Evaluation of [18F]-N-Methyl lansoprazole as a Tau PET Imaging Agent in First-in-Human Studies.

Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [18F]N-methyl lansoprazole ([18F]NML). Herein we report validation of the synthesis of [18F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether precursor. This is the first use of this method for clinical production of PET radiotracers and confirmed that it can be readily implemented at multiple production facilities to provide [18F]NML in good noncorrected radiochemical yield (3.4 ± 1.5 GBq, 4.6% ± 2.6%) and molar activity (120.1 ± 186.3 GBq/µmol), excellent radiochemical purity (>97%), and suitable for human use (n = 15). With [18F]NML in hand, we conducted rodent biodistribution, estimates of human dosimetry, and preliminary evaluation of [18F]NML in human subjects at two imaging sites. Healthy controls (n = 4) and mildly cognitively impaired (MCI) AD patients (n = 6) received [18F]NML (tau), [18F]AV1451 (tau), and [18F]florbetaben or [18F]florbetapir (amyloid) PET scans. A single progressive supranuclear palsy (PSP) patient also received [18F]NML and [18F]AV1451 PET scans. [18F]NML showed good brain uptake, reasonable pharmacokinetics, and appropriate imaging characteristics in healthy controls. The mean ± SD of the administered mass of [18F/19F]NML was 2.01 ± 2.17 µg (range, 0.16-8.27 µg) and the mean administered activity was 350 ± 62 MBq (range, 199-403 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 11 subjects, and no significant changes in vital signs were observed. However, despite high affinity for tau in vitro, brain retention in MCI/AD and PSP patients was low, and there was no evidence of specific signals in vivo that corresponded to tau. Although it is still unclear why clinical translation of the radiotracer was unsuccessful, we nevertheless conclude that further development of [18F]NML as a tau PET imaging agent is not warranted at this time.

Tackling the elusive challenges relevant to conquering the 100-plus year old problem of Alzheimer's disease.

Despite over one hundred years of intense effort studying Alzheimer's disease (AD), we still do not understand its cause(s) and this adversely affects our ability to develop strongly effective treatments and means to prevent it. This is because our research efforts are not aligned to decipher this age-related disorder that, well after its discovery, has become a major cause of death throughout the world. We are therefore recommending a process to analyze some of the principal factors that hinder our progress in this field of research. Recognizing these barriers - and acting on such a recognition by seeking to resolve them experimentally and garnering societal support to do so - will constitute critical steps towards establishing strategies that will lead to a sorely needed paradigm shift in AD research, and ultimately to the prevention and the effective treatment of this devastating condition. This will probably also spur progress in many related neuropsychiatric disorders, and in that sense act as a seminal endeavor with far-reaching consequences. In order to accomplish this complex task, the biomedical community must acknowledge and come to a consensus about the factors that limit our progress, and then work together to generate new algorithms to tackle these fundamental issues rationally, effectively and deliberately.

Biological basis for cerebral dysfunction in schizophrenia in contrast with Alzheimer's disease.

Schizophrenia and Alzheimer's disease are two disorders that, while conceptualized as pathophysiologically and clinically distinct, cause substantial cognitive and behavioral impairment worldwide, and target apparently similar - or nearby - circuitry in regions such as the temporal and frontal lobes. We review the salient differences and similarities from selected historical, nosological, and putative mechanistic viewpoints, as a means to help both clinicians and researchers gain a better insight into these intriguing disorders, for which over a century of research and decades of translational development was needed to begin yielding treatments that are objectively effective, but still very far from entirely satisfactory. Ongoing comparison and "cross-pollination" among these approaches to disorders that produce similar deficits is likely to continue improving both our insight into the mechanisms at play, and the development of biotechnological approaches to tackle both conditions - and related disorders - more rapidly and efficaciously.

Exercise-induced cognitive plasticity, implications for mild cognitive impairment and Alzheimer's disease.

Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer's disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE ε4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The "inward" continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal "outward" continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise-induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid ß (Aß) levels by increased clearance via the choroid plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders.

Dementia, diabetes, Alzheimer's disease, and insulin resistance in the brain: progress, dilemmas, new opportunities, and a hypothesis to tackle intersecting epidemics.

