Journal of Alzheimer's Disease - Volume 66, issue 1

Authors: Medvedev, Alexei E. | Radko, Sergey P. | Yurinskaya, Marina M. | Vinokurov, Maxim G. | Buneeva, Olga A. | Kopylov, Arthur T. | Kozin, Sergey A. | Mitkevich, Vladimir A. | Makarov, Alexander A.

Article Type: Research Article

Abstract: Angiotensin converting enzyme (ACE) is involved in proteolytic processing of the amyloid-β(Aβ) peptide implicated in the development of Alzheimer’s disease (AD) and known products of ACE-based processing of Aβ42 are characterized by reduced aggregability and cytotoxicity. Recently it has been demonstrated that ACE can act as an arginine specific endopeptidase cleaving the N-terminal pentapeptide (Aβ1-5 ) from synthetic Aβ peptide analogues. In the context of proteolytic processing of full length Aβ42 , this suggests possible formation of Aβ6-42 species. The aim of this study was to test a hypothesis that some N-terminally truncated Aβ peptide(s) could retain aggregability …and neurotoxic properties typical for Aβ42 . We have investigated aggregability of two amyloid-β peptides, Aβ6-42 and isoD7-Aβ6-42 , mimicking potential proteolytic products of Aβ42 and isoD7-Aβ42 , and evaluated their effects on the repertoire of brain Aβ binding proteins, and cytotoxicity towards neuroblastoma SH-SY5Y cells. Aggregability of isoD7-Aβ6-42 and Aβ6-42 was higher than that of full-length peptides Aβ42 and isoD7-Aβ42 , while the repertoire of mouse brain Aβ binding proteins dramatically decreased. Aβ6-42 and isoD7-Aβ6-42 exhibited higher neurotoxicity towards SH-SY5Y cells than Aβ42 and isoD7-Aβ42 , respectively. They effectively stimulated production of ROS and NO, and also TNFα secretion by cells. Thus, our results suggest that ACE-dependent processing of full-length Aβs could result in formation of more pathogenic peptides. Show more

Keywords: Aβ6-42 species, Aβ42 , Aβ binding proteins, aggregability, angiotensin converting enzyme, cytotoxicity, proteolytic processing

DOI: 10.3233/JAD-180500

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 263-270, 2018

Authors: Bera, Géraldine | Migliaccio, Raffaella | Michelin, Thibaut | Lamari, Foudil | Ferrieux, Sophie | Nogues, Marie | Bertin, Hugo | Habert, Marie Odile | Dubois, Bruno | Teichmann, Marc | Kas, Aurélie

Article Type: Research Article

Abstract: Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer’s disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this …PPA variant. Show more

Keywords: Alzheimer’s disease, atypical AD, cerebrospinal fluid examination, parietal lobe, semantic variant of primary progressive aphasia, single photon emission computed tomography

DOI: 10.3233/JAD-180087

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 271-280, 2018

Authors: Monacelli, Fiammetta | Pizzonia, Monica | Signori, Alessio | Nencioni, Alessio | Giannotti, Chiara | Minaglia, Cecilia | Granello di Casaleto, Tommaso | Podestà, Silvia | Santolini, Federico | Odetti, Patrizio

Article Type: Research Article

Abstract: Background: Hip fracture is a major health problem and a patient’s biological age, comorbidity, and cognitive vulnerability have an impact on its related outcomes. Length of stay (LOS) for these highly vulnerable patients is rather long and the possible causes have not been clearly identified yet. Objective: We aimed to assess the main clinical factors associated with protracted LOS, focusing on delirium with or without dementia in older age hip fractured patients. Methods: 218 subjects (mean age 86.70±6.18 years), admitted to the Orthogeriatric Unit of the Ospedale Policlinico San Martino (Italy), were recruited. …All patients received physical and comprehensive geriatric assessment. Days to surgery, days from surgery to rehabilitation, and LOS were recorded. In-hospital and three months’ mortality were reported. Results: Prevalent delirium at hospital admission was of 3.1%. 35% of patients developed incident delirium. 56.4% were affected by dementia of Alzheimer-type. In addition, 52% of patients developed delirium superimposed to dementia. Mean LOS was 13.5±4.99 days. Namely, delirium, time to surgery, and complication rate disproportionally affected LOS. The analysis with 3 months mortality, based on cognitive vulnerability profiles, showed how delirium mainly affect short-term mortality in patients with dementia. Conclusion: Our exploratory study originally pointed out the high incidence of delirium superimposed to dementia in orthogeriatric wards and how delirium turns to be a moderator of LOS. The results meet the need for additional research by virtue of a deeper understanding of the impact of delirium and dementia on orthogeriatric clinical management and outcomes. Show more

