Journal of Alzheimer's Disease - Volume 67, issue 4

Authors: Spallazzi, Marco | Barocco, Federica | Michelini, Giovanni | Morelli, Nicola | Scarlattei, Maura | Baldari, Giorgio | Ruffini, Livia | Caffarra, Paolo

Article Type: Research Article

Abstract: Background: Amyloid pathology is a key feature of Alzheimer’s disease (AD) and can be assessed in vivo with amyloid positron emission tomography (PET) imaging. Objective: The objective of this study was to evaluate the incremental value of a PET scan with [18 F]florbetaben, in terms of changes of diagnosis, diagnostic confidence, and treatment plan when added to a standardized diagnostic workup for cognitive disorders, with particular focus on the role of the neuropsychological assessment, including the Free and Cued Selective Reminding Test (FCSRT). Methods: A total of 104 patients (69 mild cognitive impairment, 35 dementia), …with diagnostic uncertainty after diagnostic workup, were recruited from our memory clinic. [18 F]florbetaben PET scans were interpreted as amyloid negative or positive on the basis of a semi-quantitative visual rating. Clinical diagnosis and diagnostic confidence for AD or non-AD dementia were rated before and after PET result disclosure, as was the impact of PET on the patient management plan. Results: There were 69/104 (66%) [18 F]florbetaben positive scans, 51/62 (82%) patients were suspected as having AD before the PET scan and 18/42 (43%) were not. Overall, the data obtained at PET changed 18/104 diagnoses (17%) and increased diagnostic confidence from 69.1±8.1% to 83.5±9.1 (p  < 0.001), with the greatest impact on diagnosis and confidence in PET negative patients with an initial diagnosis of AD (p  < 0.01) and in early-onset patients (p  = 0.01). Conclusion: Amyloid PET represents a source of added value in dementia diagnosis, with a significant effect on diagnosis and diagnostic confidence. However, the use of a complete neuropsychological assessment has an add-on value on limiting the amyloid PET influence on change of diagnosis, and the real impact of amyloid PET should always be weighed up together with an accurate standardized diagnostic workup. Show more

Keywords: Amyloid PET, dementia, diagnosis, Free and Cued Selective Reminding Test, mild cognitive impairment

DOI: 10.3233/JAD-180646

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1235-1244, 2019

Authors: Bebe, Anna | Siersma, Volkert | Kragstrup, Jakob | Nielsen, Anni Brit Sternhagen | Møller, Anne | Søndergaard, Jens | Nicolaisdóttir, Dagný Rós | Waldorff, Frans Boch

Article Type: Research Article

Abstract: Background: We investigated the effect of economic assets on mortality in patients with dementia in a national cohort of elderly individuals aged 65 or older. Objective: To examine the effect of economic assets on mortality in patients with dementia. Methods: Incidence of dementia and all-cause mortality was analyzed with incidence rate ratios (IRR) in three different categories of economic assets by means of Cox regression models. Results: A total of 874,246 individuals aged 65+ were included. The risk of receiving a dementia diagnosis was highest in the low economic asset group (IRR 1.19). Patients …with dementia had a higher mortality compared to those without a diagnosis (IRR 2.85). The mortality in the dementia group was lowest in the high economic asset group (IRR 3.31). However, the increase associated with dementia was lowest within the low economic assets group (IRR 2.57). Conclusion: Mortality is increased with a dementia diagnosis and highest for the low economic asset group. However, the increase in mortality attributable to dementia was higher in the high economic assets group. Show more

Keywords: Comorbidity, dementia, economic assets, epidemiology, mortality, socio economy

DOI: 10.3233/JAD-181107

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1245-1253, 2019

Authors: Wang, Fei | Luo, Jianfeng | Ding, Ding | Zhao, Qianhua | Guo, Qihao | Liang, Xiaoniu | Zhou, Fen | Deng, Wei | Hong, Zhen

