Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease

Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD

Why Pleiotropic Interventions are Needed for Alzheimer's Disease

Alzheimer's disease (AD) involves a complex pathological cascade thought to be initially triggered by the accumulation of β-amyloid (Aβ) peptide aggregates or aberrant amyloid precursor protein (APP) processing. Much is known of the factors initiating the disease process decades prior to the onset of cognitive deficits, but an unclear understanding of events immediately preceding and precipitating cognitive decline is a major factor limiting the rapid development of adequate prevention and treatment strategies. Multiple pathways are known to contribute to cognitive deficits by disruption of neuronal signal transduction pathways involved in memory. These pathways are altered by aberrant signaling, inflammation, oxidative damage, tau pathology, neuron loss, and synapse loss. We need to develop stage-specific interventions that not only block causal events in pathogenesis (aberrant tau phosphorylation, Aβ production and accumulation, and oxidative damage), but also address damage from these pathways that will not be reversed by targeting prodromal pathways. This approach would not only focus on blocking early events in pathogenesis, but also adequately correct for loss of synapses, substrates for neuroprotective pathways (e.g., docosahexaenoic acid), defects in energy metabolism, and adverse consequences of inappropriate compensatory responses (aberrant sprouting). Monotherapy targeting early single steps in this complicated cascade may explain disappointments in trials with agents inhibiting production, clearance, or aggregation of the initiating Aβ peptide or its aggregates. Both plaque and tangle pathogenesis have already reached AD levels in the more vulnerable brain regions during the “prodromal” period prior to conversion to “mild cognitive impairment (MCI).” Furthermore, many of the pathological events are no longer proceeding in series, but are going on in parallel. By the MCI stage, we stand a greater chance of success by considering pleiotropic drugs or cocktails that can independently limit the parallel steps of the AD cascade at all stages, but that do not completely inhibit the constitutive normal functions of these pathways. Based on this hypothesis, efforts in our laboratories have focused on the pleiotropic activities of omega-3 fatty acids and the anti-inflammatory, antioxidant, and anti-amyloid activity of curcumin in multiple models that cover many steps of the AD pathogenic cascade (Cole and Frautschy, Alzheimers Dement 2:284–286, 2006)

Influence of infected cell growth state on bacteriophage reactivation levels.

Reactivation of UV-C-inactivated Pseudomonas aeruginosa bacteriophages D3C3, F116, G101, and UNL-1 was quantified in host cells infected during the exponential phase, during the stationary phase, and after starvation (1 day, 1 and 5 weeks) under conditions designed to detect dark repair and photoreactivation. Our experiments revealed that while the photoreactivation capacity of stationary-phase or starved cells remained about the same as that of exponential-phase cells, in some cases their capacity to support dark repair of UV-inactivated bacteriophages increased over 10-fold. This enhanced reactivation capacity was correlated with the ca. 30-fold-greater UV-C resistance of P. aeruginosa host cells that were in the stationary phase or exposed to starvation conditions prior to irradiation. The dark repair capacity of P. aeruginosa cells that were infected while they were starved for prolonged periods depended on the bacteriophage examined. For bacteriophage D3C3 this dark repair capacity declined with prolonged starvation, while for bacteriophage G101 the dark repair capacity continued to increase when cells were starved for 24 h or 1 week prior to infection. For G101, the reactivation potentials were 16-, 18-, 10-, and 3-fold at starvation intervals of 1 day, 1 week, 5 weeks, and 1. 5 years, respectively. Exclusive use of exponential-phase cells to quantify bacteriophage reactivation should detect only a fraction of the true phage reactivation potential

Influence of infected cell growth state on bacteriophage reactivation levels.

Reactivation of UV-C-inactivated Pseudomonas aeruginosa bacteriophages D3C3, F116, G101, and UNL-1 was quantified in host cells infected during the exponential phase, during the stationary phase, and after starvation (1 day, 1 and 5 weeks) under conditions designed to detect dark repair and photoreactivation. Our experiments revealed that while the photoreactivation capacity of stationary-phase or starved cells remained about the same as that of exponential-phase cells, in some cases their capacity to support dark repair of UV-inactivated bacteriophages increased over 10-fold. This enhanced reactivation capacity was correlated with the ca. 30-fold-greater UV-C resistance of P. aeruginosa host cells that were in the stationary phase or exposed to starvation conditions prior to irradiation. The dark repair capacity of P. aeruginosa cells that were infected while they were starved for prolonged periods depended on the bacteriophage examined. For bacteriophage D3C3 this dark repair capacity declined with prolonged starvation, while for bacteriophage G101 the dark repair capacity continued to increase when cells were starved for 24 h or 1 week prior to infection. For G101, the reactivation potentials were 16-, 18-, 10-, and 3-fold at starvation intervals of 1 day, 1 week, 5 weeks, and 1. 5 years, respectively. Exclusive use of exponential-phase cells to quantify bacteriophage reactivation should detect only a fraction of the true phage reactivation potential

Influence of infected cell growth state on bacteriophage reactivation levels.

