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

Authors: O’Caoimh, Rónán | Molloy, D. William

Article Type: Research Article

Abstract: Background: Short cognitive screening instruments (CSI) are required to identify cognitive impairment in busy outpatient clinics. While the Six Item Cognitive Impairment Test (6CIT) is commonly used, its accuracy in those with mild cognitive impairment (MCI) and subjective cognitive decline (SCD) and against more widely-used CSIs is less well established. Objective: To examine the diagnostic accuracy of the 6CIT against the Montreal Cognitive Assessment (MoCA) and Quick Mild Cognitive Impairment (Qmci ) screen across the cognitive spectrum in a memory clinic population. Methods: In total, 142 paired assessments were available (21 with SCD, 32 MCI, and …89 with dementia). Consecutive patients underwent a comprehensive assessment and were screened using the 6CIT, Qmci , and MoCA. Accuracy was determined from the area under receiver operating characteristic curves (AUC). Results: The median age of patients was 76 (±11) years; 68% were female. The median 6CIT score was 10/28 (±14). The 6CIT was strongly, negatively, and statistically significantly correlated with the Qmc i (r  = –0.84) and MoCA (r  = –0.86). The 6CIT had good accuracy for separating cognitive impairment (MCI or dementia) from SCD, (AUC:0.88; 0.82–0.94), similar to the MoCA (AUC:0.92; 0.87–0.97, p  = 0.308), but statistically lower than the Qmci (AUC:0.96; 0.94–0.99, p  = 0.01). The 6CIT was faster to administer, median time 2.05 minutes versus 4.38 and 9.5 for the Qmci and MoCA, respectively. Conclusion: While the Qmci was more accurate than the 6CIT, the shorter administration time of the 6CIT, suggests it may be useful when assessing or monitoring cognitive impairment in busy memory clinics, though larger samples are required to evaluate. Show more

Keywords: Cognitive screening, diagnostic accuracy, memory clinic, Six Item Cognitive Impairment Test, Montreal Cognitive Assessment, Quick Mild Cognitive Impairment screen

DOI: 10.3233/ADR220117

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 299-306, 2023

Authors: Nakanishi, Miharu | Ogawa, Asao | Sakai, Mai | Yoshii, Hatsumi | Miyashita, Mitsuhiro | Yamasaki, Syudo | Nishida, Atsushi

Article Type: Short Communication

Abstract: This study examined the longitudinal association between dementia, activity participation, the coronavirus disease 2019 pandemic period, and 1-year mental health changes. We obtained data from the National Health and Aging Trends Study in the United States. We included 4,548 older adult participants of two or more survey rounds between 2018 and 2021. We identified baseline dementia status, and assessed depressive symptoms and anxiety at baseline and follow-up. Dementia and poor activity participation were independently associated with an increased prevalence of depressive symptoms and anxiety. Dementia care and support should address emotional and social needs under continued public health restrictions.

Keywords: Activity participation, Alzheimer’s disease, anxiety, COVID-19, dementia, depression

DOI: 10.3233/ADR-230019

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 307-315, 2023

Authors: Morrison-Koechl, Jill | Fearon, Danielle O. | Fernandes, Myra A. | Tyas, Suzanne L.

Article Type: Research Article

Abstract: Background: Risk factors for dementia, such as Alzheimer’s disease, are complex and span a lifetime. Exploring novel factors, such as characteristics of writing, may provide insight into dementia risk. Objective: To investigate the association between emotional expressivity and risk of dementia in the context of a previously identified risk factor, written language skills. Methods: The Nun Study recruited 678 religious sisters aged 75 + years. Of these, 149 U.S.-born participants had archived autobiographies handwritten at a mean age of 22 years. The autobiographies were scored for frequency of emotion word usage and language skills (e.g., idea density). The …association of emotional expressivity and a four-level composite variable (combining high/low emotional expressivity and high/low idea density) with dementia was assessed using logistic regression models adjusted for age, education, and apolipoprotein E. Results: Within the composite variable, odds of dementia increased incrementally, with opposing effects of emotional expressivity across the two idea density levels. Compared to the referent category (low emotional expressivity/high idea density), the risk of dementia increased in those with high emotional expressivity/high idea density (OR = 2.73, 95% CI = 1.05–7.08), while those with low emotional expressivity/low idea density had the highest risk (OR = 18.58, 95% CI = 4.01–86.09). Conclusion: Dementia risk is better captured by inclusion of multiple measures relating to characteristics of writing. Emotional expressivity may be protective when individuals are at increased risk due to poor written language skills (i.e., low idea density), but detrimental when not at risk (i.e., high idea density). Our findings indicate that emotional expressivity is a contextually-dependent novel risk factor for dementia. Show more

