Journal of Alzheimer's Disease Reports - Volume 7, issue 1

Authors: Sanders, Owen Davis

Article Type: Review Article

Abstract: Oxidative stress, inflammation, and amyloid-β are Alzheimer’s disease (AD) hallmarks that cause each other and other AD hallmarks. Most amyloid-β-lowering, antioxidant, anti-inflammatory, and antimicrobial AD clinical trials failed; none stopped or reversed AD. Although signs suggest an infectious etiology, no pathogen accumulated consistently in AD patients. Neuropathology, neuronal cell culture, rodent, genome-wide association, epidemiological, biomarker, and clinical studies, plus analysis using Hill causality criteria and revised Koch’s postulates, indicate that the virus-like oxidative damage-associated molecular-pattern (DAMP) cytosolic and cell-free nucleic acids accumulated in AD patients’ brains likely drive neuroinflammation, synaptotoxicity, and neurotoxicity. Cytosolic oxidatively-damaged mitochondrial DNA accumulated outside mitochondria dose-dependently …in preclinical AD and AD patients’ hippocampal neurons, and in AD patients’ neocortical neurons but not cerebellar neurons or glia. In oxidatively-stressed neural cells and rodents’ brains, cytosolic oxidatively-damaged mitochondrial DNA accumulated and increased antiviral and inflammatory proteins, including cleaved caspase-1, interleukin-1β, and interferon-β. Cytosolic double-stranded RNA and DNA are DAMPs that induce antiviral interferons and/or inflammatory proteins by oligomerizing with various innate-immune pattern-recognition receptors, e.g., cyclic GMP-AMP synthase and the nucleotide-binding-oligomerization-domain-like-receptor-pyrin-domain-containing-3 inflammasome. In oxidatively-stressed neural cells, cytosolic oxidatively-damaged mitochondrial DNA caused synaptotoxicity and neurotoxicity. Depleting mitochondrial DNA prevented these effects. Additionally, cell-free nucleic acids accumulated in AD patients’ blood, extracellular vesicles, and senile plaques. Injecting cell-free nucleic acids bound to albumin oligomers into wild-type mice’s hippocampi triggered antiviral interferon-β secretion; interferon-β injection caused synapse degeneration. Deoxyribonuclease-I treatment appeared to improve a severe-AD patient’s Mini-Mental Status Exam by 15 points. Preclinical and clinical studies of deoxyribonuclease-I and a ribonuclease for AD should be prioritized. Show more

Keywords: Cell-free nucleic acids, deoxyribonuclease I, mitochondrial DNA, neuroinflammatory diseases, oxidative stress, ribonucleases, wounds and injuries

DOI: 10.3233/ADR-220047

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1-19, 2023

Authors: Volloch, Vladimir | Rits-Volloch, Sophia

Article Type: Research Article

Abstract: Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the ACH. In the former, in contrast to the latter, Alzheimer’s disease (AD) is driven by intraneuronal amyloid-β (i Aβ) and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived i Aβ activates, upon reaching a critical threshold, the AβPP-independent i Aβ-generating pathway, triggering a devastating second stage resulting in neuronal death. While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intra- rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only i …Aβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD. Whereas the notion of differentially derived i Aβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived i Aβ-activated self-sustaining mechanism producing a yet undefined deleterious “substance X” (s X) which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the i Aβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD. Show more

Keywords: Age-related cognitive decline, Alzheimer’s disease, Amyloid Cascade Hypothesis 2.0, amyloid-β protein precursor, BACE1 and BACE2 activators, intraneuronal amyloid-β

DOI: 10.3233/ADR-220079

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 21-35, 2023

Authors: Rosenbloom, Michael H. | Barclay, Terry

Article Type: Short Communication

Abstract: Prodromal Alzheimer’s disease (AD) is a neurodegenerative condition typically progressing to dementia within 3 years. We describe a case of a mild cognitive impairment (MCI) patient with biomarker evidence for amyloidosis, tau, and neurodegeneration who had minimal changes in clinical phenotype during an 11-year period. AD biomarkers were obtained with cerebrospinal fluid analysis and amyloid PET imaging, both of which supported a biological diagnosis of AD. However, the patient’s neuropsychological profile remained stable over 11 years except for mild memory-retrieval changes. This case provides evidence that MCI with supportive AD biomarkers may have an atypically minimal progression.