Article Type: Research Article

Abstract: Background: Several studies have demonstrated that the elevated fasting blood glucose (FBG) may increase the risk of incident dementia in older adults with or without diabetes mellitus (DM). However, similar results are rarely reported in Chinese population. Objective: This study aimed to demonstrate the association between FBG and risk of incident cognitive decline in older Chinese adults. Methods: We prospectively followed up 1,555 dementia-free participants with baseline FBG measurement in the Shanghai Aging Study. Results: We identified 126 incident dementia cases across a mean of 5.2 years. Cumulative dementia incidence in type II DM …participants with higher FBG (>6.1 mmol/L) increased most dramatically, second with that of non-DM participants with higher FBG, than that of participants with lower FBG (≤6.1 mmol/L). DM participants had a significant higher risk of incident dementia (adjusted HR 1.51, 95% CI 1.25–1.82) by every 1 mmol/L increment of FBG. Among DM participants, baseline FBG was positively related to the rate of annual decline of MMSE (β= 0.10, p  = 0.0018). Conclusions: Our results suggest that especially in people with type II DM, effective blood glucose control may help to prevent cognitive impairment in later life. Show more

Keywords: Cognitive function, cohort study, dementia, diabetes mellitus, fasting glucose, incidence

DOI: 10.3233/JAD-180662

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1255-1265, 2019

Authors: Garnier-Crussard, Antoine | Vernaudon, Julien | Auguste, Nicolas | Moutet, Claire | Dauphinot, Virginie | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Neurocognitive disorders (NCD) are underdiagnosed in primary care, mainly because of the misunderstanding of benefits associated with timely diagnosis. Objective: The aim of this study was to explore the benefits and risks of diagnosis in a population of general practitioners (GPs), specialized physicians (SPs), other healthcare professionals (HPs), and informal caregivers (ICs). Methods: A questionnaire was submitted to GPs, SPs, HPs. and ICs. It aimed at evaluating benefits and risks related to NCD diagnosis associated with four prototypical clinical cases at different stages: isolated cognitive complaint/mild NCD, major NCD at mild/moderate stage, moderate stage with …behavioral and psychotic symptoms, and severe stage. The concepts of early, timely, and personalized diagnosis were evaluated. Results: A total of 719 completed surveys were collected from 183 GPs, 176 SPs, 281 HPs, and 79 ICs. More than 90% of the participants considered initiating a diagnosis as relevant except at the severe stage. Benefits were superior to risks for all groups and all four cases alike (p  < 0.001). Benefits were lower according to GPs and higher for SPs than the other groups at the first two stages (p  < 0.001). At the moderate stage, there were few differences between groups. At the severe stage, GPs and SPs claimed it was less relevant to carry out a diagnosis than the other groups (p  < 0.001). Risks were higher for ICs and lower for SPs (p  < 0.001). The best diagnosis concept was the personalized diagnosis. Conclusion: Benefits appeared more relevant than risks with differences according to the stage of the disease and type of respondents. Show more

Keywords: Dementia, diagnosis, ethical issues, neurocognitive disorders, survey

DOI: 10.3233/JAD-180403

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1267-1275, 2019

Authors: Tripathy, Arushi | Shade, Ashley | Erskine, Brittany | Bailey, Kristi | Grande, Abigail | deLong, Joyce J. | Perry, George | Castellani, Rudy J.

Article Type: Research Article

Abstract: It is presently unknown whether military service members are at risk for chronic traumatic encephalopathy (CTE) or Alzheimer’s disease (AD) pathology, due to traumatic brain injury (TBI). Studies with respect to AD have had mixed results with respect to mild TBI, although an increased risk of clinical AD with moderate and severe TBI is more consistently demonstrated. No studies to date have demonstrated a longitudinal progression from TBI to autopsy. We therefore initiated a cross-sectional survey of former military service members. 18 brain specimens have been examined to date, with a mean age of 68.9±16 years (range 32–94). Twelve had …a history of psychiatric problems; 10 had a history of PTSD specifically. Five had neurological problems including stroke and seizures. One subject had early-onset AD. Two subjects had a history of TBI and two had a history of blast exposure. Age-related proteinopathy, ranging from AD neuropathologic change A0B1C0 to A3B3C3 by NIA-AA guidelines, was identified. None of the cases showed changes specific for CTE pathology. There was no relationship between p-tau in the amygdala and psychiatric signs. There was no significant difference in phosphorylated tau (p-tau) or amyloid-β burden compared to age-matched controls. These preliminary data suggest that military service per se is not a risk factor for CTE pathology or neurodegenerative proteinopathy. More research is needed to study the relationship, if any, between TBI and neurodegenerative proteinopathy. Show more

Keywords: Alzheimer’s disease, chronic traumatic encephalopathy, tauopathy, traumatic brain injury, veterans