Keywords: Cognitive vulnerability, dedicated orthogeriatric pathway, hip fracture, length of stay

DOI: 10.3233/JAD-180153

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 281-288, 2018

Authors: Ohtani, Ryo | Nirengi, Shinsuke | Nakamura, Michikazu | Murase, Nagako | Sainouchi, Makoto | Kuwata, Yasuhiro | Takata, Masaki | Masuda, Yuuichi | Kotani, Kazuhiko | Sakane, Naoki

Article Type: Research Article

Abstract: Background: High-density lipoprotein (HDL) containing apolipoprotein A-I is associated with the pathogenesis of Alzheimer’s disease (AD). HDL particle size is modified in the presence of pathological conditions, while the significance of the HDL particle size remains controversial. Objective: The aim of this study was to investigate the HDL lipoprotein subclasses in mild cognitive impairment (MCI) and AD. Methods: This cross-sectional study included 20 AD patients, 17 MCI patients, and 17 age-matched controls without cognitive impairment, selected from the database of the Study of Outcome and aPolipoproteins in Dementia (STOP-Dementia) registry. The diagnoses of …AD and MCI were performed by expert neurologists according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria. Serum HDL subclasses were measured by electrophoretic separation of lipoproteins using the Lipoprint System. The neutrophil-lymphocyte ratio (NLR), a marker of inflammation, was calculated by dividing the neutrophil count by the lymphocyte count. Results: Small-sized HDL particle levels in the MCI group were significantly higher than in the control group, although there was no difference in serum HDL-cholesterol levels between MCI and control groups. NLR in the MCI group was higher than in the control group, but this difference was non-significant (p  = 0.09). There was no difference in HDL subclasses or NLR between the AD and control groups. Conclusion: These findings suggest that HDL subclasses might be associated with the development of MCI. Show more

Keywords: Alzheimer’s disease, HDL subfraction, high-density lipoprotein, inflammation, mild cognitive impairment

DOI: 10.3233/JAD-180135

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 289-296, 2018

Authors: Cui, Chendi | Sekikawa, Akira | Kuller, Lewis H. | Lopez, Oscar L. | Newman, Anne B. | Kuipers, Allison L. | Mackey, Rachel H.

Article Type: Research Article

Abstract: Cardiovascular disease risk factors, including age, hypertension, and diabetes, contribute to aortic stiffness and subclinical cardiovascular and brain disease, increasing dementia risk. Aortic stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), reduces the buffering of pulsatile blood flow, exposing cerebral small arteries to microvascular damage. High cfPWV is related to white matter hyperintensities and brain amyloid deposition, and to cognitive decline, but it is unclear whether cfPWV independently predicts incident dementia. Therefore, we tested the hypothesis that cfPWV predicts incident dementia in older adults, independent of potential confounders. The Cardiovascular Health Study Cognition Study followed 532 non-demented older adults with …annual cognitive exams from 1998-99 through 2013. CfPWV was measured on 356 (mean age = 78, 59% women) between 1996–2000. Over 15 years, 212 (59.6%) developed dementia (median time from cfPWV measurement = 4 years). In age and sex-adjusted Cox models, cfPWV was significantly associated with increased risk of dementia, but systolic blood pressure, mean arterial pressure and pulse pressure were not. CfPWV (transformed as – 1/cfPWV) remained significantly associated with dementia risk when further adjusted for education, race, APOE ɛ 4, diabetes, body mass index, mean arterial pressure, and anti-hypertensive medication (hazard ratio = 1.60, 95% CI = 1.02, 2.51). Results were similar when further adjusted for baseline global cognition, subclinical brain measures, and coronary artery calcification. Finally, higher cfPWV was related to lower physical activity intensity and higher systolic blood pressure, heart rate, and waist circumference measured 5 years prior. An important unanswered question is whether interventions to slow arterial stiffening can reduce the risk of dementia. Show more