Reactivation of UV-C-inactivated Pseudomonas aeruginosa bacteriophages D3C3, F116, G101, and UNL-1 was quantified in host cells infected during the exponential phase, during the stationary phase, and after starvation (1 day, 1 and 5 weeks) under conditions designed to detect dark repair and photoreactivation. Our experiments revealed that while the photoreactivation capacity of stationary-phase or starved cells remained about the same as that of exponential-phase cells, in some cases their capacity to support dark repair of UV-inactivated bacteriophages increased over 10-fold. This enhanced reactivation capacity was correlated with the ca. 30-fold-greater UV-C resistance of P. aeruginosa host cells that were in the stationary phase or exposed to starvation conditions prior to irradiation. The dark repair capacity of P. aeruginosa cells that were infected while they were starved for prolonged periods depended on the bacteriophage examined. For bacteriophage D3C3 this dark repair capacity declined with prolonged starvation, while for bacteriophage G101 the dark repair capacity continued to increase when cells were starved for 24 h or 1 week prior to infection. For G101, the reactivation potentials were 16-, 18-, 10-, and 3-fold at starvation intervals of 1 day, 1 week, 5 weeks, and 1. 5 years, respectively. Exclusive use of exponential-phase cells to quantify bacteriophage reactivation should detect only a fraction of the true phage reactivation potential

Cerebral blood flow in Alzheimer’s disease

Alex E Roher,1 Josef P Debbins,2 Michael Malek-Ahmadi,3 Kewei Chen,4 James G Pipe,2 Sharmeen Maze,2 Christine Belden,3 Chera L Maarouf,1 Pradeep Thiyyagura,4 Hua Mo,4 Jesse M Hunter,1 Tyler A Kokjohn,1,5 Douglas G Walker,6 Jane C Kruchowsky,6 Marek Belohlavek,7 Marwan N Sabbagh,3 Thomas G Beach81The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute, Sun City, 2Keller Center for Imaging Innovation, Neuroimaging Research, Barrow Neurological Institute, Phoenix, 3Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, Sun City, 4Computational Image Analysis Program, Banner Alzheimer’s Institute, Phoenix, 5Department of Microbiology, Midwestern University, Glendale, 6Laboratory of Neuroinflammation, Banner Sun Health Research Institute, Sun City, 7Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, 8Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USABackground: Alzheimer’s disease (AD) dementia is a consequence of heterogeneous and complex interactions of age-related neurodegeneration and vascular-associated pathologies. Evidence has accumulated that there is increased atherosclerosis/arteriosclerosis of the intracranial arteries in AD and that this may be additive or synergistic with respect to the generation of hypoxia/ischemia and cognitive dysfunction. The effectiveness of pharmacologic therapies and lifestyle modification in reducing cardiovascular disease has prompted a reconsideration of the roles that cardiovascular disease and cerebrovascular function play in the pathogenesis of dementia.Methods: Using two-dimensional phase-contrast magnetic resonance imaging, we quantified cerebral blood flow within the internal carotid, basilar, and middle cerebral arteries in a group of individuals with mild to moderate AD (n = 8) and compared the results with those from a group of age-matched nondemented control (NDC) subjects (n = 9). Clinical and psychometric testing was performed on all individuals, as well as obtaining their magnetic resonance imaging-based hippocampal volumes.Results: Our experiments reveal that total cerebral blood flow was 20% lower in the AD group than in the NDC group, and that these values were directly correlated with pulse pressure and cognitive measures. The AD group had a significantly lower pulse pressure (mean AD 48, mean NDC 71; P = 0.0004). A significant group difference was also observed in their hippocampal volumes. Composite z-scores for clinical, psychometric, hippocampal volume, and hemodynamic data differed between the AD and NDC subjects, with values in the former being significantly lower (t = 12.00, df = 1, P = 0.001) than in the latter.Conclusion: These results indicate an association between brain hypoperfusion and the dementia of AD. Cardiovascular disease combined with brain hypoperfusion may participate in the pathogenesis/pathophysiology of neurodegenerative diseases. Future longitudinal and larger-scale confirmatory investigations measuring multidomain parameters are warranted.Keywords: Alzheimer’s disease, cerebral blood flow, brain hypoperfusion, two-dimensional phase-contrast magnetic resonance imaging, brain morphometric analyses, atherosclerosis, arteriosclerosis, cognitive impairmen