Current Alzheimer Research - Volume 15, Issue 11, 2018

Background: It is well known that alterations in astrocytes occur in Alzheimer's disease and reactive astrogliosis is one of the hallmarks of the disease. Recently, data has emerged that suggests that alterations in astrocytes may also occur early in the pathogenesis of the disease. Objective: The aim of present work was to characterize the transcriptional alterations occurring in cultured astrocytes from 3xTg-AD mouse pups compared to control non-transgenic mice. Furthermore, we also compared these changes to those reported by others in astrocytes from symptomatic AD mice. Method: We conducted a whole-genome microarray study on primary cultured astrocytes from the hippocampus of 3xTg-AD and non-transgenic mouse newborn pups. We used cross-platform normalization and an unsupervised hierarchical clustering algorithm to compare our results with other datasets of cultured or freshly isolated astrocytes, including those isolated from plaque-stage APPswe/PS1dE9 AD mice. Results: We found a set of 993 genes differentially expressed in 3xTg-AD as compared with non-Tg astrocytes. Over-represented gene ontology terms were related to calcium, cell-cell communication, mitochondria, transcription, nucleotide binding and phosphorylation. Of note, no genes related to inflammation were found in cultured 3xTg-AD astrocytes. Comparison with astrocytes isolated from plaque stage APPswe/PS1dE9 showed that 882 out of 993 genes were selectively changed in primary 3xTg-AD astrocytes while 50 genes were co-regulated and 61 were anti-regulated (regulated in the opposite direction in the datasets). Conclusion: Our data show that in cultured astrocytes from an AD mouse model, transcriptional changes occur and are different from those reported in models mimicking later stages of the disease.

Background: Hippocampal mean diffusivity (MD) measured by Diffusion-Tensor Imaging is a promising diagnostic marker for Mild Cognitive Impairment (MCI) and dementia. Its performance has yet to be evaluated in primary care patients, who vary systematically from patients visiting specialized care settings. Objective: We assessed the diagnostic accuracy of hippocampus diffusivity for detecting MCI and dementia in a sample recruited from primary care, compared to a sample from specialized care. Method: One sample was recruited from a primary care intervention trial (DelpHi-MV) (n=70), and the other sample was recruited from our memory clinic (n=70). The samples were matched pairwise for diagnosis, MMSE, age, gender, and education. They included dementia patients, MCI patients and healthy subjects. Mean MD was calculated for the left and right hippocampus, corrected for partial volume effects. Within each sample, left or right hippocampal MD served as predictor for diagnostic group in logistic regressions, which were additionally controlled for white matter lesions. Results: In the primary care sample, hippocampal MD detected dementia with high cross-validated accuracy (left: AUC=.92; right: AUC=.85), but did not classify MCI with an accuracy above chance (left: AUC=.58; right: AUC=.44). In the memory clinic sample, hippocampal MD classified both dementia (left: AUC=.91; right: AUC=.91) and MCI (left: AUC=.86; right: AUC=.83) with high cross-validated accuracy. Conclusion: Hippocampal MD supported the identification of dementia but did not contribute to the detection of MCI in the primary care patient population.

Background: Mild Parkinsonian signs (MPS) are commonly seen in aging, and have been related to cerebral Small Vessel Diseases (SVD) with no univocal results. Objective: The aim of this study was to investigate the cross-sectional relation between MPS and White Matter Hyperintensities (WMH), lacunes, caudate atrophy, and global cerebral atrophy in a large cohort of Neurologically and Cognitively Healthy (NCH) aging individuals. Method: 1,219 NCH individuals were included in the analysis, and underwent standard brain MRI. The items of the motor section of the Unified Parkinson's Disease Rating Scale were used to evaluate tremor, rigidity, bradykinesia, and gait/balance/axial dysfunction. Caudate atrophy and global cerebral atrophy were assessed through the bicaudate ratio and the lateral ventricles to brain ratio, respectively. WMH were assessed through two visual rating scales. Lacunes were also rated. Associations of MPS with vascular risk factors/diseases and imaging findings were determined through the logistic regression analysis. Results: Frontal and basal ganglia lacunes, frontal WMH, caudate atrophy, and global cerebral atrophy were associated with bradykinesia. Basal ganglia lacunes, caudate atrophy, and global cerebral atrophy were associated with gait/balance/axial dysfunction. Rigidity was associated with frontal WMH, and tremor with caudate atrophy and global cerebral atrophy. NCH subjects with MPS, performed less than subjects without MPS in tests evaluating global cognition and language. Conclusion: This study demonstrates that in NCH aging individuals, MPS are associated with cortical and subcortical vascular and atrophic changes, and are probably, a warning sign of incipient cognitive decline. Subjects with MPS should manage rigorously cerebral SVD to prevent future physical and cognitive disabilities.