Keywords: Dementia, pulse wave velocity, risk factors, vascular stiffness

DOI: 10.3233/JAD-180449

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 297-306, 2018

Authors: Baran, Timothy M. | Lin, Feng Vankee | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Some individuals, called Supernormals (SN), maintain excellent memory in old age. While brain structural and functional integrity in SN seem to be aging-resistant, their amyloidosis and neural injury status has not been well studied. Objective: The goal of this study was to compare cortical amyloid deposition and glucose metabolism between SN and older adults with normal cognition (NC), amnestic mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Methods: Subjects from the ADNI database were included if they received T1-weighted MRI, amyloid PET, FDG-PET, and cognitive testing within a 6-month period, yielding 27 AD, 69 MCI, …172 NC, and 122 SN. PET standardized uptake value ratios (SUVrs) were calculated for the whole cortex and 68 regions of interest, with whole cerebellum serving as reference. Results: SN had lower whole cortex amyloid than MCI, and higher glucose metabolism than all others. Regional analysis revealed that amyloid burden and glucose metabolism in the right isthmus cingulate cortex differed in SN compared to others, while SN glucose metabolism also differed from others in several frontal and temporal regions. Conclusion: Preserved cortical glucose metabolism, and lower levels of amyloidosis and glucose hypometabolism in the right isthmus cingulate cortex, contributes to the Supernormal phenomenon. These findings may be informative for development of early screening biomarkers and therapeutic targets for modification of cognitive trajectories. Show more

Keywords: Amyloid-β, glucose metabolism, magnetic resonance imaging, positron emission tomography, successful cognitive aging, supernormal

DOI: 10.3233/JAD-180360

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 307-318, 2018

Authors: Nakajima, Madoka | Miyajima, Masakazu | Ogino, Ikuko | Akiba, Chihiro | Kawamura, Kaito | Kamohara, Chihiro | Fusegi, Keiko | Harada, Yoshinao | Hara, Takeshi | Sugano, Hidenori | Tange, Yuichi | Karagiozov, Kostadin | Kasuga, Kensaku | Ikeuchi, Takeshi | Tokuda, Takahiko | Arai, Hajime

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer’s disease (AD) pathology is debated. Objective: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. Methods: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal …Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n  = 24; mean age 75.7 years [SD 5.3]) and high (n  = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. Results: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p  = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p  = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2  = 0.352, p  < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group. Conclusions: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid shunt, normal pressure hydrocephalus, phosphorylation, prognosis, tau proteins