DOI: 10.3233/JAD-181039

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1277-1289, 2019

Authors: Lai, Chih-Chia | Lo, Hsuan | Lin, Hong-Guo | Lin, Hsun-Hsun

Article Type: Research Article

Abstract: The abnormal accumulation of amyloid-β peptides (Aβ) is one of the main characteristics of Alzheimer’s disease (AD). Cerebro- and cardiovascular diseases may be the risk factors for developing AD. The effect of Aβ on central sympathetic control of cardiovascular function remains unclear. The present study examines the acute effects of Aβ oligomers on the function of NMDA receptors, a subtype of ionotropic glutamate receptors, in rat sympathetic preganglionic neurons (SPNs). In the in vitro electrophysiological study, Aβ1-40 but not Aβ1-42 applied by superfusion for 5 min significantly potentiated NMDA-induced depolarizations in SPNs of neonatal rat spinal cord slice …preparation. Application of Aβ1-40 had little effects on AMPA-induced depolarizations or GABA-induced hyperpolarizations. Treatment with a selective protein kinase C (PKC) inhibitor applied together with Aβ1-40 blocked the augmentation by Aβ1-40 of NMDA-induced depolarizations. Western blot analysis showed an increase in the levels of phosphoserine 896, selectively regulated by PKC, without significant changes in phosphoserine 897 on GluN1 subunits in lateral horn areas of spinal cord slices following treatment with Aβ1-40 . In the in vivo study, intrathecal injection of Aβ1-40 (0.2 nmol) potentiated the pressor effects induced by NMDA (2 nmol) injected intrathecally in urethane-anesthetized rats. These results suggest that different fragments of Aβ may have differential effects on the NMDA receptor function and the selective augmentation of NMDA receptor function by Aβ1-40 may involve PKC-dependent mechanisms in sympathetic preganglionic neurons. Show more

Keywords: Amyloid-β peptide, GABA receptor, glutamate receptor, protein kinase C, sympathetic activity

DOI: 10.3233/JAD-180886

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1291-1303, 2019

Authors: Fischer, Corinne E. | Kortebi, Ines | Karameh, Wael K. | Kumar, Sanjeev | Gallagher, Damien | Golas, Angela | Munoz, David | Barfett, Joseph | Butters, Meryl A. | Bowie, Christopher R. | Flint, Alastair | Rajji, Tarek | Herrmann, Nathan | Pollock, Bruce G. | Mulsant, Benoit | Schweizer, Tom A. | Mah, Linda | and the PACT-MD Study Group

Article Type: Research Article

Abstract: Background: Cardiovascular risk factors (CVRFs) have been linked to both depression and cognitive decline but their role in neuropsychiatric symptoms (NPS) has yet to be clarified. Objective: Understanding the role of CVRFs in the etiology of NPS for prospective treatments and preventive strategies to minimize these symptoms. Methods: We examined the distribution of NPS using the Neuropsychiatric Inventory (NPI) scores in three cohorts from the Prevention of Alzheimer’s Dementia with Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression (PACt-MD) study: older patients with a lifetime history of major depressive disorder (MDD) …in remission, patients with mild cognitive impairment (MCI), and patients with combined MCI and MDD. We also examined the link between individual NPS and CVRFs, Framingham risk score, and Hachinski ischemic score in a combined sample. Results: Analyses were based on a sample of 140 subjects, 70 with MCI, 38 with MCI plus MDD, and 32 with MDD. There was no effect of age, gender, education, cognition, or CVRFs on the presence (NPI >1) or absence (NPI = 0) of NPS. Depression was the most prevalent affective NPS domain followed by night-time behaviors and appetite changes across all three diagnostic groups. Agitation and aggression correlated negatively while anxiety, disinhibition, night-time behaviors, and irritability correlated positively with CVRFs (all p -values <0.05). Other NPS domains showed no significant association with CVRFs. Conclusion: CVRFs are significantly associated with individual NPI sub-scores but not with total NPI scores, suggesting that different pathologies may contribute to different NPS domains. Show more

Keywords: Affective symptoms, sep alzheimer’s disease, sep cardiovascular diseases, sep cognitive dysfunction, sep dementia, sep major depressive disorder, sep mental status and dementia tests, sep neurobehavioral manifestations

