Journal of Alzheimer's Disease - Volume 80, issue 4

Authors: Drake, Jonathan D. | Chambers, Alison B. | Ott, Brian R. | Daiello, Lori A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer’s disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. Objective: We utilized Alzheimer’s Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. Methods: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n  = 112 AD, n  = 396 mild …cognitive impairment (MCI), n  = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n  = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). Results: Higher mean VCAM-1 (p  = 0.0026) and ICAM-1 (p  = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p  = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ42 ), total tau, phosphorylated tau (P-tau), or P-tau/Aβ42 (all < p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent. Conclusion: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment. Show more

Keywords: Alzheimer’s disease, E-Selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1

DOI: 10.3233/JAD-200759

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1553-1565, 2021

Authors: Beishon, Lucy C. | Panerai, Ronney B. | Budgeon, Charley | Subramaniam, Hari | Mukaetova-Ladinska, Elizabeta | Robinson, Thompson G. | Haunton, Victoria J.

Article Type: Research Article

Abstract: Background: Cognitive training (CT) has demonstrated benefits for healthy older adults (HG) and mild cognitive impairment (MCI), but the effects on vascular function are unknown. Objective: This is a feasibility trial investigating the effects of CT on cerebral blood flow velocity (CBFv). Methods: Twenty HG, 24 with Alzheimer’s disease (AD), and 12 with MCI were randomized to 12 weeks of multi-domain CT or control. Outcomes included: cognition (Addenbrooke’s Cognitive Examination III), mood, quality of life (QoL), physical, and neurovascular function (transcranial Doppler ultrasonography measured task activation of CBFv responses). Data are presented as mean difference (MD) …and 95% confidence interval (CI). Results: 47 participants completed the trial. There were three dropouts from the training arm in the AD group, and one in the HG group. The intervention was acceptable and feasible to the majority of participants with a high completion rate (89%). The dropout rate was higher among participants with dementia. Few changes were identified on secondary analyses, but QoL was significantly improved in HG post-training (MD: 4.83 [95% CI: 1.13, 8.54]). CBFv response rate was not significantly different in HG (MD: 1.84 [95% CI: –4.81, 1.12]), but a significant increase was seen in the patient group (MD: 1.79 [95% CI: 0.005, 3.58]), requiring sample sizes of 56 and 84 participants respectively for a fully-powered trial. Conclusion: A 12-week CT program was acceptable and feasible in HG, AD, and MCI. CT may be associated with alterations in vascular physiology which require further investigation in an appropriately powered randomized controlled trial. Show more

Keywords: Cerebral blood flow, cerebral hemodynamics, cognition, cognitive impairment, dementia

DOI: 10.3233/JAD-201444

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1567-1581, 2021

Authors: El Said, Salma M.S. | Adly, Nermien N. | Abdul-Rahman, Samia A.

Article Type: Research Article

Abstract: Background: The ongoing scientific debate regarding the association between physical function and cognitive impairment has focused mainly on global cognitive performance rather than specific cognitive functions tests and the importance of recognition of its associations and any factors that could play a role later in the prevention of such decline. Objective: This study examined the association between physical function, using handgrip strength (HGS) and Timed Up-and-Go test (TUGT), and executive function (EF), using Clock Drawing Test (CDT), among community-dwelling Egyptian elderly. Methods: A cross-sectional study was conducted in 5 social clubs in Cairo, Egypt and included …a sample of 136 elderly males and females aged≥55 years old. All participants had their physical function assessed using TUGT, and measurement of HGS using a pneumatic hand-held dynamometer. Assessment of EF using CDT was also done. Results: Higher CDT scores were significantly associated with both better HGS, and lower TUGT (OR = 3.77, and 0.65 respectively). This persisted even after adjustment for age and gender (OR = 2.56, and 0.71 respectively) and after further adjustment for weight, systolic blood pressure, education, smoking, hyperlipidemia, hypothyroidism, and physical activity (O.R. = 4.79, and 0.76 respectively). Adjustment for both male and female genders showed an association between physical (HGS and TUGT) and EF was stronger among men. Conclusion: A strong association between CDT score and both of HGS and TUGT was found among the studied sample. Higher HGS and lower TUGT was significantly associated with better performance in the CDT. This association is stronger in males than in females for both HGS and TUGT. Show more