DOI: 10.3233/JAD-180557

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 319-331, 2018

Authors: Gao, Yuan | Liu, En-Jie | Wang, Wei-Jin | Wang, Ya-Li | Li, Xiao-Guang | Wang, Xin | Li, Shi-Hong | Zhang, Shu-Juan | Li, Meng-Zhu | Zhou, Qiu-Zhi | Long, Xiao-Bing | Zhang, Hua-Qiu | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Extracellular accumulation of amyloid-β (Aβ) forming senile plaques is one of the hallmark pathologies in Alzheimer’s disease (AD), while the mechanisms underlying the neuronal toxic effect of Aβ are not fully understood. Here, we found that intracerebroventricular infusion of the aged Aβ42 in mice only induces memory deficit at 24 h but not at 7 days. Interestingly, a remarkably increased CREB (cAMP response element-binding protein) Ser133-phosphorylation (pS133-CREB) with microglial activation was detected at 24 h but not at 7 days after Aβ infusion. Aβ treatment for 24 h increased pS133-CREB level in microglia of the hippocampal non-granular cell layers with remarkably decreased …pS133-CREB immunoreactivity in neurons of the hippocampal granular cell layers, including CA1, CA3, and DG subsets. Inhibition of microglia activation by minocycline or CREB phosphorylation by H89, an inhibitor of protein kinase A (PKA), abolished Aβ-induced microglia CREB hyperphosphorylation with restoration of neuronal function and attenuation of inflammatory response, i.e., reduced levels of interleukin-6 (IL6) and pCREB binding of matrix metalloproteinase-9 (MMP9) DNA. Finally, treatment of the primary hippocampal neurons with Aβ-potentiated microglia media decreased neuronal GluN1 and GluA2 levels, while simultaneous inhibition of PKA restored the levels. These novel findings reveal that intracerebroventricular infusion of Aβ only induces transient memory deficit in mice and the molecular mechanisms involve a stimulated microglial CREB phosphorylation. Show more

Keywords: Alzheimer’s disease, amyloid-β, cAMP response element-binding protein, microglia, protein kinase A

DOI: 10.3233/JAD-180286

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 333-345, 2018

Authors: Zammit, Andrea R. | Hall, Charles B. | Katz, Mindy J. | Muniz-Terrera, Graciela | Ezzati, Ali | Bennett, David A. | Lipton, Richard B.

Article Type: Research Article

Abstract: Identifying preclinical Alzheimer’s disease (AD) is an important step toward developing approaches to early treatment and dementia prevention. We applied latent class analysis (LCA) to 10 baseline neuropsychological assessments for 1,345 participants from Einstein Aging Study. Time-to-event models for all-cause dementia and AD were run examining events in 4-year intervals. Five classes were identified: Mixed-Domain Impairment (n = 107), Memory-Specific Impairment (n = 457), Average (n = 539), Frontal Impairment (n = 118), and Superior Cognition (n = 124). Compared to the Average class, the Mixed-Domain Impairment and Memory-Specific Impairment classes were at higher risk …of incident all-cause dementia and AD in the first 4 years from baseline, while the Frontal Impairment class was associated with higher risk between 4 and 8 years of follow-up. LCA identified classes which differ in cross-sectional cognitive patterns and in risk of dementia over specific follow-up intervals. Show more

Keywords: All-cause dementia, Alzheimer’s disease, cognitive aging, cognitive subtypes, heterogeneity, individual differences, neuropsychology

DOI: 10.3233/JAD-180604

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 347-357, 2018

Authors: Schlenzig, Dagmar | Cynis, Holger | Hartlage-Rübsamen, Maike | Zeitschel, Ulrike | Menge, Katja | Fothe, Anja | Ramsbeck, Daniel | Spahn, Claudia | Wermann, Michael | Roßner, Steffen | Buchholz, Mirko | Schilling, Stephan | Demuth, Hans-Ulrich

Article Type: Research Article

Abstract: The formation of amyloid-β (Aβ) peptides is causally involved in the development of Alzheimer’s disease (AD). A significant proportion of deposited Aβ is N-terminally truncated and modified at the N-terminus by a pGlu-residue (pGlu-Aβ). These forms show enhanced neurotoxicity compared to full-length Aβ. Although the truncation may occur by aminopeptidases after formation of Aβ, recently discovered processing pathways of amyloid-β protein precursor (AβPP) by proteases such as meprin β may also be involved. Here, we assessed a role of meprin β in forming Aβ3 -40/42 , which is the precursor of pGlu-Aβ3 -40/42 generated by glutaminyl cyclase (QC). Similar …to QC, meprin β mRNA is significantly upregulated in postmortem brain from AD patients. A histochemical analysis supports the presence of meprin β in neurons and astrocytes in the vicinity of pGlu-Aβ containing deposits. Cleavage of AβPP-derived peptides by meprin β in vitro results in peptides Aβ1 -x , Aβ2 -x , and Aβ3 -x . The formation of N-truncated Aβ by meprin β was also corroborated in cell culture. A subset of the generated peptides was converted into pGlu-Aβ3 -40 by an addition of glutaminyl cyclase, supporting the preceding formation of Aβ3 -40 . Further analysis of the meprin β cleavage revealed a yet unknown dipeptidyl-peptidase–like activity specific for the N-terminus of Aβ1 -x . Thus, our data suggest that meprin β contributes to the formation of N-truncated Aβ by endopeptidase and exopeptidase activity to generate the substrate for QC-catalyzed pGlu-Aβ formation. Show more