DOI: 10.3233/JAD-181099

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1305-1311, 2019

Authors: Bohlken, Jens | Kostev, Karel

Article Type: Research Article

Abstract: Background: The diagnosis of mild cognitive impairment (MCI) is becoming increasingly important for the medical treatment of dementia. Objective: The aim of this study was to investigate whether the coded prevalence of MCI changed in the period from 2007 to 2017 compared to dementia diagnoses. Methods: This was a retrospective evaluation of diagnostic data from 432 general practitioner (GP) practices and 53 neuropsychiatrist (NP) practices in Germany based on the Disease Analyzer database (IQVIA). The frequencies with which MCI and dementia were diagnosed in these practices were determined. The frequency with which dementia was …diagnosed was included to determine whether the change in the frequency of MCI diagnoses was due to the increase in dementia prevalence. Results: It was found that the number of GP practices with patients receiving MCI diagnoses increased from 16% to 46%, while the number of NP practices with patients receiving MCI diagnoses increased from 55% to 75%. Moreover, the study found an increase in the coded prevalence of MCI from 0.4 to 1.9 patients/GP practice and from 6.5 to 11.1 patients/NP practice were observed. Conclusions: A growing number of GPs and NPs code MCI with increasing frequency. However, the coding frequency of MCI in 2017 corresponded to less than 10% of its true prevalence. A sharp increase in MCI diagnoses can be expected, along with the establishment of preventive and disease-modifying dementia strategies. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, preclinical dementia, prevalence, real-world data

DOI: 10.3233/JAD-181180

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1313-1318, 2019

Authors: Tan, Eva Y.L. | Köhler, Sebastian | Hamel, Renske E.G. | Muñoz-Sánchez, Juan Luis | Verhey, Frans R.J. | Ramakers, Inez H.G.B.

Article Type: Research Article

Abstract: Background: Affective symptoms are considered a risk factor or prodromal symptom for dementia. Recent reviews indicate that depressive symptoms predict progression from mild cognitive impairment (MCI) to dementia, but results need to be further explored. Objective: To investigate the effect of depressive symptoms on the development of dementia in people with MCI, and explore potential sources of between-study variability, including study setting by a systematic review and meta-analysis. Methods: Databases were searched for prospective studies defining people with MCI at baseline, investigating dementia at follow-up and giving information about depressive symptoms. Two authors independently extracted data …from the studies and rated the methodological quality. Meta-analyses were conducted using random-effect models to yield pooled risk ratios (RR). Meta-regression analyses tested differences between clinical and community-based studies and other sources of heterogeneity. Results: Thirty-five studies, representing 14,158 individuals with MCI, were included in the meta-analysis. Depressive symptoms in MCI predicted dementia in 15 community-based studies (RR = 1.69, 95% CI 1.49–1.93, I2  = 0.0%), but not in 20 clinical studies (RR = 1.02, 95% CI 0.92–1.14, I2  = 73.0%). Further investigation of this effect showed that the mean age of community-based studies was significantly higher than of clinical studies but neither this nor other study characteristics explained variability in study outcomes. Conclusions: Depressive symptoms are associated with an increased risk of conversion from MCI to dementia in community-based studies. In contrast, evidence in clinical populations was insufficient with high heterogeneity. Show more

Keywords: Dementia, depression, depressive symptoms, meta-analysis, mild cognitive impairment, risk factors, systematic review

DOI: 10.3233/JAD-180513

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1319-1329, 2019

Authors: Lu, Hanna | Chan, Sandra S.M. | Lam, Linda C. W.

Article Type: Research Article

Abstract: Background: Scalp to cortex distance (SCD), as a key technological parameter, has been highlighted in the guidelines of non-invasive brain stimulation. However, in the context of age-related brain changes, the region-specific SCD and its impact on stimulation-induced electric field remain unclear. Objective: This study aimed to investigate the region-specific SCD and its relationship with morphometric features and cognitive function in age- and disease-specific populations. Methods: We analyzed the SCD and cortical thickness (CT) of left primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) in 214 cognitively normal adults and 43 dementia patients. CT-adjusted SCD was …used to control the influence of CT on SCD. Head model was developed to simulate the impact of SCD on the electric field induced by transcranial electrical stimulation. Results: We found age-related increased SCD in the left DLPFC (p  < 0.001), but not M1 (p  = 0.134), and dementia-related increased SCD in both left DLPFC (p  < 0.001) and M1 (p  < 0.001). CT-adjusted SCD showed greater region-specific impact on left DLPFC rather than M1. The electric field induced by stimulation was consequently decreased with the increased SCD across normal aging and dementia groups. Conclusions: Age and dementia have differential impacts on the SCDs of left DLPFC and M1. The findings suggest that it is important to be aware of region-specific distance measures when conducting neuromodulation in individuals with old age and dementia. Show more