Keywords: Clock Drawing Test, elderly, executive function, handgrip strength, Timed Up-and-Go test

DOI: 10.3233/JAD-201423

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1583-1589, 2021

Authors: Zhou, Rui | Liu, Hua-Min | Li, Fu-Rong | Yang, Hai-Lian | Zheng, Jia-Zhen | Zou, Meng-Chen | Zou, Lian-Wu | Wu, Xiao-Xiang | Wu, Xian-Bo

Article Type: Research Article

Abstract: Background: Wealth and income are potential modifiable risk factors for dementia, but whether wealth status, which is composed of a combination of debt and poverty, and assessed by wealth and income, is associated with cognitive impairment among elderly adults remains unknown. Objective: To examine the associations of different combinations of debt and poverty with the incidence of dementia and cognitive impairment without dementia (CIND) and to evaluate the mediating role of depression in these relationships. Methods: We included 15,565 participants aged 51 years or older from the Health and Retirement Study (1992–2012) who were free of …CIND and dementia at baseline. Dementia and CIND were assessed using either the modified Telephone Interview for Cognitive Status (mTICS) or a proxy assessment. Cox models with time-dependent covariates and mediation analysis were used. Results: During a median of 14.4 years of follow-up, 4,484 participants experienced CIND and 1,774 were diagnosed with dementia. Both debt and poverty were independently associated with increased dementia and CIND risks, and the risks were augmented when both debt and poverty were present together (the hazard ratios [95% confidence intervals] were 1.35 [1.08–1.70] and 1.96 [1.48–2.60] for CIND and dementia, respectively). The associations between different wealth statuses and cognition were partially (mediation ratio range: 11.8–29.7%) mediated by depression. Conclusion: Debt and poverty were associated with an increased risk of dementia and CIND, and these associations were partially mediated by depression. Alleviating poverty and debt may be effective for improving mental health and therefore curbing the risk of cognitive impairment and dementia. Show more

Keywords: Cognitive impairment, cohort studies, dementia, depression, mediation analysis, wealth status

DOI: 10.3233/JAD-201239

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1591-1601, 2021

Authors: Gupta, Harsh V. | Beach, Thomas G. | Mehta, Shyamal H. | Shill, Holly A. | Driver-Dunckley, Erika | Sabbagh, Marwan N. | Belden, Christine M. | Liebsack, Carolyn | Dugger, Brittany N. | Serrano, Geidy E. | Sue, Lucia I. | Siderowf, Andrew | Pontecorvo, Michael J. | Mintun, Mark A. | Joshi, Abhinay D. | Adler, Charles H.

Article Type: Research Article

Abstract: Background: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer’s disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker. Objective: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Methods: Three subjects who had PET imaging with …both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared. Results: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD. Conclusion: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed. Show more

Keywords: Alzheimer’s disease, amyloid, AV-133, dementia with Lewy bodies, synucleinopathy, VMAT2

DOI: 10.3233/JAD-200323

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1603-1612, 2021

Authors: Poptsi, Eleni | Tsolaki, Magda | Bergh, Sverre | Cesana, Bruno Mario | Ciccone, Alfonso | Fabbo, Andrea | Frisoni, Giovanni B. | Frölich, Lutz | Lavolpe, Sara | Guazzarini, Anna Giulia | Hugon, Jacques | Fascendini, Sara | Defanti, Carlo Alberto