Keywords: Amyloid-β, dipeptidyl peptidase, meprin β, secretase

DOI: 10.3233/JAD-171183

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 359-375, 2018

Authors: Mendiratta, Priya | Wei, Jeanne Y. | Dayama, Neeraj | Li, Xiaocong

Article Type: Research Article

Abstract: Background: Patients with Down syndrome (DS) often survive into adulthood. Relatively little information is currently available regarding hospitalization outcomes among mature, older adults with DS. Objective: To identify risk factors associated with hospital mortality rates and increased costs for hospitalized older adults with DS. Methods: Data on hospitalized older adults with DS (≥65 years) were identified from the Nationwide Inpatient Sample database (6) from 2002 through 2012. Multivariate analyses were performed to evaluate risk factors associated with hospital mortality and hospitalization cost in these patients. Results: A total of 2,134 older adults with DS …were identified. A temporal increase over the 11-year period was observed in the number of older adults with DS who were hospitalized (trend p < 0.0001). However, the hospital mortality rate and post-hospital discharge to skilled nursing facilities have decreased during the same time period. Risk factors associated with increased hospital mortality included advanced age (70–79 years), female gender, admissions in the western United States, and presence of comorbid conditions (ischemic heart disease, Alzheimer’s disease, and cerebrovascular accident). The mean cost was $18,241 (SD $56,105) over the 11-year period. However, no significant temporal changes in costs were noted (trend p = 0.14). Conclusions: The number of hospitalized elderly Americans with DS has increased over the 11-year period. However, hospital mortality and discharge to skilled nursing facilities have decreased during the same time period. Several demographic and co-morbid factors are associated with increased mortality. No significant differences in temporal trends in costs were noted. Show more

Keywords: Down syndrome, elderly, outcomes

DOI: 10.3233/JAD-171067

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 377-386, 2018

Authors: Sarycheva, Tatyana | Taipale, Heidi | Lavikainen, Piia | Tiihonen, Jari | Tanskanen, Antti | Hartikainen, Sirpa | Tolppanen, Anna-Maija

Article Type: Research Article

Abstract: Background: Although antiepileptic drugs (AEDs) have a potential for adverse drug reactions in older populations, little is known about their use in relation to Alzheimer’s disease (AD) diagnosis. Objectives: In this study, we investigated the incidence and prevalence of AED use in relation to AD diagnosis. Methods: The MEDALZ–study includes all Finnish persons who received clinically verified AD diagnoses (n  = 70,718) during 2005–2011 and a matched comparison cohort without AD (n  = 70,718). AD diagnoses were identified from the Special Reimbursement Register. We used the Prescription Register to identify dispensed AEDs. Incident AED users were identified with …a one-year washout period 9-10 years before AD diagnosis, and incidence rates per 100 person-years were calculated for each six-month period from nine years before to five years after AD diagnosis. Prevalence was assessed as proportion using AEDs during each six-month time period for incident use. Results: Persons with AD were more likely to use AEDs during the study period (4.3%) than persons without AD (3.2%). The incidence and prevalence of AED use was higher among persons with AD and increased around the time of AD diagnosis. Epilepsy diagnoses did not explain these differences. Persons with AD were more likely to use older AEDs. Conclusion: Our study highlights the need to balance effective symptom control with the possible risks of treatment. Show more

Keywords: Alzheimer’s disease, antiepileptic drugs, dementia, incidence, prevalence

