with pre-clinical or very early AD. In this study we investigated whether sphingolipid levels …are affected as a function of age or APOE genotype, in the hippocampus of neurologically normal subjects over the age of 65. Lipids were quantified in 80 postmortem tissue samples using liquid chromatography tandem mass spectrometry (LC-MS/MS). Sphingolipid levels were not significantly affected by the presence of one ɛ4 or ɛ2 allele. However, ceramide, sphingomyelin, and sulfatide content was very significantly correlated with age in the hippocampus of males. On the other hand, S1P, normalized to its non-phosphorylated precursor sphingosine, was inversely correlated with age in females. Our results therefore establish gender-specific differences in sphingolipid metabolism in the aging human brain. Ceramide is a pro-apoptotic lipid, and heavily implicated as a driver of insulin resistance in metabolic tissues. S1P is a neuroprotective lipid that supports glutamatergic neurotransmission. Increasing ceramide and decreasing S1P levels may contribute significantly to a pro-neurodegenerative phenotype in the aging brain. Show more

Keywords: Aging, Alzheimer’s disease, APOE, ApoE, ceramide, sphingolipid, sphingomyelin, sphingosine 1-phosphate

DOI: 10.3233/JAD-171054

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 503-514, 2018

Authors: van den Berg, Esther | Geerlings, Mirjam I. | Biessels, Geert Jan | Nederkoorn, Paul J. | Kloppenborg, Raoul P.

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMHs) are related to cognitive dysfunction in the general population. The clinical relevance of WMHs in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) is, however, unclear. Objective: This meta-analysis aimed to quantify the association of WMHs and specific cognitive domains in patients with MCI or AD. Methods: PubMed (January 1990-January 2017) was searched for studies that used MRI to quantify WMHs, and measured cognitive functioning (≥1 predefined cognitive domain with ≥1 test) in a well-defined population of persons diagnosed with MCI or AD. Fischer’s Z was used as the …common metric for effect size. Modifying effects of demographics, MMSE, and WMH location were examined. Results: Twelve cross-sectional studies on AD (total n  = 1,370, median age 75 years) and 10 studies on MCI (9 cross-sectional, 1 longitudinal; total n  = 2,286, median age 73 years) were included. The association between WMHs and overall cognition was significantly stronger for MCI (–0.25, –0.36 to –0.14) than for AD (–0.11, –0.14 to –0.08; QM  = 10.7, p  < 0.05). For both groups, largest effect sizes were found in attention and executive functions (–0.26, –0.36 to –0.15) and processing speed (–0.21, –0.35 to –0.12). No significant modifying effects of age and gender were found. Conclusion: WMHs have a medium-sized association with different cognitive functions in patients with MCI and a small, but statistically significant, association with cognition in AD. These result underscore the role of co-occurring vascular brain damage in MCI and AD. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, meta-analysis, vascular dementia, vascular risk factor, white matter

DOI: 10.3233/JAD-170573

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 515-527, 2018

Authors: Amen, Daniel G. | Taylor, Derek V. | Meysami, Somayeh | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Depression remains an important risk factor for Alzheimer’s disease, yet few neuroimaging biomarkers are available to identify treatment response in depression. Objective: To analyze and compare functional perfusion neuroimaging in persons with treatment resistant depression (TRD) compared to those experiencing full remission. Methods: A total of 951 subjects from a community psychiatry cohort were scanned with perfusion single photon emission computed tomography (SPECT) of the brain in both resting and task related settings. Of these, 78% experienced either full remission (n  = 506) or partial remission (n  = 237) and 11% were minimally responsive (n  = 103) or …non-responsive (11%. n  = 106). Severity of depression symptoms were used to define these groups with changes in the Beck Depression Inventory prior to and following treatment. Voxel-based analyses of brain SPECT images from full remission compared to the worsening group was conducted with the statistical parametric mapping software, version 8 (SPM 8). Multiple comparisons were accounted for with a false discovery rate (p  < 0.001). Results: Persons with depression that worsened following treatment had reduced cerebral perfusion compared to full remission in the multiple regions including the bilateral frontal lobes, right hippocampus, left precuneus, and cerebellar vermis. Such differences were observed on both resting and concentration SPECT scans. Conclusion: Our findings identify imaging-based biomarkers in persons with depression related to treatment response. These findings have implications in understanding both depression to prognosis and its role as a risk factor for dementia. Show more

Keywords: Brain SPECT, depression, treatment response

DOI: 10.3233/JAD-170855

Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 529-538, 2018