Background: Caregivers of persons with Alzheimer's Disease (AD) often experience feelings of lack of support and information from specialists when operating in real scenarios, inclusive of old-age psychiatric wards, care homes, community, and patient's home. Objective: AD caregivers can provide narrative about what issues need to be addressed in Ecological Momentary Assessment (EMA) to capture real-time and real-scenario needs in AD caregiving, and Ecological Momentary Interventions (EMI) as online e-learning to assist in areas of concerns. Method: Twelve focus group discussions took place with AD caregivers for a total of 62 people interviewed. Once major themes in surveys and learning were identified by using discourse analysis, AD caregivers expressed the likelihood that these themes (where 0 meant “nil” and 1 meant “completely”) would address their focal needs in caregiving and topics in learning. Z scores for proportions and Cohen's d effect size were calculated for each item reporting the averaged scores. Results: AD caregivers indicated that the major areas of concern that could benefit from an EMA/EMI online platform were: support (d=3.08), collaboration (d=1.85), medication review (d=1.21), dealing with grief and mourning, and time (d=0.97). Moreover, they identified personal resources available to provide help to colleagues: support (d=1.34), information (d=0.97), collaboration (d=2.06), hospital admission (d=3.08), and hospital discharge (d=5.50). Conclusion: Focus groups and narratives can be the initial stage in creating a dedicated AD app supporting EMA/EMI in AD care.

Background: Studies have shown select associations between cardiovascular risk factors and dementia, but mostly focused on Alzheimer's Disease (AD). Objective: We enhance these works by evaluating the relationship between the presence of cardiovascular risk factors and the rate of cognitive decline, measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Sum of Boxes (CDR-SUM) on four common dementia subtypes (AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VaD), as well as non-demented elderly individuals (normal)). Method: We used generalized linear mixed models with random intercepts to account for correlation at the patient and center levels for each dementia subtype adjusting for time since initial visit, baseline cognitive score, age, and demographic factors. The cardiovascular risk factors evaluated included body mass index, diabetes, years of smoking, atrial fibrillation, hypertension, and hypercholesterolemia. Results: Patients diagnosed with AD (n=1899), DLB (n=65), FTD (n=168), or VaD (n=13); or lacked cognitive impairment (normal) (n=3583) were evaluated using data from the National Alzheimer's Coordinating Centers. Cardiovascular risk factors were associated with select dementia subtypes including AD and FTD. Using MMSE and CDR-SUM, recent or active hypertension and hypercholesterolemia were associated with a slower cognitive decline for AD patients, while higher body mass index and years of smoking were associated with a slower cognitive decline for FTD patients. However, several cardiovascular factors demonstrated associations with more rapid cognitive decline. Conclusion: These results demonstrate disease specific associations and can provide clinicians guidance on predicted cognitive changes at the group level using information about cardiovascular risk factors.

Background: Berberine (BBR) has neuroprotective effects on many brain diseases, including Alzheimer’s disease (AD). Amyloid -beta (Aβ) senile plaque is the most classical pathological hallmarks of AD. Aβ produces from a sequential cleavage by β-secretase (beta-site amyloid precursor protein cleaving enzyme 1, BACE1) and γ -secretase. The aim of our work was to investigate whether the neuroprotective effects of BBR on AD is related to inhibiting Aβ pathology. Method: The cognitive function of mice was assessed by the Morris water maze (MWM) test. The Aβ levels were determined by enzyme linked immunosorbent assay; the expression of APP, sAPPα, ADAM10 and ADAM17, sAPPβ and BACE1 was detected by Western blotting; and the activity of γ -secretase complex (NCT, PS1, Aph-1α and Pen-2) was determined by Western blotting and immunohistochemistry. Results: BBR improved learning and memory deficits of APP/PS1 mice. BBR decreased Aβ levels in the hippocampus of APP/PS1 mice. BACE1 and sAPP -β levels in the BBR-treated groups were significantly reduced in the hippocampus of AD mice. BBR markedly decreased the expression of PS1, Aph-1α and Pen-2, but had no effect on NCT. The levels of sAPPα, ADAM10 and ADAM17 in the hippocampus of BBR-treated mice significantly increased, compared with the control ones (P<0.05). Conclusion: BBR inhibits the activity of β/γ-secretases, enhances α-secretases, and lowers the Aβ level in the hippocampus of AD mice, and improves Alzheimer's-like cognitive impairment.

Background: Mice co-expressing human amyloid precursor protein with the Swedish mutation (APPswe) and exon-9-deleted presenilin (PS1dE9) has become one of the most widely used mouse models for studying Alzheimer's disease (AD) pathogenesis and preclinical studies of AD therapeutic approaches. Objective: In this study, we systematically investigated cognitive decline, amyloid-β (Aβ) deposition and cerebral or Aβ serum levels as well as the relationships among these measures in APPswe/PS1dE9 transgenic mice. Method: APPswe/PS1dE9 mice were separated into four equal age cohorts (4, 6, 9, and 12 months). We assessed cognitive capacity, deposited plaques, and the levels of Aβ40/Aβ42 in brain tissue and serum of mice at different ages. Results: APPswe/PS1dE9 mice exhibited declined memory beginning at 6 months of age, with cognitive capacity remarkably impaired at 12-months. Coincidently, amyloid deposits began to develop in transgenic mice brain at 6-months and increased with age. In addition, Aβ42 levels in brains of APPswe/ PS1dE9 mice increased with age with no parallel increase in Aβ40. The concentration of serum Aβ42 declined from 4 to 6 months of age, but a similar age-dependent decrease was not observed for Aβ40. Conclusion: APPswe/PS1dE9 transgenic mice began to develop amyloid plaques at 6 months of age and exhibited a corresponding impairment of spatial learning capacity. Serum Aβ42 level decreased remarkably from 4 to 6 months, at which stage Aβ42 began to accumulate in the brain and deposit as plaques.

