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

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