Evaluation of [F]--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 [F]-methyl lansoprazole ([F]NML). Herein we report validation of the synthesis of [F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding -difluoro enol ether precursor.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.