Background: Type 2 diabetes mellitus (DM) has been shown to increase the risk for cognitive decline and dementia, such as Alzheimer disease (AD) and vascular dementia (VaD). In addition to AD and VaD, there may be a dementia subgroup associated with specific DM-related metabolic abnormalities rather than AD pathology or cerebrovascular disease, referred to as diabetes-related dementia (DrD). Method: We studied 11C-PiB and 11C-PBB3 positron emission tomography (PET) in 31 subjects with DrD and 5 subjects with AD associated with DM to assess amyloid and tau deposits in the brain. Results: All subjects with AD showed both positive PiB and PBB3. However, only 12 out of 31 subjects (39%) with DrD showed positive PiB, whereas 17 out of 21 subjects (81%) who underwent PBB3 PET showed positive PBB3. Depending on the positivity of PiB and PBB3, we classified 21 subjects into a negative PiB and a positive PBB3 pattern (11 cases, 52%), indicating tauopathy, a positive PiB and a positive PBB3 pattern (6 cases, 29%), indicating AD pathology, or a negative PiB and a negative PBB3 pattern (4 cases, 19%). Among 11 subjects showing a negative PiB and a positive PBB3 pattern, there were 2 PBB3 deposit patterns, including the medial temporal lobe only and extensive neocortex beyond the medial temporal lobe. Conclusion: DrD showed variable amyloid and tau accumulation patterns in the brain. DrD may be associated predominantly with tau pathology, in addition to AD pathology and non-amyloid/non-tau neuronal damage due to DM-related metabolic abnormalities.

Objectives: Research suggests beneficial effects of minimal interference on item memory in mild Alzheimer's disease (AD). We conducted a study to test whether these beneficial effects extend to source memory, i.e., the ability to remember the episodic context in which an information was previously acquired. Method: Twenty-six mild AD participants and 28 controls manipulated six objects or watched the experimenter manipulating six other objects. After immediate item recall (“what were the items?”) and source recall (“by whom the items were previously manipulated?”), an interference or a minimal interference condition was administrated. In the interference condition, participants were assessed with neuropsychological tests for 10 min. In the minimal interference condition, they rested alone in a dark and quiet room for 10 minutes. Both interference and minimal interference conditions were followed by the delayed recall, on which participants were asked to remember the previously-presented objects and their source. Results: Higher item memory was observed following minimal interference than following interference in AD participants (p < .01) and controls (p < .01). Also, AD participants demonstrated higher item memory on immediate recall than following interference (p < .001) or minimal interference (p < .001); controls also demonstrated higher item memory on immediate recall than following interference (p < .001) or minimal interference (p < .001). Considering source memory, similar source memory was observed following interference and minimal interference in AD participants (p > .1) and controls (p > .1). Also, AD participants demonstrated higher source memory on immediate recall than following interference (p < .001) or minimal interference (p < .001); controls also demonstrated higher source memory on immediate recall than following interference (p < .001) or minimal interference (p < .001). Conclusion: Failures of hippocampus-dependent associative or consolidation processes in AD may preclude benefits of minimal interference for source memory. Nevertheless, AD patients may show some capacity to retain simple material, should the material presentation be followed by short delays that are free of further stimuli.

This review has two aims. First, to examine whether or not sex and gender may influence the brain cholinergic system in animals and in humans. Second, to examine the available evidence of sexually dimorphic response to the therapeutic and toxic effects of cholinesterase inhibitors. Animal research reveals no marked difference in the general morphology of the brain cholinergic system but subtle functional gender differences have been reported. In humans, gender differences in nucleus basalis of Meynert (NBM) exist. In animals, some cholinergic neurons express estrogen alpha receptors in females and androgens in males. It is known that sex hormones exert trophic effects on the cholinergic system. Females show higher frontal cortex cholinergic activity whereas males have higher activity in the hippocampus. Gender differences in the pharmacological effects result in higher sensitivity to the toxic effects of organophosphate cholinesterase inhibitors in males. A stronger and more selective benefit of ChEI treatment in AD has been reported in men by several authors. Sex and estrogen receptor phenotype may both influence the response to donepezil and rivastigmine. Hence, aged male and female individuals might respond differently to ChEI due to either sex-specific differences in structures and function of the cholinergic system, pharmacokinetics, memory function or in the way aging or AD affects these processes.