Journal of Alzheimer's Disease Reports - Volume 5, issue 1

Authors: Rangasamy, Suresh B. | Dasarathi, Sridevi | Nutakki, Aparna | Mukherjee, Shreya | Nellivalasa, Rohith | Pahan, Kalipada

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is one of the most important neurodegenerative disorders in human in which recovery of functions could be achieved by improving the survival and function of residual dopaminergic neurons in the substantia nigra pars compacta. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the dopamine (DA) biosynthesis pathway. Objective: Earlier our laboratory has shown that sodium benzoate (NaB), a metabolite of cinnamon and an FDA-approved drug against urea cycle disorders and glycine encephalopathy, increases neuroprotective molecules and protects dopaminergic neurons in a mouse model of PD. Here, we examined whether NaB could stimulate the production …of DA in dopaminergic neurons. Methods: We employed PCR, real-time PCR, western blot, immunostaining, and HPLC to study the signature function of dopaminergic neurons. Locomotor functions were monitored in mice by open-field. Results: NaB increased the mRNA and protein expression of TH to produce DA in mouse MN9D dopaminergic neuronal cells. Accordingly, oral feeding of NaB increased the expression of TH in the nigra, upregulated striatal DA, and improved locomotor activities in striatum of normal C57/BL6 and aged A53T-α -syn transgenic mice. Rapid induction of cAMP response element binding (CREB) activation by NaB in dopaminergic neuronal cells and the abrogation of NaB-induced expression of TH by siRNA knockdown of CREB suggest that NaB stimulates the transcription of TH in dopaminergic neurons via CREB. Conclusion: These results indicate a new function of NaB in which it may be beneficial in PD via stimulation of DA production from residual dopaminergic neurons. Show more

Keywords: A53T, CREB, dopamine, sodium benzoate, striatum, substantia nigra pars compacta, tyrosine hydroxylase

DOI: 10.3233/ADR-210001

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 295-310, 2021

Authors: Pezzoli, Stefania | De Marco, Matteo | Zorzi, Giovanni | Cagnin, Annachiara | Venneri, Annalena

Article Type: Research Article

Abstract: Background: The presence of recurrent, complex visual hallucinations (VH) is among the core clinical features of dementia with Lewy bodies (DLB). It has been proposed that VH arise from a disrupted organization of functional brain networks. However, studies are still limited, especially investigating the resting-state functional brain features underpinning VH in patients with dementia. Objective: The aim of the present pilot study was to investigate whether there were any alterations in functional connectivity associated with VH in DLB. Methods: Seed-based analyses and independent component analysis (ICA) of resting-state fMRI scans were carried out to explore differences …in functional connectivity between DLB patients with and without VH. Results: Seed-based analyses reported decreased connectivity of the lateral geniculate nucleus, the superior parietal lobule and the putamen with the medial frontal gyrus in DLB patients with VH. Visual areas showed a pattern of both decreased and increased functional connectivity. ICA revealed between-group differences in the default mode network (DMN). Conclusion: Functional connectivity analyses suggest dysfunctional top-down and bottom-up processes and DMN-related alterations in DLB patients with VH. This impairment might foster the generation of false visual images that are misinterpreted, ultimately resulting in VH. Show more

Keywords: Dementia with Lewy bodies, functional connectivity, resting-state fMRI, resting-state networks, visual hallucinations

DOI: 10.3233/ADR-200288

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 311-320, 2021

Authors: Lo, Albert C. | Evans, Cynthia Duggan | Mancini, Michele | Wang, Hong | Shcherbinin, Sergey | Lu, Ming | Natanegara, Fanni | Willis, Brian A.

Article Type: Research Article

Abstract: Background: LY3202626 is a small molecule inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-β (Aβ)1–40 and Aβ1–42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer’s disease (AD). Objective: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia. Methods: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated …early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. Results: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. Conclusion: LY3202626 tested at doses generating 70–90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo. Show more

Keywords: Alzheimer’s disease, amyloid, neurofibrillary tangles, positron-emission tomography, tau

DOI: 10.3233/ADR-210296

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 321-336, 2021

Authors: Chung, Hojune E. | Chen, Jessica | Ghosalkar, Dhairyasheel | Christensen, Jared L. | Chu, Alice J. | Mantsounga, Chris S. | Neverson, Jade | Soares, Cullen | Shah, Nishant R. | Wu, Wen-Chih | Choudhary, Gaurav | Morrison, Alan R.

