Journal of Alzheimer's Disease - Volume 92, issue 1

Authors: Chen, Shanquan | Cardinal, Rudolf N. | Auckland, Kathryn | Gräf, Stefan | O’Brien, John T. | Underwood, Benjamin R.

Article Type: Research Article

Abstract: Background: Persisting symptoms and increased mortality after SARS–CoV–2 infection has been described in COVID-19 survivors. Objective: We examined longer-term mortality in patients with dementia and SARS-CoV-2 infection. Methods: A retrospective matched case-control study of 165 patients with dementia who survived an acute hospital admission with COVID-19 infection, and 1325 patients with dementia who survived a hospital admission but without SARS-CoV-2 infection. Potential risk factors investigated included socio-demographic factors, clinical features, and results of investigations. Data were fitted using a Cox proportional hazard model. Results: Compared to patients with dementia but without SARS-CoV-2 infection, people …with dementia and SARS-CoV-2 infection had a 4.4-fold risk of death (adjusted hazard ratio [aHR] = 4.44, 95% confidence interval [CI] 3.13–6.30) even beyond the acute phase of infection. This excess mortality could be seen up to 125 days after initial recovery but was not elevated beyond this time. Risk factors for COVID-19-associated mortality included prescription of antipsychotics (aHR = 3.06, 95% CI 1.40–6.69) and benzodiazepines (aHR = 3.00, 95% CI 1.28–7.03). Abnormalities on investigation associated with increased mortality included high white cell count (aHR = 1.21, 95% CI 1.04–1.39), higher absolute neutrophil count (aHR = 1.28, 95% CI 1.12–1.46), higher C-reactive protein (aHR = 1.01, 95% CI 1.00–1.02), higher serum sodium (aHR = 1.09, 95% CI 1.01–1.19), and higher ionized calcium (aHR = 1.03, 95% CI 1.00–1.06). The post-acute COVID mortality could be modeled for the first 120 days after recovery with a balanced accuracy of 87.2%. Conclusion: We found an increased mortality in patients with dementia beyond the acute phase of illness. We identified several investigation results associated with increased mortality, and increased mortality in patients prescribed antipsychotics or benzodiazepines. Show more

Keywords: Dementia, longer-term mortality, post-acute COVID-19, SARS-CoV-2

DOI: 10.3233/JAD-221093

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 295-309, 2023

Authors: Wu, Chao | Ma, Ya-Hui | Hu, Hao | Zhao, Bing | Tan, Lan

Article Type: Research Article

Abstract: Background Until recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimer’s disease (AD), but they have not been fully explored in CSVD. Objective To determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression. Methods A total of 426 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements …of CSF sTREM2 and AD pathology (Aβ1-42 , P-tau181P ). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology. Results Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR = 1.28 [95% CI, 1.01–1.62]) and CMBs counts (OR = 1.32 [95% CI, 1.03–1.68]). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR = 1.44 [95% CI, 1.05–1.98]). Participants with AD pathology (Aβ1-42 and P-tau181P ) showed a stronger association between CSF sTREM2 and CSVD progression. Conclusion This longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebral small vessel disease, microglia, neuroinflammation, sTREM2

DOI: 10.3233/JAD-220731

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 311-322, 2023

Authors: Newton, Princess | Tchounguen, Jonathan | Pettigrew, Corinne | Lim, Chantelle | Lin, Zixuan | Lu, Hanzhang | Moghekar, Abhay | Albert, Marilyn | Soldan, Anja

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders. Objective: We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD. Methods: WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aβ 40 , Aβ 42 , Aβ 42 /Aβ 40 ratio, phosphorylated tau-181 [p-tau181 ], and total tau …[t-tau]) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)). Results: Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181 , t-tau, and Aβ 40 ), particularly among APOE ɛ 4 carriers (independent of Aβ 42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aβ 42 /Aβ 40 . In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (∼<65 versus 65+ years), independent of Aβ 42 /Aβ 40 and p-tau181 . Conclusion: These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aβ 42 /Aβ 40 ) in parietal WMHs. Show more

Keywords: Alzheimer’s disease, amyloid, APOE, cerebrospinal fluid, magnetic resonance imaging, tau, vascular risk, white matter hyperintensity volumes

DOI: 10.3233/JAD-220846

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 323-339, 2023

Authors: Voss, Tiffini | Kost, James | Mercer, Swati Pal | Furtek, Christine | Randolph, Christopher | Lines, Christopher | Egan, Michael F. | Cummings, Jeffrey L.