Keywords: Alzheimer’s disease, cognition, dementia, emotions, language, life course perspective, logistic models, longitudinal studies, risk factors

DOI: 10.3233/ADR-220106

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 317-326, 2023

Authors: Schramm, Sara | Krizanovic, Nela | Roggenbuck, Ulla | Jöckel, Karl-Heinz | Herring, Arne | Keyvani, Kathy | Jokisch, Martha

Article Type: Research Article

Abstract: Background: Blood kallikrein-8 is supposed to be a biomarker for mild cognitive impairment (MCI) due to Alzheimer’s disease (AD), a precursor of AD dementia. Little is known about the association of kallikrein-8 and non-AD type dementias. Objective: To investigate whether blood kallikrein-8 is elevated in individuals with non-amnestic MCI (naMCI), which has a higher probability to progress to a non-AD type dementia, compared with cognitively unimpaired (CU) controls. Methods: We measured blood kallikrein-8 at ten-year follow-up (T2) in 75 cases and 75 controls matched for age and sex who were participants of the population-based Heinz Nixdorf …Recall study (baseline: 2000–2003). Cognitive performance was assessed in a standardized manner at five (T1) and ten-year follow-up. Cases were CU or had subjective cognitive decline (SCD) at T1 and had naMCI at T2. Controls were CU at both follow-ups. The association between kallikrein-8 (per 500 pg/ml increase) and naMCI was estimated using conditional logistic regression: odds ratios (OR) and 95% confidence intervals (95% CI) were determined, adjusted for inter-assay variability and freezing duration. Results: Valid kallikrein-8 values were measured in 121 participants (45% cases, 54.5% women, 70.5±7.1 years). In cases, the mean kallikrein-8 was higher than in controls (922±797 pg/ml versus 884±782 pg/ml). Kallikrein-8 was not associated with having naMCI compared to being CU (adjusted; OR: 1.03 [95% CI: 0.80–1.32]). Conclusion: This is the first population-based study that shows that blood kallikrein-8 tends not to be elevated in individuals with naMCI compared with CU. This adds to the evidence of the possible AD specificity of kallikrein-8. Show more

Keywords: Alzheimer’s disease, biomarker, dementia, Heinz Nixdorf Recall study, kallikrein-8, mild cognitive impairment, neurodegeneration, neuropsin

DOI: 10.3233/ADR-220073

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 327-337, 2023

Authors: den Hoedt, Sandra | Dorst-Lagerwerf, Kristien Y. | de Vries, Helga E. | Rozemuller, Annemieke J.M. | Scheltens, Philip | Walter, Jochen | Sijbrands, Eric J.G. | Martinez-Martinez, Pilar | Verhoeven, Adrie J.M. | Teunissen, Charlotte E. | Mulder, Monique T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The APOE4 genotype increases the risk of developing AD. Objective: To test the hypothesis that the APOE4 genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD. Methods: Patients homozygous for APOE4 and non-APOE4 carriers with mild cognitive impairment (MCI; n  = 20 versus 20) were compared to patients with subjective cognitive decline (SCD; n  = 18 versus 20). Sphingolipids in CSF and plasma lipoproteins were determined by liquid-chromatography-tandem mass spectrometry. Aβ42 levels …in CSF were determined by immunoassay. Results: APOE4 homozygotes displayed lower levels of sphingomyelin (SM; p  = 0.042), SM(d18:1/18:0) (p  = 0.026), and Aβ42 (p  < 0.001) in CSF than non-APOE4 carriers. CSF-Aβ42 correlated with Cer(d18:1/18:0), SM(d18:1/18:0), and SM(d18:1/18:1) levels in APOE4 homozygotes (r  > 0.49; p  < 0.032) and with Cer(d18:1/24:1) in non-APOE4 carriers (r  = 0.50; p  = 0.025). CSF-Aβ42 correlated positively with Cer(d18:1/24:0) in MCI (p  = 0.028), but negatively in SCD patients (p  = 0.019). Levels of Cer(d18:1/22:0) and long-chain SMs were inversely correlated with Mini-Mental State Examination score among MCI patients, independent of APOE4 genotype (r < –0.47; p  < 0.039). Nevertheless, age and sex are stronger determinants of individual sphingolipid levels in CSF than either the APOE genotype or the cognitive state. In HDL, ratios of Cer(d18:1/18:0) and Cer(d18:1/22:0) to cholesterol were higher in APOE4 homozygotes than in non-APOE4 carriers (p  = 0.048 and 0.047, respectively). Conclusion: The APOE4 genotype affects sphingolipid profiles of CSF and plasma lipoproteins already at early stages of AD. ApoE4 may contribute to the early development of AD through modulation of sphingolipid metabolism. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, Apolipoprotein E4, ceramides, cerebrospinal fluid, cognitive dysfunction, lipoproteins, sphingolipids

DOI: 10.3233/ADR220072

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 339-354, 2023

Authors: Pais, Marcos V. | Forlenza, Orestes V. | Diniz, Breno S.