Article Type: Research Article

Abstract: Background: While an association between atherosclerosis and dementia has been identified, few studies have assessed the longitudinal relationship between aortic valve calcification (AVC) and cognitive impairment (CI). Objective: We sought to determine whether AVC derived from lung cancer screening CT (LCSCT) was associated with CI in a moderate-to-high atherosclerotic risk cohort. Methods: This was a single site, retrospective analysis of 1401 U.S. veterans (65 years [IQI: 61, 68] years; 97%male) who underwent quantification of AVC from LCSCT indicated for smoking history. The primary outcome was new diagnosis of CI identified by objective testing (Mini-Mental Status Exam …or Montreal Cognitive Assessment) or by ICD coding. Time-to-event analysis was carried out using AVC as a continuous variable. Results: Over 5 years, 110 patients (8%) were diagnosed with CI. AVC was associated with new diagnosis of CI using 3 Models for adjustment: 1) age (HR: 1.104; CI: 1.023–1.191; p  = 0.011); 2) Model 1 plus hypertension, hyperlipidemia, diabetes, CKD stage 3 or higher (glomerular filtration rate < 60 mL/min) and CAD (HR: 1.097; CI: 1.014–1.186; p  = 0.020); and 3) Model 2 plus CVA (HR: 1.094; CI: 1.011–1.182; p  = 0.024). Sensitivity analysis demonstrated that the association between AVC and new diagnosis of CI remained significant upon exclusion of severe AVC (HR: 1.100 [1.013–1.194 ]; p  = 0.023). Subgroup analysis demonstrated that this association remained significant when including education in the multivariate analysis (HR: 1.127 [1.030–1.233 ]; p  = 0.009). Conclusion: This is the first study demonstrating that among mostly male individuals who underwent LCSCT, quantified aortic valve calcification is associated with new diagnosis of CI. Show more

Keywords: Atherosclerosis, calcific aortic valve disease, computed tomography, dementia

DOI: 10.3233/ADR-200253

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 337-343, 2021

Authors: Ávila-Villanueva, Marina | Gómez-Ramírez, Jaime | Ávila, Jesús | Fernández-Blázquez, Miguel A.

Article Type: Review Article

Abstract: In recent years there has been increasing interest in examining the role of empathic abilities in Alzheimer’s disease (AD). Empathy, the ability to understand and share another person’s feelings, implies the existence of emotional and cognitive processes and is a pivotal aspect for success in social interactions. In turn, self-empathy is oriented to one’s thoughts and feelings. Decline of empathy and self-empathy can occur during the AD continuum and can be linked to different neuroanatomical pathways in which the cingulate cortex may play a crucial role. Here, we will summarize the involvement of empathic abilities through the AD continuum and …further discuss the potential neurocognitive mechanisms that contribute to decline of empathy and self-empathy in AD. Show more

Keywords: Aging, Alzheimer’s disease, anosognosia, cingulate cortex, empathy

DOI: 10.3233/ADR-200282

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 345-352, 2021

Authors: Emblad, Shayla Y.M. | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: Non-pharmacological therapies have been shown to be effective in managing challenging behavior in people with dementia. However, the efficacy of art therapy has yet to be determined. Objective: In the present systematic review, we evaluate the efficacy of art therapy as a non-pharmacological intervention for dementia and examine whether art therapy improves wellbeing and quality of life while decreasing biological and psychological symptoms of dementia (BPSD). Methods: Research undertaken between 2015 and 2020 was examined and a total of seventeen studies met the specified search criteria, with 853 participants (657 people with dementia, 180 formal …and informal carers, and 16 volunteers) involved. Results: We identified four outcome domains: wellbeing, quality of life, BPSD, and cognitive function. One or more significant outcomes as having an impact on the efficacy of the intervention were reported in 88% (15/17) of the studies, whereas 17% (3/17) demonstrated significant outcomes across quality of life, wellbeing, and BPSD. Conclusion: People with dementia benefit from art therapy. These interventions when incorporating elements of being ‘in the moment’ increase opportunities for communication between people with dementia and their caregiver(s) and facilitate person-centered therapeutic activities. Show more

Keywords: Art therapy, behavioral and psychological symptoms of dementia, cognition, dementia, non-pharmacological therapy, systematic review

DOI: 10.3233/ADR-201002

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 353-364, 2021

Authors: Gallucci, Maurizio | Mazzarolo, Anna Paola | Focella, Lucia | Berlin, Elisa | Fiore, Vittorio | Di Paola, Francesco | Bendini, Matteo | Zanusso, Gianluigi | Fenoglio, Chiara | Galimberti, Daniela | Bonanni, Laura