Keywords: Biomarkers, cognitive reserve, longitudinal progression, prodromal AD

DOI: 10.3233/ADR-220065

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 37-40, 2023

Authors: Zingel, Rebecca | Jacob, Louis | Smith, Lee | Konrad, Marcel | Kostev, Karel

Article Type: Research Article

Abstract: Background: To date, no large study has examined the relationship between psoriasis and dementia in Germany. Objective: The aim of this study was to assess the association between psoriasis and the risk of all-cause dementia in patients followed in general practices in Germany. Methods: This retrospective cohort study is based on longitudinal data from the IQVIATM Disease Analyzer database and included patients with an initial diagnosis of psoriasis between January 1995 and December 2014 in 1,173 general practices in Germany. Patients without psoriasis were matched individually (1:1) to psoriasis patients using propensity scores. The main …outcome of the study was the cumulative incidence of dementia diagnoses within up to 15 years of the index date. Univariate Cox proportional regression models were used to assess the relationship between psoriasis or psoriatic arthritis and dementia. Results: The present study included 10,583 patients with a diagnosis of psoriasis and 10,583 controls without psoriasis. After 15 years of follow-up, 22.0% of the psoriasis patients and 19.1% (p  < 0.001) of the non-psoriasis patients developed dementia. The incidence rate of dementia in 1,000 person-years was 15.0 in psoriasis patients and 11.9 in the non-psoriasis cohort. Psoriasis was significantly associated with a dementia risk (HR: 1.24; 95% CI: (1.14–1.35); p  < 0.001). The association was stronger in patients with PsA (HR: 1.35; 95% CI: (0.98–1.86)) but this was not significant (p  = 0.070). Conclusion: The present study found a positive association between psoriasis and all-cause dementia in patients in general practices in Germany. Show more

Keywords: Dementia, Germany, psoriasis, psoriatic arthritis, retrospective cohort study

DOI: 10.3233/ADR-220060

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 41-49, 2023

Authors: Lin, Ni-Hsuan | Goh, Angela | Lin, Shyh-Horng | Chuang, Kai-An | Chang, Chih-Hsuan | Li, Ming-Han | Lu, Chu-Hsun | Chen, Wen-Yin | Wei, Pei-Hsuan | Pan, I-Hong | Perng, Ming-Der | Wen, Shu-Fang

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multifactorial disorder characterized by cognitive decline. Current available therapeutics for AD have limited clinical benefit. Therefore, preventive therapies for interrupting the development of AD are critically needed. Molecules targeting multifunction to interact with various pathlogical components have been considered to improve the therapeutic efficiency of AD. In particular, herbal medicines with multiplicity of actions produce cognitive benefits on AD. Bugu-M is a multi-herbal extract composed of Ganoderma lucidum (Antler form), Nelumbo nucifera Gaertn., Ziziphus jujuba Mill., and Dimocarpus longan, with the ability of its various components to confer resilience to …cognitive deficits. Objective: To evaluate the potential of Bugu-M on amyloid-β (Aβ) toxicity and its in vitro mechanisms and on in vivo cognitive function. Methods: We illustrated the effect of Bugu-M on Aβ25–35 -evoked toxicity as well as its possible mechanisms to diminish the pathogenesis of AD in rat cortical neurons. For cognitive function studies, 2-month-old female 3×Tg-AD mice were administered 400 mg/kg Bugu-M for 30 days. Behavioral tests were performed to assess the efficacy of Bugu-M on cognitive impairment. Results: In primary cortical neuronal cultures, Bugu-M mitigated Aβ-evoked toxicity by reducing cytoskeletal aberrations and axonal disruption, restoring presynaptic and postsynaptic protein expression, suppressing mitochondrial damage and apoptotic signaling, and reserving neurogenic and neurotrophic factors. Importantly, 30-day administration of Bugu-M effectively prevented development of cognitive impairment in 3-month-old female 3×Tg-AD mice. Conclusion: Bugu-M might be beneficial in delaying the progression of AD, and thus warrants consideration for its preventive potential for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, axon, cognition, dementia, herbal, mild cognitive impairment, natural product, prevention, synapse

DOI: 10.3233/ADR-220056

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 51-76, 2023

Authors: Naeser, Margaret A. | Martin, Paula I. | Ho, Michael D. | Krengel, Maxine H. | Bogdanova, Yelena | Knight, Jeffrey A. | Hamblin, Michael R. | Fedoruk, Andrea E. | Poole, Luke G. | Cheng, ChiaHsin | Koo, BangBon