Dementia is an increasingly prevalent condition that intersects worldwide with the epidemic of type 2 diabetes mellitus (DM2). It would seem logical to expect that the occurrence of DM2 increases the likelihood of developing dementia, due to its deleterious effect on the cerebral vasculature and the associated hormonal and metabolic changes. Many reports indicate that it also increases the risk of developing Alzheimer's disease (AD). However, other studies suggest that diabetes might have a relatively strong protective effect against AD, whereas genetically engineered animal models of the condition deteriorate more severely when there is a concomitant insulin resistant brain state (IRBS). Furthermore, IRBS alone is associated with anatomical, behavioral, and molecular changes that justify the proposal that AD may be due to an IRBS. This is explored in the context of accumulating evidence that the IRBS need not be related to peripheral insulin resistance, and that administration of insulin directly to the brain improves selected cognitive parameters targeted in AD. This view is consistent with the Damage Signals hypothesis of AD pathogenesis, which can help unifying the pleiotropic effects of agents toxic to insulin-producing/secreting (e.g., pancreatic ß) cells, as well as IRBS caused by different mechanisms in AD. Such approach may help tackling the Innovation Gap, which results from a host of factors slowing down progress towards innovative palliation and prevention of AD, as well as dementia due to complications of diabetes distinct from AD, and both conditions combined with their commonly associated metabolic and hormonal alterations.

Integrative Understanding of Emergent Brain Properties, Quantum Brain Hypotheses, and Connectome Alterations in Dementia are Key Challenges to Conquer Alzheimer's Disease.

The biological substrate for cognition remains a challenge as much as defining this function of living beings. Here, we examine some of the difficulties to understand normal and disordered cognition in humans. We use aspects of Alzheimer's disease and related disorders to illustrate how the wealth of information at many conceptually separate, even intellectually decoupled, physical scales - in particular at the Molecular Neuroscience versus Systems Neuroscience/Neuropsychology levels - presents a challenge in terms of true interdisciplinary integration towards a coherent understanding. These unresolved dilemmas include critically the as yet untested quantum brain hypothesis, and the embryonic attempts to develop and define the so-called connectome in humans and in non-human models of disease. To mitigate these challenges, we propose a scheme incorporating the vast array of scales of the space and time (space-time) manifold from at least the subatomic through cognitive-behavioral dimensions of inquiry, to achieve a new understanding of both normal and disordered cognition, that is essential for a new era of progress in the Generative Sciences and its application to translational efforts for disease prevention and treatment.

The fourth element targeting hypothesis of Alzheimer's disease pathogenesis and pathophysiology.

Despite well over a century of research on all forms of the disorder known as Alzheimer's disease (AD), it is still not known whether the condition targets initially neurons, glial cells, other cellular elements in the brain, or components of cells, such as synapses, or molecules independently of their cellular compartmentalization, or otherwise (e.g., specific neuronal circuits). Multiple lines of highly suggestive but as yet insufficient experimental evidence are discussed here to formulate the hypothesis that AD results from primary (i.e., direct and initial) or secondary targeting of what we designate as the Fourth Element Cell (4EC): a relatively recently identified type of brain cell that exhibits features in common with neurons (e.g., synapses, participation in glutamatergic, and GABAergic neurotransmission), astrocytes, oligodendrocytes, and their precursors, but is in other respects clearly distinct from all of them. The 4EC is proposed to be the main target of both: (1) converging insults (i.e., not true "causes") that over time cause sporadic forms of AD as postulated by the Danger Signal Hypothesis - which was not formulated with 4EC in mind - as well as (2) the causes of inherited (i.e., familial) forms of neurodegeneration that resemble certain aspects of the clinical manifestations of sporadic AD.

Toward a multi-dimensional formulation of the pathogenesis and pathophysiology of the Alzheimer dementia-like syndrome applicable to a variety of degenerative disorders and normal cognition.

Neurodegenerative disorders constitute a set of heterogeneous conditions lacking a satisfactory unifying conceptual scheme. This situation is widely perceived as hampering progress in understanding them adequately in order to develop effective treatment and prevention, but there is no unanimously or even generally agreed upon solution to this dilemma. Here, we propose that progress in resolving this conundrum requires addressing in an integrated fashion multiple dimensions and scales of organization and (normal and disordered) function that include, but transcend the conventional levels of space, time, Molecular Biology/Biochemistry and Systems Neuroscience, among others. This approach must include also a revision of the nosological concepts that currently attempt to force pathophysiological and etiological explanations within a single domain (nowadays predominantly the Molecular/Biochemical) that have virtually always failed to deliver on titillating expectations based on relatively simple "atomizing" schemes focusing on one domain/level, while ignoring virtually all others. This multi-dimensional integrated approach is illustrated for the Alzheimer dementia-like syndrome taking advantage of the wealth of knowledge in several of the relevant domains, but is generally applicable to potentially the entire range of neurodegenerative disorders, and probably also to other aspects of normal and disordered cognition and behavior.