Article Type: Research Article

Abstract: Background: A 57-year-old right-handed man was admitted to the Treviso Memory Clinic due to the presence of memory forgetfulness, repetition of the same questions, episodes of confusion, initial difficulties in performing complex tasks and easy distraction over the past two years, as well as recurrent and never-happened-before car accidents. Objective: We report a peculiar case of an early onset Alzheimer’s disease (AD) with an unusual symptomatology, apparently not fitting in any of the categorized atypical forms of AD nor being representative of a typical amnestic AD. Methods: The patient underwent a neuropsychological, structural, and metabolic cerebral …evaluation by MRI and 18 F-FDG PET, together with the search for cerebral amyloid (amyloid PET), a genetic testing for dementia related genes and the dosage of CSF protein biomarkers of neurodegenerative conditions. Results: We observed a convergence of predominant frontal (dysexecutive, verbal disinhibition) and posterior (visuospatial) features of cognitive impairment. Structural MRI sequences showed subarachnoid spaces of the vault enlarged in the fronto-parietal region with anterior and posterior cortical atrophy. The hippocampus appeared preserved. The 18 F-FDG PET scans showed hypometabolism in the prefrontal, lateral temporal, posterior parietal, and occipital regions bilaterally. The 18 F-Flutemetamol scan showed a diffused uptake of the amyloid tracer at the cerebral cortex. CSF biomarkers were compatible with Alzheimer’s disease (AD). Conclusion: This case report presented with clinical phenotypic aspects atypical of AD, both frontal and posterior, never described as concomitant in the most accredited criteria for atypical AD, and appeared therefore more atypical than each of the atypical AD phenotypes already reported. Show more

Keywords: Alzheimer’s disease, frontal variant, magnetic resonance, neurodegenerative diseases, PET scan, posterior cortical atrophy, TREDEM

DOI: 10.3233/ADR-210009

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 365-374, 2021

Authors: Fereshetian, Shaunt | Agranat, Joshua S. | Siegel, Nicole | Ness, Steven | Stein, Thor D. | Subramanian, Manju L.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most common causes of dementia worldwide. Although no formal curative therapy exists for the treatment of AD, considerable research has been performed to identify biomarkers for early detection of this disease, and thus improved subsequent management. Given that the eye can be examined and imaged non-invasively with relative ease, it has emerged as an exciting area of research for evidence of biomarkers and to aid in the early diagnosis of AD. This review explores the current understanding of both protein and retinal imaging biomarkers in the eye. Herein, primary findings in the literature …regarding AD biomarkers associated with the lens, retina, and other ocular structures are reviewed. Show more

Keywords: Alzheimer’s disease, amyloid, cataract, crystalline, eye, lens, retina, vitreous

DOI: 10.3233/ADR-210283

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 375-387, 2021

Authors: Deutsch, Curtis K. | Patnaik, Pooja P. | Greco, Frank A.

Article Type: Short Communication

Abstract: We sought to determine whether skin conductance level could warn of outbursts of combative behavior in dementia patients by using a wristband device. Two outbursts were captured and are reported here. Although no physiologic parameter measured by the wristband gave advance warning, there is a common pattern of parasympathetic withdrawal (increased heart rate) followed approximately 30 seconds later by sympathetic activation (increased skin conductance). In the literature, a similar pattern occurs in psychogenic non-epileptic seizures. We hypothesize that similar autonomic responses reflect similarities in pathophysiology and that physical activity may partially account for the time course of skin conductance.

Keywords: Autonomic nervous system, dementia, galvanic skin response, heart rate, non-epileptic seizures

DOI: 10.3233/ADR-210007

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 389-394, 2021

Authors: Barthelson, Karissa | Pederson, Stephen Martin | Newman, Morgan | Jiang, Haowei | Lardelli, Michael

Article Type: Research Article

Abstract: Background: Mutations in PRESENILIN 2 (PSEN2 ) cause early onset familial Alzheimer’s disease (EOfAD) but their mode of action remains elusive. One consistent observation for all PRESENILIN gene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon—the “reading frame preservation rule”. Mutations that do not obey this rule do not cause the disease. The reasons for this are debated. Objective: To predict cellular functions affected by heterozygosity for a frameshift, or a reading frame-preserving mutation in zebrafish psen2 using bioinformatic techniques. Methods: A …frameshift mutation (psen2N 140fs ) and a reading frame-preserving (in-frame) mutation (psen2T 141 _ L 142delinsMISLISV ) were previously isolated during genome editing directed at the N140 codon of zebrafish psen2 (equivalent to N141 of human PSEN2 ). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analyzed. Results: The in-frame mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long-term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signaling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions. Conclusion: A frameshift and an in-frame mutation at the same position in zebrafish psen2 cause discrete effects. Changes in oxidative phosphorylation, long-term potentiation and the cell cycle may promote EOfAD pathogenesis in humans. Show more

Keywords: Alzheimer’s disease, mitochondria, PSEN2, RNA-seq, zebrafish

DOI: 10.3233/ADR-200279

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 395-404, 2021