Article Type: Research Article

Abstract: Background: Delay of progression from prodromal Alzheimer’s disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized. Objective: To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR). Methods: We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) …the participant’s CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression. Results: 581/1,451 (40%) participants had changes triggering adjudication and most (83%) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria. Conclusion: A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful. Show more

Keywords: Alzheimer’s disease, APECS, Clinical Dementia Rating, diagnosis, mild cognitive impairment, randomized controlled trial

DOI: 10.3233/JAD-220836

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 341-348, 2023

Authors: Toppala, Sini | Ekblad, Laura L. | Viitanen, Matti | Rinne, Juha O. | Jula, Antti

Article Type: Research Article

Abstract: Background: Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimer’s disease. Objective: To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years. Methods: This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In …total, 961 45–74-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001–2002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOE &z.epsi; 4 genotype, vascular risk factors including diabetes, and depressive symptoms. Results: A lower early insulin response to glucose load predicted lower performance (β : 0.21, p  = 0.03) and greater decline (β : 0.19, p  = 0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p -values≥0.13). Conclusion: Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women. Show more

Keywords: Cognitive decline, early insulin response, episodic memory, insulin secretion, insulin resistance, oral glucose tolerance test

DOI: 10.3233/JAD-220894

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 349-359, 2023

Authors: Yoshida, Madoka | Uemura, Takeshi | Mizoi, Mutsumi | Waragai, Masaaki | Sakamoto, Akihiko | Terui, Yusuke | Kashiwagi, Keiko | Igarashi, Kazuei

Article Type: Research Article

Abstract: Background: Dementia, including Alzheimer’s disease (AD), is one of the serious diseases at advanced age, and its early detection is important for maintaining quality of life (QOL). Objective: In this study, we sought novel biomarkers for dementia in urine. Methods: Samples of urine were collected from 57 control subjects without dementia, 62 mild cognitive impairment (MCI) patients, and 42 AD patients. Mini-Mental State Examination (MMSE) was evaluated when subjects were examined by medical doctors. Urinary amino acid (lysine)-conjugated acrolein (AC-Acro) was measured using N ɛ -(3-formyl-3, 4-dehydropiperidine) lysine (FDP-Lys) ELISA kit, and taurine content was …measured using a taurine assay kit. Values were normalized by creatinine content which was measured with the colorimetric assay kit. Results: We found that urinary amino acid (lysine)-conjugated acrolein (AC-Acro) and taurine negatively correlated with MMSE score and are significantly lower in dementia patients compared to the normal subjects. When AC-Acro and taurine were evaluated together with age using an artificial neural network model, median relative risk values for subjects with AD, subjects with mild cognitive impairment, and control subjects were 0.96, 0.53, and 0.06, respectively. Conclusion: Since urine is relatively easy to collect, our findings provide a novel biomarker for dementia without invasiveness. Show more

Keywords: Alzheimer’s disease, amino acid-conjugated acrolein (AC-Acro), Mini-Mental State Examination, taurine, urinary biomarkers

DOI: 10.3233/JAD-220912

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 361-369, 2023

Authors: Highet, Blake | Wiseman, James A. | Mein, Hannah | Parker, Remai | Ryan, Brigid | Turner, Clinton P. | Jing, Yu | Singh-Bains, Malvindar K. | Liu, Ping | Dragunow, Mike | Faull, Richard L.M. | Murray, Helen C. | Curtis, Maurice A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a substantial reduction of neuroplasticity. Our previous work demonstrated that neurons involved in memory function may lose plasticity because of decreased protein levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the entorhinal cortex (EC) of the human AD brain, but the cause of this decrease is unclear. Objective: To investigate genes involved in PSA-NCAM regulation which may underlie its decrease in the AD EC. Methods: We subjected neurologically normal and AD human EC sections to multiplexed fluorescent in situ …hybridization and immunohistochemistry to investigate genes involved in PSA-NCAM regulation. Gene expression changes were sought to be validated in both human tissue and a mouse model of AD. Results: In the AD EC, a cell population expressing a high level of CALB2 mRNA and a cell population expressing a high level of PST mRNA were both decreased. CALB2 mRNA and protein were not decreased globally, indicating that the decrease in CALB2 was specific to a sub-population of cells. A significant decrease in PST mRNA expression was observed with single-plex in situ hybridization in middle temporal gyrus tissue microarray cores from AD patients, which negatively correlated with tau pathology, hinting at global loss in PST expression across the AD brain. No significant differences in PSA-NCAM or PST protein expression were observed in the MAPT P301S mouse brain at 9 months of age. Conclusion: We conclude that PSA-NCAM dysregulation may cause subsequent loss of structural plasticity in AD, and this may result from a loss of PST mRNA expression. Due PSTs involvement in structural plasticity, intervention for AD may be possible by targeting this disrupted plasticity pathway. Show more

Keywords: Alzheimer’s disease, calretinin, entorhinal cortex, polysialyltransferase, PSA-NCAM

DOI: 10.3233/JAD-220986

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 371-390, 2023