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) are quite challenging problems during the dementia course. Special Care Units for people with dementia (PwD) and BPSD (SCU-B) are residential medical structures, where BPSD patients are temporarily admitted, in case of unmanageable behavioral disturbances at home. Objective: RECage (REspectful Caring for AGitated Elderly) aspires to assess the short and long-term effectiveness of SCU-Bs toward alleviating BPSD and improving the quality of life (QoL) of PwD and their caregivers. Methods: RECage is a three-year, prospective study enrolling 500 PwD. Particularly, 250 community-dwelling PwDs presenting with severe BPSD will …be recruited by five clinical centers across Europe, endowed with a SCU-B, for a short period of time; a second similar group of 250 PwD will be followed by six other no-SCU-B centers solely via outpatient visits. RECage’s endpoints include short and long-term SCU-B clinical efficacy, QoL of patients and caregivers, cost-effectiveness of the SCU-B, psychotropic drug consumption, caregivers’ attitude toward dementia, and time to nursing home placement. Results: PwD admitted in SCU-Bs are expected to have diminished rates of BPSD and better QoL and their caregivers are also expected to have better QoL and improved attitude towards dementia, compared to those followed in no-SCU-Bs. Also, the cost of care and the psychotropic drug consumption are expected to be lower. Finally, PwD followed in no-SCU-Bs are expected to have earlier admission to nursing homes. Conclusion: The cohort study results will refine the SCU-B model, issuing recommendations for implementation of SCU-Bs in the countries where they are scarce or non-existent. Show more

Keywords: Behavioral disturbances, dementia, special care units

DOI: 10.3233/JAD-201215

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1613-1627, 2021

Authors: Lukkarinen, Heikki | Tesseur, Ina | Pemberton, Darrel | Van Der Ark, Peter | Timmers, Maarten | Slemmon, Randy | Janssens, Luc | Streffer, Johannes | Van Nueten, Luc | Bottelbergs, Astrid | Rauramaa, Tuomas | Koivisto, Anne M. | Herukka, Sanna-Kaisa | Korhonen, Ville E. | Junkkari, Antti | Hiltunen, Mikko | Engelborghs, Sebastiaan | Blennow, Kaj | Zetterberg, Henrik | Kolb, Hartmuth C. | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. Objective: To examine alteration of CSF biomarkers reflecting Alzheimer’s disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3–73 months after surgery. Thereafter, additional CSF sampling …took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42 ), total tau (T-tau), phosphorylated tau (P-tau181 ), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. Results: All biomarkers but Aβ42 increased notably by 140–810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p  < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ 4. Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations. Show more

Keywords: Aβ42 , biomarkers, idiopathic normal pressure hydrocephalus, neurofilament light, neurogranin, P-tau, T-tau

DOI: 10.3233/JAD-201361

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1629-1642, 2021

Authors: van Zutphen, Elisabeth Maria | Rijnhart, Judith Johanna Maria | Rhebergen, Didericke | Muller, Majon | Huisman, Martijn | Beekman, Aartjan | Kok, Almar | Appelman, Yolande

Article Type: Research Article

Abstract: Background: Sex differences in cognitive functioning in old age are known to exist yet are still poorly understood. Objective: This study examines to what extent differences in cardiovascular risk factors and cardiovascular disease between men and women explain sex differences in cognitive functioning. Methods: Data from 2,724 older adults from the Longitudinal Aging Study Amsterdam were used. Information processing speed and episodic memory, measured three times during six years of follow-up, served as outcomes. The mediating role of cardiovascular risk factors and cardiovascular disease was examined in single and multiple mediator models. Determinant-mediator effects were estimated …using linear or logistic regression, and determinant-outcome and mediator-outcome effects were estimated using linear mixed models. Indirect effects were estimated using the product-of-coefficients estimator. Results: Women scored 1.58 points higher on information processing speed and 1.53 points higher on episodic memory. Several cardiovascular risk factors had small mediating effects. The sex difference in information processing speed was mediated by smoking, depressive symptoms, obesity, and systolic blood pressure. The sex difference in episodic memory was mediated by smoking, physical activity, and depressive symptoms. Effects of smoking, LDL cholesterol, and diabetes mellitus on information processing speed differed between men and women. Conclusion: Differences in cardiovascular risk factors between women and men partially explained why women had better cognitive functioning. A healthy cardiovascular lifestyle seems beneficial for cognition and sex-specific strategies may be important to preserve cognitive functioning at older age. Show more

Keywords: Aged, behavior, cardiovascular diseases, cognition, epidemiology, episodic memory, sex

DOI: 10.3233/JAD-201173

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1643-1655, 2021

Authors: Valotassiou, Varvara | Sifakis, Nikolaos | Tzavara, Chara | Lykou, Evi | Tsinia, Niki | Kamtsadeli, Vasiliki | Sali, Dimitra | Angelidis, George | Psimadas, Dimitrios | Tsougos, Ioannis | Papageorgiou, Sokratis G. | Georgoulias, Panagiotis | Papatriantafyllou, John