Article Type: Review Article

Abstract: Recently, low-sensitive plasma assays have been replaced by new ultra-sensitive assays such as single molecule enzyme-linked immunosorbent assay (Simoa), the Mesoscale Discovery (MSD) platform, and immunoprecipitation-mass spectrometry (IP-MS) with higher accuracy in the determination of plasma biomarkers of Alzheimer’s disease (AD). Despite the significant variability, many studies have established in-house cut-off values for the most promising available biomarkers. We first reviewed the most used laboratory methods and assays to measure plasma AD biomarkers. Next, we review studies focused on the diagnostic performance of these biomarkers to identify AD cases, predict cognitive decline in pre-clinical AD cases, and differentiate AD cases …from other dementia. We summarized data from studies published until January 2023. A combination of plasma Aβ42/40 ratio, age, and APOE status showed the best accuracy in diagnosing brain amyloidosis with a liquid chromatography–mass spectrometry (LC–MS) assay. Plasma p-tau217 has shown the best accuracy in distinguishing Aβ-PET+ from Aβ-PET–even in cognitively unimpaired individuals. We also summarized the different cut-off values for each biomarker when available. Recently developed assays for plasma biomarkers have undeniable importance in AD research, with improved analytical and diagnostic performance. Some biomarkers have been extensively used in clinical trials and are now clinically available. Nonetheless, several challenges remain to their widespread use in clinical practice. Show more

Keywords: Alzheimer’s disease, amyloid-β , GFAP, NfL protein, plasma biomarkers, phosphorylated tau

DOI: 10.3233/ADR-230029

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 355-380, 2023

Authors: Das, Tushar Kanti | Ganesh, Bhanu Priya | Fatima-Shad, Kaneez

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) and stroke are two interrelated neurodegenerative disorders which are the leading cause of death and affect the neurons in the brain and central nervous system. Although amyloid-β aggregation, tau hyperphosphorylation, and inflammation are the hallmarks of AD, the exact cause and origin of AD are still undefined. Recent enormous fundamental discoveries suggest that the amyloid hypothesis of AD has not been proven and anti-amyloid therapies that remove amyloid deposition have not yet slowed cognitive decline. However, stroke, mainly ischemic stroke (IS), is caused by an interruption in the cerebral blood flow. Significant features of both disorders are …the disruption of neuronal circuitry at different levels of cellular signaling, leading to the death of neurons and glial cells in the brain. Therefore, it is necessary to find out the common molecular mechanisms of these two diseases to understand their etiological connections. Here, we summarized the most common signaling cascades including autotoxicity, ApoE4, insulin signaling, inflammation, mTOR-autophagy, notch signaling, and microbiota-gut-brain axis, present in both AD and IS. These targeted signaling pathways reveal a better understanding of AD and IS and could provide a distinguished platform to develop improved therapeutics for these diseases. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, excitotoxicity, glucose, insulin, ischemic stroke, microbiota-gut-brain axis, mTOR-autophagy, Notch signaling, PI3K/Akt

