Michael L. Spinner

Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans

Amyloid‐β42 (Aβ42) appears central to Alzheimers disease (AD) pathogenesis and is a major component of amyloid plaques. Mean cerebrospinal fluid (CSF) Aβ42 is decreased in dementia of the Alzheimers type. This decrease may reflect plaques acting as an Aβ42 “sink,” hindering transport of soluble Aβ42 between brain and CSF. We investigated this hypothesis.

P-glycoprotein deficiency at the blood-brain barrier increases amyloid-β deposition in an Alzheimer disease mouse model

Accumulation of amyloid-beta (Abeta) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased Abeta production, suggesting that decreased elimination from the brain may contribute to elevated levels of Abeta and plaque formation. Efflux transport of Abeta across the blood-brain barrier (BBB) contributes to Abeta removal from the brain. P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In Pgp-null mice, we show that [I]Abeta40 and [I]Abeta42 microinjected into the CNS clear at half the rate that they do in WT mice. When amyloid precursor protein-transgenic (APP-transgenic) mice were administered a Pgp inhibitor, Abeta levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain Abeta and enhanced Abeta deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and Abeta metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing AD as well as provide a novel diagnostic and therapeutic target.

Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain

The amyloid-β peptide (Aβ) plays a central pathophysiological role in Alzheimers disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Aβ concentrations and neurological status, with Aβ concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Aβ concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Aβ concentration.

ApoAI Deficiency Results in Marked Reductions in Plasma Cholesterol But No Alterations in Amyloid-β Pathology in a Mouse Model of Alzheimer's Disease-Like Cerebral Amyloidosis

Epidemiological studies suggest links between cholesterol metabolism and Alzheimers disease (AD), with hypercholesterolemia associated with increased AD risk, and use of cholesterol-lowering drugs associated with decreased risk. Animal models using cholesterol-modifying dietary or pharmacological interventions demonstrate similar findings. Proposed mechanisms include effects of cholesterol on the metabolism of amyloid-beta (Abeta), the protein that deposits in AD brain. To investigate the effect of genetic alterations in plasma cholesterol on Abeta pathology, we crossed the PDAPP transgenic mouse model of AD-like cerebral amyloidosis to apolipoprotein AI-null mice that have markedly reduced plasma cholesterol levels due to a virtual absence of high density lipoproteins, the primary lipoprotein in mice. Interestingly and in contrast to models using non-physiological high fat diets or cholesterol-lowering drugs to modify plasma cholesterol, we observed no differences in Abeta pathology in PDAPP mice of the various apoAI genotypes despite robust differences in plasma cholesterol levels between the groups. Absence of apoAI also resulted in reductions in brain but not cerebrospinal fluid cholesterol, but had no effect on brain apolipoprotein E levels. These and other data suggest that it is perhaps the level of brain apolipoprotein E, not cholesterol per se, that plays a primary role in brain Abeta metabolism.

Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes.

Background. Both prophylactic and preemptive oral valganciclovir therapy are effective for the management of cytomegalovirus (CMV) postrenal transplantation in the short term. The long-term effect of either strategy is less well defined. Methods. We analyzed the data on 115 adult recipients previously enrolled in a prospective randomized controlled trial of prophylaxis versus preemptive therapy for CMV. The primary outcome was a composite of freedom from acute rejection, graft loss, or death. Secondary outcomes included individual primary outcomes, posttransplant cardiovascular events, new-onset diabetes mellitus after transplantation, achievement of goal blood pressure, change in body mass index, interstitial fibrosis/tubular atrophy, and change in renal function. The analysis period was a minimum of 48-month posttransplant or a date of death or graft loss, whichever was earlier. Results. The primary outcome was similar between groups (83% prophylactic vs. 81% preemptive, P=0.754). The secondary outcomes showed similarities between the prophylactic and preemptive groups. Four patients in the prophylactic group (8%) compared with none in the preemptive group (0%) died with a functioning graft, P=0.043. Conclusions. Within the limitations of sample size, our data suggest that either strategy for the management of CMV immediately after transplantation seems effective for patient and graft survival in the long term. CMV management is one of the many therapeutic strategies incorporated into a renal transplantation protocol, which often differs among institutions, and the decision as to which approach to use remains center- and resource-specific. The increased incidence of death in the prophylactic group requires further investigation.