Article Type: Research Article

Abstract: Background: Chronic traumatic encephalopathy, diagnosed postmortem (hyperphosphorylated tau), is preceded by traumatic encephalopathy syndrome with worsening cognition and behavior/mood disturbances, over years. Transcranial photobiomodulation (tPBM) may promote improvements by increasing ATP in compromised/stressed cells and increasing local blood, lymphatic vessel vasodilation. Objective: Aim 1: Examine cognition, behavior/mood changes Post-tPBM. Aim 2: MRI changes - resting-state functional-connectivity MRI: salience, central executive, default mode networks (SN, CEN, DMN); magnetic resonance spectroscopy, cingulate cortex. Methods: Four ex-players with traumatic encephalopathy syndrome/possible chronic traumatic encephalopathy, playing 11– 16 years, received In-office, red/near-infrared tPBM to scalp, 3x/week for 6 weeks. Two …had cavum septum pellucidum. Results: The three younger cases (ages 55, 57, 65) improved 2 SD (p  < 0.05) on three to six neuropsychological tests/subtests at 1 week or 1 month Post-tPBM, compared to Pre-Treatment, while the older case (age 74) improved by 1.5 SD on three tests. There was significant improvement at 1 month on post-traumatic stress disorder (PTSD), depression, pain, and sleep. One case discontinued narcotic pain medications and had reduced tinnitus. The possible placebo effect is unknown. At 2 months Post-tPBM, two cases regressed. Then, home tPBM was applied to only cortical nodes, DMN (12 weeks); again, significant improvements were seen. Significant correlations for increased SN functional connectivity (FC) over time, with executive function, attention, PTSD, pain, and sleep; and CEN FC, with verbal learning/memory, depression. Increased n-acetyl-aspartate (NAA) (oxygen consumption, mitochondria) was present in anterior cingulate cortex (ACC), parallel to less pain and PTSD. Conclusion: After tPBM, these ex-football players improved. Significant correlations of increased SN FC and CEN FC with specific cognitive tests and behavior/mood ratings, plus increased NAA in ACC support beneficial effects from tPBM. Show more

Keywords: Chronic traumatic encephalopathy, dementia, depression, neurodegenerative, pain, photobiomodulation, post-traumatic stress disorder, sleep, traumatic brain injury, traumatic encephalopathy syndrome

DOI: 10.3233/ADR-220022

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 77-105, 2023

Authors: Okahara, Kazunori | Ohsawa, Makoto | Haruta-Tsukamoto, Ayaka | Miyoshi, Ryoei | Funahashi, Hideki | Fukutani, Yasuhiro | Makita, Setsuko | Matsuo, Hisae | Ishida, Yasushi

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and dementia have increasingly been conceived of as “complex diseases of aging”, determined by multiple, simultaneous, interacting pathophysiological processes. The condition known as frailty is a phenotype of aging and its comprehensive pathophysiology is thought to be closely related to the incidence of mild cognitive impairment (MCI) and the exacerbation of dementia. Objective: This study aimed to investigate the effect of the multicomponent drug, ninjin’yoeito (NYT), on frailty in MCI and mild AD patients. Methods: This study was an open-label trial. A total of 14 patients, including 9 with MCI and 5 …with mild AD, were enrolled. Among them, 11 were frail while 3 were prefrail. NYT (6–9 g/day) was administered orally for 24 weeks, and assessments were carried out at baseline (week 0), and at 4, 8, 16, and 24 weeks. Results: In the primary endpoint, significant early improvements were observed in the anorexia scores according to the Neuropsychiatric Inventory after four weeks of treatment with NYT. The Cardiovascular Health Study score was significantly improved, and no frailty was observed after 24 weeks. The fatigue visual analog scale scores also significantly improved. The Clinical Dementia Rating and the Montreal Cognitive Assessment scores remained at baseline levels during the NYT treatment period. Conclusion: The results suggest that NYT may be effective in the treatment of frailty, especially for anorexia and fatigue, in both MCI and mild AD patients, which would be beneficial for the prognosis of dementia. Show more

Keywords: Alzheimer’s disease, anorexia, dementia, fatigue, frailty, Kampo, mild cognitive impairment, Ninjin’yoeito

DOI: 10.3233/ADR-220074

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 107-117, 2023

Authors: Dubey, Souvik | Das, Shambaditya | Ghosh, Ritwik | Dubey, Mahua Jana | Chakraborty, Arka Prava | Roy, Dipayan | Das, Gautam | Dutta, Ajitava | Santra, Arindam | Sengupta, Samya | Benito-León, Juliàn