DOI: 10.3233/JAD-180594

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 387-395, 2018

Authors: McCade, Donna L. | Guastella, Adam J. | Chen, Nigel T.M. | Lewis, Simon J.G. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Research suggests that deficits in emotion recognition are evident in individuals with amnestic mild cognitive impairment (aMCI), a group ‘at risk’ of developing dementia. The mechanisms underlying this deficit, however, are unclear. Objective: In this study, we sought to determine whether there are alterations in the way in which individuals with MCI visually explore emotional facial stimuli. Methods: Eighteen healthy older controls (mean age = 64.6 years) and 32 individuals with MCI were recruited including 18 with the non-amnestic multiple domain (naMCI-md) subtype (mean age = 63.8 years) and 14 with the amnestic multiple domain (aMCI-md) subtype (mean age = 67.9 …years). All participants were given a novel eye-tracking paradigm to investigate eye gaze while viewing images of emotional faces on a computer screen. Results: Analyses of eye gaze revealed no significant difference in the percentage of time that groups spent fixating on facial and peripheral facial regions when viewing emotional faces. All participants showed a relative preference for the eye region of faces relative to all other regions. Individuals with aMCI-md were found to be less accurate than controls and naMCI-md on emotion recognition measures. For naMCI-md individuals, significant relationships were found between efficiencies in visual scanning and increased fixation time on the eye region. Conclusions: Visual processing strategies adopted by aMCI-md individuals when exploring emotional faces do not significantly differ from those of healthy controls or naMCI-md individuals. This suggests that impaired facial emotion recognition in aMCI-md is not likely accounted for by visual processing differences, but rather may reflect an eroded ability to extract meaningful cues from the eye region. Show more

Keywords: Dementia, emotion recognition, eye tracking, mild cognitive impairment

DOI: 10.3233/JAD-170175

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 397-405, 2018

Authors: Wirth, Klaus J.

Article Type: Research Article

Abstract: Background: Cerebral hypoperfusion and degeneration of the noradrenergic locus coeruleus (LC) occur early in Alzheimer’s disease (AD). Cerebral blood vessels are densely innervated by noradrenergic projections from the LC suggesting a functional role for the regulation of cerebral blood flow (CBF). Experimental LC stimulation, however, has provided no clarity as decreases or increases in CBF were reported from different experimental settings and investigators. Objective: To find out with pharmacological methods whether endogenously released norepinephrine (NE) increases or decreases carotid artery blood flow (CABF) in anesthetized pigs by investigating the effect of centrally acting alpha-2 adrenergic drugs, which increase …(atipamezole) or decrease (xylazine) NE in the brain. Methods: CABF was measured by a Doppler-flow probe placed around the left carotid artery in pentobarbital anesthetized young pigs. Results: Neither current antihypertensive drugs nor pharmacological stimulation of dopamine, histamine, serotonin or acetylcholine receptors changed CABF. The alpha-2 adrenergic-receptor agonist xylazine decreased, while the antagonist atipamezole raised CABF. This rise was abolished by a combined treatment with endothelial NO-synthase inhibitor Nω -Nitro-L-arginine methyl ester (L-NAME) and the non-selective β-receptor antagonist propranolol. Propranolol alone did not decrease CABF in contrast to L-NAME but decreased CABF after L-NAME, surprisingly. Conclusion: Pharmacological evidence suggests that NE released in the brain of anesthetized pigs raises CABF involving β-adrenergic mechanisms and nitric oxide. If in awake humans NE released from the LC had vasodilator effects early LC degeneration could be involved in early cerebral hypoperfusion of AD. Moreover, a cerebral adrenergic vascular innervation deficit, possibly resulting from LC degeneration, and systemic endothelial dysfunction together may act synergistically to reduce CBF. Show more

Keywords: Alpha-2 adrenergic drugs, Alzheimer’s disease, atipamezole, carotid artery blood flow, cerebral blood flow, cerebral hypoperfusion, degeneration, locus coeruleus, pigs, propranolol, xylazine

DOI: 10.3233/JAD-180340

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 407-419, 2018