Neurofilament light chain levels in ventricular cerebrospinal fluid after acute aneurysmal subarachnoid haemorrhage

Purpose The contribution of axonal injury to brain damage after aneurysmal subarachnoid haemorrhage (aSAH) is unknown. Neurofilament light chain (NF-L), a component of the axonal cytoskeleton, has been shown to be elevated in the cerebrospinal fluid of patients with many types of axonal injury. We hypothesised that patients with aSAH would have elevated cerebrospinal fluid (CSF) NF-L levels and sought to explore the clinical correlates of CSF NF-L dynamics. Methods Serial ventricular CSF (vCSF) samples were collected from 35 patients with aSAH for up to 15 days. vCSF NF-L measurements were determined by enzyme-linked immunosorbent assay. NF-L levels were analysed in relation to acute clinical status, radiological findings and 6-month outcomes. Results vCSF NF-L concentrations were elevated in all patients with aSAH. Patients with early cerebral ischaemia (ECI), defined as a CT hypodense lesion visible within the first 3 days, had higher acute vCSF NF-L levels than patients without ECI. These elevated NF-L levels were similar in patients with ECI associated with intracranial haemorrhage and ECI associated with surgical/endovascular complications. vCSF NF-L levels did not differ as a function of acute clinical status, clinical vasospasm, delayed cerebral ischaemia or 6-month Glasgow Outcome Scale. Conclusions Elevated vCSF NF-L levels may in part reflect increased injury to axons associated with ECI. However, our results suggest that axonal injury after aSAH as reflected by release of NF-L into the CSF may not play a major role in either secondary adverse events or long-term clinical outcomes.

Single-dose rituximab for recurrent glomerulonephritis post-renal transplant.

Background/Aims: Post-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach. Methods: A single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) <0.3). Secondary outcomes included partial response (PR >50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence. Results: The median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16). Conclusion: Single-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.

Amyloid-ss Dynamics Correlate with Neurological Status in the Injured Human Brain

The amyloid-β peptide (Aβ) plays a central pathophysiological role in Alzheimer’s disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain. We used intracerebral microdialysis to obtain serial brain interstitial fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain ISF Aβ concentrations and neurological status, with Aβ concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Aβ concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Aβ concentration. Aβ is the principal constituent of the hallmark amyloid plaques found in Alzheimer’s disease and is the target of many potential treatments for the disease (1). However, little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human brain where these plaques form. In vitro and animal studies have shown that neuronal and synaptic activity dynamically regulate soluble extracellular Aβ concentrations (2–4). Whether similar regulation of Aβ levels occurs in the human brain is unknown. We used intracerebral microdialysis (5) to obtain serial brain interstitial fluid (ISF) samples in 18 intensive care unit (ICU) patients who had sustained acute brain injury and were undergoing invasive intracranial monitoring for clinical purposes. In all patients, Aβ1−x was detected in hourly or bihourly intracranial microdialysis samples. None had a diagnosis of Alzheimer’s disease or dementia, demonstrating that Aβ is a normal constituent of human brain extracellular fluid (6). The Aβ1−x enzyme-linked immunosorbent assay (ELISA) used detects Aβ species from amino acid 1 to amino acid 28 or greater (3,7). There were rising trends in brain ISF Aβ concentrations over several hours to days in most patients, though the specific pattern of these trends was variable (Fig. 1, B, D, and F;Fig. 2B; and Fig. 4, A to D). Median brain ISF Aβ1−x at 60 to 72 hours was 59% higher than at 0 to 12 hours (Fig. 1G) (P = 0.0002, Wilcoxon signed rank test). Urea concentrations in the same samples, which control for the stability of

Amyloid-beta dynamics in the injured human brain

Background: The amyloid-beta peptide (Ab) plays a central role in the pathophysiology of Alzheimer disease (AD), and is the principal component of the senile plaques that are a pathological hallmark of this condition. Despite over 20 years of intensive investigations of the Ab peptide, its concentration and dynamics in the extracellular space of the human brain remain largely unknown. Methods: We used intracerebral microdialysis to measure Ab dynamics in the extracellular space of the injured human brain in 18 severe traumatic brain injury and aneurysmal subarachnoid hemorrhage patients. Neurological status was assessed using serial Glasgow Coma Scores. Results: We found a strong positive correlation between changes in brain ISF Ab levels and neurological status, and correlations with other cerebral physiological and metabolic abnormalities reflecting depressed neuronal function. Conclusions: These dynamics fit well with the hypothesis that neuronal activity regulates extracellular Ab concentration. This microdialysis-based approach may allow a broad range of pathophysiological and pharmacodynamic investigations related to key therapeutic targets in human patients.