Article Type: Research Article

Abstract: Background: Cognitive postscripts of COVID-19, codenamed as ‘cognitive COVID’ or ‘brain fog,’ characterized by multidomain cognitive impairments, are now being reckoned as the most devastating sequelae of COVID-19. However, the impact on the already demented brain has not been studied. Objective: We aimed to assess the cognitive functioning and neuroimaging following SARS-CoV-2 infection in patients with pre-existing dementia. Methods: Fourteen COVID-19 survivors with pre-existing dementia (four with Alzheimer’s disease, five with vascular dementia, three with Parkinson’s disease dementia, and two with the behavioral variant of frontotemporal dementia) were recruited. All these patients had detailed cognitive and …neuroimaging evaluations within three months before suffering from COVID-19 and one year later. Results: Of the 14 patients, ten required hospitalization. All developed or increased white matter hyperintensities that mimicked multiple sclerosis and small vessel disease. There was a significant increase in fatigue (p  = 0.001) and depression (p  = 0.016) scores following COVID-19. The mean Frontal Assessment Battery (p < 0.001) and Addenbrooke’s Cognitive Examination (p  = 0.001) scores also significantly worsened. Conclusion: The rapid progression of dementia, the addition of further impairments/deterioration of cognitive abilities, and the increase or new appearance of white matter lesion burden suggest that previously compromised brains have little defense to withstand a new insult (i.e., ‘second hit’ like infection/dysregulated immune response, and inflammation). ‘Brain fog’ is an ambiguous terminology without specific attribution to the spectrum of post-COVID-19 cognitive sequelae. We propose a new codename, i.e. ‘FADE-IN MEMORY’ (i.e., Fatigue, decreased Fluency, Attention deficit, Depression, Executive dysfunction, slowed INformation processing speed, and subcortical MEMORY impairment). Show more

Keywords: Cognitive impairment, COVID-19, dementia, post-COVID-19

DOI: 10.3233/ADR-220090

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 119-128, 2023

Authors: Leccese, Deborah | Cornacchini, Sara | Nacmias, Benedetta | Sorbi, Sandro | Bessi, Valentina

Article Type: Short Communication

Abstract: Recent studies have speculated a link between Creutzfeldt-Jakob disease (CJD) and COVID-19, following the description of CJD cases after COVID-19 infection. We report the case of a 71-year-old female patient who developed neuropsychiatric and neurological symptoms after COVID-19 infection and was later diagnosed with CJD. Cerebrospinal fluid (CSF) total tau levels were slightly increased. She resulted prion protein gene (PRNP) M129V heterozygous. We aim to emphasize the role of the polymorphism at codon 129 of PRNP gene on the clinical phenotype and duration of CJD, and the CSF total tau levels that likely correlate with the rate of disease progression.

Keywords: Cerebrospinal fluid total tau, COVID-19 infection, Creutzfeldt-Jakob disease, prion disease, SARS-CoV-2

DOI: 10.3233/ADR-220095

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 129-134, 2023

Authors: Mozersky, Jessica | Solomon, Erin D. | Baldwin, Kari | Wroblewski, Matthew | Parsons, Meredith | Goodman, Melody | DuBois, James M.

Article Type: Research Article

Abstract: Background: Older adults are at increased risk of cognitive impairments including Alzheimer’s disease dementia. Legally authorized representatives (LARs) can provide informed consent when a participant is no longer able to, but little is known about barriers to incorporating them in research. Objective: Explore reasons for not asking and documenting participant decisions to appoint LARs among researchers conducting clinical intervention trials studying older adults or individuals with cognitive impairments. Methods: Mixed method design consisting of a survey (N  = 1,284) and qualitative interviews (N  = 40) regarding barriers to incorporating LARs. Participants were principal investigators and clinical research coordinators. …Results: 37% (N  = 469) had not asked and documented participant decisions about appointing LARs in the prior year. They had significantly lower confidence in resources available to incorporate LARs and lower positive attitudes compared to their counterparts who had done so. The majority (83%) had no trials studying individuals with cognitive impairments and reported LARs were not applicable. A minority (17%) had at least one trial studying individuals with cognitive impairments and reported being unaware of LARs. Qualitative findings indicate discomfort broaching a sensitive topic especially with individuals who are not yet impaired. Conclusion: Resources and education to increase awareness and knowledge of LARs are needed. Researchers studying older adults should, at minimum, have the knowledge and resources to incorporate LARs when necessary. Stigma and discomfort discussing LARs will need to be overcome, as early proactive discussions before a participant loses decisional capacity could enhance participant autonomy and facilitate recruitment and retention of older adults to research. Show more

Keywords: Clinical research, cognitive impairments, informed consent, legally authorized representatives, older adults, proxy, research ethics, surrogate

DOI: 10.3233/ADR-220103

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 135-149, 2023