DOI: 10.3233/ADR-220108

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 381-398, 2023

Authors: Won, Junyeon | Nielson, Kristy A. | Smith, J. Carson

Article Type: Research Article

Abstract: Background: Despite growing evidence regarding the association between exercise training (ET) and functional brain network connectivity, little is known about the effects of ET on large-scale within- and between-network functional connectivity (FC) of core brain networks. Objective: We investigated the effects of ET on within- and between-network functional connectivity of the default mode network (DMN), frontoparietal network (FPN), and salience network (SAL) in older adults with intact cognition (CN) and older adults diagnosed with mild cognitive impairment (MCI). The association between ET-induced changes in FC and cognitive performance was examined. Methods: 33 older adults (78.0±7.0 years; …16 MCI and 17 CN) participated in this study. Before and after a 12-week walking ET intervention, participants underwent a graded exercise test, Controlled Oral Word Association Test (COWAT), Rey Auditory Verbal Learning Test (RAVLT), a narrative memory test (logical memory; LM), and a resting-state fMRI scan. We examined the within (W ) and between (B ) network connectivity of the DMN, FPN, and SAL. We used linear regression to examine associations between ET-related changes in network connectivity and cognitive function. Results: There were significant improvements in cardiorespiratory fitness, COWAT, RAVLT, and LM after ET across participants. Significant increases in DMNW and SALW , and DMN-FPNB , DMN-SALB , and FPN-SALB were observed after ET. Greater SALW and FPN-SALB were associated with enhanced LM immediate recall performance after ET in both groups. Conclusion: Increased within- and between-network connectivity following ET may subserve improvements in memory performance in older individuals with intact cognition and with MCI due to Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive function, exercise training, functional connectivity, mild cognitive impairment, neural network, older adults, physical activity

DOI: 10.3233/ADR-220062

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 399-413, 2023

Authors: Benichou Haziot, Carla | Birak, Kulbir Singh

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease, yet it currently lacks effective treatment due to its complex etiology. The pathological changes in AD have been linked to the neurotoxic immune responses following aggregation of Aβ and phosphorylated tau. The gut microbiota (GM) is increasingly studied for modulating neuroinflammation in neurodegenerative diseases and in vivo studies emerge for AD. This critical review selected 7 empirical preclinical studies from 2019 onwards assessing therapy approaches targeting GM modulating microglia neuroinflammation in AD mouse models. Results from probiotics, fecal microbiota transplantation, and drugs were compared and contrasted, including for cognition, neuroinflammation, …and toxic aggregation of proteins. Studies consistently reported significant amelioration or prevention of cognitive deficits, decrease in microglial activation, and lower levels of pro-inflammatory cytokines, compared to AD mouse models. However, there were differences across papers for the brain regions affected, and changes in astrocytes were inconsistent. Aβ plaques deposition significantly decreased in all papers, apart from Byur dMar Nyer lNga Ril Bu (BdNlRB ) treatment. Tau phosphorylation significantly declined in 5 studies. Effects in microbial diversity following treatment varied across studies. Findings are encouraging regarding the efficacy of study but information on the effect size is limited. Potentially, GM reverses GM derived abnormalities, decreasing neuroinflammation, which reduces AD toxic aggregations of proteins in the brain, resulting in cognitive improvements. Results support the hypothesis of AD being a multifactorial disease and the potential synergies through multi-target approaches. The use of AD mice models limits conclusions around effectiveness, as human translation is challenging. Show more

Keywords: Alzheimer’s disease, brain-gut axis, dysbiosis, fecal microbiota transplantation, microglia, neurodegenerative diseases, probiotics, therapeutics

DOI: 10.3233/ADR-220097

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 415-431, 2023

Authors: Silva, Rosa | Bobrowicz-Campos, Elzbieta | Santos-Costa, Paulo | Cardoso, Remy | Bernardo, Joana | Santana, Elaine | Almeida, Inês | Loureiro, Ricardo | Cardoso, Daniela | Apóstolo, João

Article Type: Systematic Review

Abstract: Background: In a society increasingly committed to promoting an active life in the community, new resources are needed to respond to the needs of citizens with Alzheimer’s disease and other forms of dementia. The potential of several individual cognitive interventions to be provided by caregivers has been explored in the literature. Objective: To synthesize the best available evidence on the effectiveness of caregiver-provided individual cognitive interventions in older adults with dementia. Methods: Systematic review of experimental studies on individual cognitive interventions for older adults with dementia. An initial search of MEDLINE and CINAHL was undertaken. Another …search for published and unpublished studies was performed on major healthcare-related online databases in March 2018 and updated in August 2022. This review considered studies that included older adults with dementia, aged 60 years and over. All studies that met the inclusion criteria were assessed for methodological quality using a JBI standardized critical appraisal checklist. Data were extracted using a JBI data extraction form for experimental studies. Results: Eleven studies were included: eight randomized controlled trials and three quasi-experimental studies. Caregiver-provided individual cognitive interventions had several beneficial effects in cognitive domains, including memory, verbal fluency, attention, problem-solving, and autonomy in activities of daily living. Conclusion: These interventions were associated with moderate improvements in cognitive performance and benefits in activities of daily living. The findings highlight the potential of caregiver-provided individual cognitive interventions for older adults with dementia. Show more

Keywords: Alzheimer’s disease, caregivers, cognitive therapies, dementia, major neurocognitive disorder, older adults, systematic review

DOI: 10.3233/ADR-220115

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 433-459, 2023