The role of neuroimmunomodulation in Alzheimer's disease.

The idea that alterations in the brain immunomodulation are critical for Alzheimer's disease (AD) pathogenesis provides the most integrative view on this cognitive disorder, considering that converging research lines have revealed the involvement of inflammatory processes in AD. We have proposed the damage signal hypothesis as a unifying scheme in that release of endogenous damage/alarm signals, in response to accumulated cell distress (dyslipidemia, vascular insults, head injury, oxidative stress, iron overload, folate deficiency), is the earliest triggering event in AD, leading to activation of innate immunity and the inflammatory cascade. Inflammatory cytokines play a dual role, either promoting neurodegeneration or neuroprotection. This equilibrium is shifted toward the neurodegenerative phenotype upon the action of several risk factors that trigger innate damage signals that activate microglia and the release of tumor necrosis factor-alpha, interleukin-6, and some trophic factors. In this neuroimmunomodulatory hypothesis we integrate different risk factors with microaglial activation and the resulting neuronal alterations and hyperphosphorylations of tau protein. The progression of AD, with slowly increasing damage in brain parenchyma preceding the onset of symptoms, suggests that tissue distress triggering damage signals drives neuroinflammation. These signals via toll-like receptors, receptors for highly glycosylated end products, or other glial receptors activate sensors of the native immune system, inducing the anomalous release of cytokines and promoting the neurodegenerative cascade, a hallmark of brain damage that correlates with cognitive decline.

The damage signals hypothesis of Alzheimer's disease pathogenesis.

Virtually none of the hypotheses on Alzheimer's disease (AD) pathogenesis address the earliest events that trigger the molecular alterations that precede cerebral degeneration and account for the diversity of risk factors that converge on a well-defined disease phenotype. We propose that long-term activation of the innate immune system by an individual array of risk factors constitutes a unifying mechanism leading to the triggering of an inflammatory cascade that converges in cytoskeletal alterations (tau aggregation, paired helical filament formation) as a previously hypothesized final common pathway in AD. The key pathogenic phenomena consist in the long-term, maladaptive activation of innate immunity-triggering receptors--such as the toll-like and advanced glycation end-products receptors, and others located in the microglial membrane--by seemingly heterogeneous risk factors such as hyperlipidemia, hyperglycemia, oxidative stress, head injury, amyloid oligomers, etc. Our hypothesis provides a unifying mechanism that explains both the diversity of risk factors acting over long periods of time and the individual response to such insults. This formulation is amenable to both empirical testing and implementation into therapeutic strategies that may lead to effective prevention of AD as well as other disorders in which impaired regulation of the innate immunity is the unifying cause of the condition.

Increased density of neurons containing NADPH diaphorase and nitric oxide synthase in the cerebral cortex of patients with HIV-1 infection and drug abuse.

To determine whether nitrogen monoxide (nitric oxide; NO) synthase (NOS) and NADPH diaphorase (NDP) co-containing cerebrocortical neurons (NOSN) neurons are affected in patients infected with human immunodeficiency virus type 1 (HIV-1) with and without associated intake of drugs of abuse, we examined the temporal neocortex of 24 individuals: 12 HIV-1 positive (including 3 drug users, 9 non-drug users) and 12 HIV-1 negative (including 6 drug users, and 6 non-drug users). Histochemical labeling for NDP-an enzymatic domain co-expressed in the NOS enzyme-was employed to visualize NOSN. Drug abuse and HIV-1 infection cause independently an increase in NOSN density, but combined they result in up to a 38-fold increase in NOSN density, suggesting that the combination of these factors induces NOS expression powerfully in neurons that normally do not synthesize NDP/NOS. This is associated with an increase in the proportion of NOSN displaying dystrophic changes, indicating that NOSN undergo massive degeneration in association with NOS synthesis induction. The increase in density of NOSN in HIV-1 infected drug abusers may be among the important sources of NO mediating cerebrocortical dysfunction, and the degeneration of NOS-containing local circuit neurons in patients with HIV-1 infection or drug abuse may underlie in part their neuropsychiatric manifestations.