Keywords: Cortical thickness, dementia, dorsolateral prefrontal cortex, electric field, neuromodulation, primary motor cortex, scalp to cortex distance

DOI: 10.3233/JAD-180732

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1331-1341, 2019

Authors: Rinne, Juha O. | Suotunen, Timo | Rummukainen, Jaana | Herukka, Sanna-Kaisa | Nerg, Ossi | Koivisto, Anne M. | Rauramaa, Tuomas | Någren, Kjell | Hiltunen, Mikko | Alafuzoff, Irina | Rinne, Jaakko | Jääskeläinen, Juha E. | Soininen, Hilkka | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-β (Aβ) pathology. Objective: To compare the [11 C]PIB PET uptake in the patients with suspected iNPH to Aβ and hyperphosphorylated-tau (HPτ ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aβ, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer’s disease (AD). Methods: Patients (n  = 21) from Kuopio NPH Registry (http://www.uef.fi/nph ) with intraventricular pressure monitoring, immunostaining for Aβ and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating …underwent [11 C]PIB PET. Aβ, total tau, and Pτ 181 were measured by ELISA from the ventricular (n  = 15) and the lumbar (n  = 9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3–1). Results: [11 C]PIB uptake in the right frontal cortex (ρ = 0.60, p  < 0.01) and the combined neocortical [11 C]PIB uptake score (ρ = 0.61, p  < 0.01) were associated with a higher Aβ load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [11 C]PIB uptake was also associated with the ventricular CSF Aβ (ρ = –0.58, p  = 0.03). Conclusions: The findings show that [11 C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aβ pathology in the patients with iNPH might also warrant treatment with current AD drugs. Show more

Keywords: Amyloid, brain biopsy, cerebrospinal fluid, normal pressure hydrocephalus, positron emission tomography

DOI: 10.3233/JAD-180645

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1343-1351, 2019

Authors: Aluganti Narasimhulu, Chandrakala | Mitra, Connie | Bhardwaj, Deepshikha | Burge, Kathryn Young | Parthasarathy, Sampath

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder associated with aging. Cardiovascular risk factors like hypertension and atherosclerosis increase the risk for AD. Polymorphic alleles of apolipoprotein E (ApoE) are one of the main genetic determinants of AD. Objective: Mice, double-knockout (DKO) for ApoE (major cholesterol carrier in brain) and PON1 (paroxonase1, reduces oxidative stress), showed severe age-dependent atherosclerosis of the arteries carrying blood to the brain even on normal diet. This prompted us to investigate the possibility of an AD pathology resulting from the deficiency of ApoE and the induction of oxidative stress. Methods: Atherosclerotic …lesions were quantified by ImageJ. The brain hippocampus of young and old ApoE-PON1 DKO mice and control mice were harvested. RT-PCR analysis was performed for mRNA levels of AD specific markers. Blood levels of S100 calcium-binding protein B (S100B) protein were measured by ELISA. H&E as well as immunostaining was performed to detect amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in brain tissues. Evans blue dye was used to evaluate the vascular permeability and blood-brain barrier (BBB) dysfunction. Results: Results showed that the older DKO mice had severe carotid atherosclerosis, increased mRNA levels of AD markers in brain tissue, and elevated levels of serum S100B protein. Immunological staining confirmed the characteristics of AD. Ex-vivo imaging showed higher levels of Evans blue dye in the ApoE-PON1 DKO mice brain tissues, pointing toward impaired vasculature. Conclusion: Aged ApoE-PON1 DKO mice displaying AD specific markers along with Aβ plaques, NFTs, and disrupted BBB suggests the animals are suffering from AD. Show more