Article Type: Research Article

Abstract: Background: Eating disorders (ED) in dementia represent a significant impairment affecting patients’ and caregivers’ lives. In frontotemporal dementia (FTD), ED include overeating, sweet food preference, stereotypical eating, and hyperorality, while in Alzheimer’s disease (AD), anorexia and appetite loss are the most common ED. Objective: The aim of our study was to highlight Brodmann areas (BAs) implicated specifically in the appearance of ED in FTD and AD. Methods: We studied 141 patients, 75 with FTD and 66 with AD. We used the NeuroGamTM software on the reconstructed single photon emission computed tomography-SPECT data for the automated …comparison of BAs perfusion on the left (L) and right (R) hemisphere with perfusion in corresponding BAs of a normal database. Results: The FTD group included 27 men and 48 women, age (mean±SD) 65.8±8.5 years, duration of disease 3.4±3.3 years, Mini-Mental State Examination (MMSE) 17.9±8.6, ED score on Neuropsychiatric Inventory (NPI) 4.7±8.5. ED in FTD were correlated with hypoperfusion in right anterior and dorsolateral prefrontal cortices (BAs 10R, 46R), left orbitofrontal cortex (BA 12L), orbital part of the right inferior frontal gyrus (BA 47R), and left parahippocampal gyrus (BA 36L). The AD group included 21 men and 45 women, age (mean±SD) 70.2±8.0 years, duration of disease 3.3±2.4 years, MMSE 20.2±6, ED-NPI score 2.7±3.9. ED in AD were correlated with hypoperfusion in left inferior temporal cortex (BA 20L). Conclusion: SPECT imaging with automated mapping of brain cortex could contribute to the understanding of the neural networks involved in the manifestation of ED in dementia. Show more

Keywords: Alzheimer’s disease, Brodmann areas, eating disorders, frontotemporal dementia, perfusion, SPECT

DOI: 10.3233/JAD-201434

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1657-1667, 2021

Authors: Luca, Antonina | Nicoletti, Alessandra | Donzuso, Giulia | Terravecchia, Claudio | Cicero, Calogero Edoardo | D’Agate, Concetta | Rascuná, Cristina | Manna, Roberta | Mostile, Giovanni | Zappia, Mario

Article Type: Research Article

Abstract: Background: The neuropsychological profile of progressive supranuclear palsy (PSP) patients is mainly characterized by executive dysfunction, but the relationship between the latter and midbrain atrophy is still unclear. Objective: The aims of the study were to investigate which test evaluating executive functioning is more frequently impaired in PSP patients and to evaluate the relationship between midbrain-based MRI morphometric measures and executive dysfunction. Methods: PSP patients who had undergone a neuropsychological battery assessing executive functioning with the Frontal Assessment Battery (FAB), the phonemic verbal fluency F-A-S, the Raven’s Progressive Colored Matrix, and the Stroop word colors test …(time and errors) were enrolled in the study. A group of Parkinson’s disease (PD) patients matched by age, sex, education, and global cognitive status was selected. All the enrolled patients also underwent a volumetric T1-3D brain MRI. Results: Thirty-five PSP patients and 35 PD patients were enrolled. Patients with PSP as compared to patients with PD showed a significant greater impairment in verbal fluency (16.0±7.9 and 23.4±8.7 words/180 s; p  < 0.001) and a significant lower score at the FAB total score (11.5±3.8 and 13.7±3.4; p  = 0.013). Midbrain area was significantly smaller in PSP patients than in PD patients (83.9±20.1 and 134.5±19.9 mm2 ; p  < 0.001). In PSP patients, a significant positive correlation between verbal fluency and the midbrain area (r  = 0.421; p  = 0.028) was observed. Conclusion: Our findings suggest that the phonemic verbal fluency is among the most frequently impaired executive functions in PSP patients and is strongly correlated to midbrain atrophy. Show more

Keywords: Executive functions, midbrain atrophy, progressive supranuclear palsy, verbal fluency

DOI: 10.3233/JAD-210023

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1669-1674, 2021