Keywords: Atherosclerosis, blood-brain barrier, neurological markers, PON1

DOI: 10.3233/JAD-180883

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1353-1365, 2019

Authors: Jenkins, Amy | Tree, Jeremy J. | Thornton, Ian M. | Tales, Andrea

Article Type: Research Article

Abstract: Although subjective cognitive impairment (SCI) is increasingly recognized clinically and in research as a risk factor for mild cognitive impairment and dementia (particularly Alzheimer’s disease), it is etiologically heterogeneous and potentially treatable. Compared to mild cognitive impairment and Alzheimer’s disease, SCI however remains poorly characterized with debate continuing regarding its clinical relevance. The primary aim of this study was to improve the characterization of SCI within the general public by investigating functions sometimes omitted clinically or in research, namely visual attention-related information processing speed (RT) and its intra-individual variability (IIVRT ), general cognition, depression, anxiety, memory, quality of life (QOL), …and neuroticism. Compared to individuals without SCI, those with SCI were more likely to reveal higher scores of anxiety, depression, and neuroticism and poorer perceived physical, psychological, and environmental QOL. Within-group analysis identified no significant relationships between any of the above variables for the non-SCI group whereas for the SCI group, poorer Cognitive Change Index scores were significantly correlated with slower RT, raised IIVRT , poorer memory, negative affective symptoms, higher neuroticism scores, and poorer QOL. This indicates that reports of perceived memory changes in SCI can also be associated with other characteristics, namely objectively measured detrimental change in other aspects of brain function and behavior. This outcome emphasizes the importance of a multi-function approach to characterizing and understanding SCI. Thus, although the effect of RT and IIVRT is not strong enough to differentiate SCI from non-SCI at group level, slowing and raised IIVRT do appear to characterize some people with SCI. Show more

Keywords: Anxiety, dementia, depression, memory, neuroticism, quality of life, reaction time, subjective cognitive impairment, visual attention

DOI: 10.3233/JAD-180810

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1367-1378, 2019

Authors: Rizzo, Roberta | Bortolotti, Daria | Gentili, Valentina | Rotola, Antonella | Bolzani, Silvia | Caselli, Elisabetta | Tola, Maria Rosaria | Di Luca, Dario

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, where neuroinflammation and immune cells are key pathological factors. Recently, it was suggested a possible association between AD and human herpesvirus 6 (HHV-6) infection. Since we recently observed that multiple sclerosis patients with KIR2DL2 expression on natural killer (NK) cells are more susceptible to herpesvirus infection, we tested the possible implication of KIR/HLA genetic for HHV-6A infection. We identified, for the first time, a possible implication of a specific KIR/HLA subset in AD. The combination KIR2DS2/KIR2DL2/C1 correlated with a lower MMSEDi score, representative of a severe AD status and an increased …susceptibility to HHV-6A infection. Therefore, the results seem to converge on the hypothesis that herpesvirus infection might play a role in AD. If this hypothesis finds experimental confirmation, a new therapeutic strategy, modulating KIR2DL2 expression on NK cells, for AD might be envisaged. Show more

Keywords: Alzheimer’s disease, herpesvirus, HHV-6A, KIR, NK cell

DOI: 10.3233/JAD-180777

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1379-1389, 2019

Authors: Evgen’ev, Michael | Bobkova, Natalia | Krasnov, George | Garbuz, David | Funikov, Sergei | Kudryavtseva, Anna | Kulikov, Alexei | Samokhin, Alexander | Maltsev, Andrey | Nesterova, Inna

Article Type: Research Article

Abstract: In humans, heat shock protein 70 is a key component of the machinery that protects neuronal cells from various stress conditions and whose production significantly declines during aging. Herein, we investigated the protective effect of sub-chronic intranasal administration of human Hsp70 on the state of neurons in the temporal cortex and areas of the hippocampus of old transgenic (Tg) 5XFAD mice (11–13 months), representing a late-onset model of hereditary Alzheimer’s disease. Quantitative analysis of the various neuronal pathologies between the two groups (Tg versus nTg) revealed maximal levels of abnormalities in the brains of aged Tg mice. Importantly, intranasal application …of HSP70 had profound beneficial effects on neuron morphology in the temporal cortex and hippocampal regions when applied to the aged Tg mice but not in the case of age-matched, non-transgenic, littermate animals. Furthermore, the effect of HSP70 administration on neurons in the hippocampus and temporal cortex differed characteristically between the groups. Using RNA-Seq, we identified a lot of differentially expressed genes in the hippocampus of old Tg mice compared with those of nTg mice. Most importantly, we observed HSP70-induced upregulation of multiple genes participating in antigen processing and presentation especially the members of major histocompatibility complex (class I and II) in the brains of old 5XFAD Tg animals, suggesting that Hsp70 executes its beneficial role via activation of adaptive immunity. Overall, our data enable to conclude that Hsp70 treatment may be a safe and effective therapeutic application against Alzheimer-type neuropathologies manifested at the late stages of the disease. Show more

Keywords: 5XFAD, Aging, hippocampus, neuronal pathology, recombinant HSP70, temporal cortex, transcriptome

DOI: 10.3233/JAD-180987

Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1391-1404, 2019