Tip of the Iceberg: Assessing the Global Socioeconomic Costs of Alzheimer's Disease and Related Dementias and Strategic Implications for Stakeholders.

While it is generally understood that Alzheimer's disease (AD) and related dementias (ADRD) is one of the costliest diseases to society, there is widespread concern that researchers and policymakers are not comprehensively capturing and describing the full scope and magnitude of the socioeconomic burden of ADRD. This review aimed to 1) catalogue the different types of AD-related socioeconomic costs described in the literature; 2) assess the challenges and gaps of existing approaches to measuring these costs; and 3) analyze and discuss the implications for stakeholders including policymakers, healthcare systems, associations, advocacy groups, clinicians, and researchers looking to improve the ability to generate reliable data that can guide evidence-based decision making. A centrally emergent theme from this review is that it is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies (in measures and real-world data) in accurately calculating the full costs to society. There is therefore an urgent need for all stakeholders to establish a common understanding of the challenges in evaluating the full cost of ADRD and define approaches that allow us to measure these costs more accurately, with a view to prioritizing evidence-based solutions to mitigate this looming public health crisis.

3-D flexible nano-textured high-density microelectrode arrays for high-performance neuro-monitoring and neuro-stimulation.

We introduce a new 3-D flexible microelectrode array for high performance electrographic neural signal recording and stimulation. The microelectrode architecture maximizes the number of channels on each shank and minimizes its footprint. The electrode was implemented on flexible polyimide substrate using microfabrication and thin-film processing. The electrode has a planar layout and comprises multiple shanks. Each shank is three mm in length and carries six gold pads representing the neuro-interfacing channels. The channels are used in recording important precursors with potential clinical relevance and consequent electrical stimulation to perturb the clinical condition. The polyimide structure satisfied the mechanical characteristics required for the proper electrode implantation and operation. Pad postprocessing technique was developed to improve the electrode electrical performance. The planar electrodes were used for creating 3-D "Waterloo Array" microelectrode with controlled gaps using custom designed stackers. Electrode characterization and benchmarking against commercial equivalents demonstrated the superiority of the Flex electrodes. The Flex and commercial electrodes were associated with low-power implantable responsive neuro-stimulation system. The electrodes performance in recording and stimulation application was quantified through in vitro and in vivo acute and chronic experiments on human brain slices and freely-moving rodents. The Flex electrodes exhibited remarkable drop in the electric impedance (100 times at 100 Hz), improved electrode-electrolyte interface noise (dropped by four times) and higher signal-to-noise ratio (3.3 times).

High-density intracortical microelectrode arrays with multiple metallization layers for fine-resolution neuromonitoring and neurostimulation.

Intracortical microelectrodes play a prominent role in the operation of neural interfacing systems. They provide an interface for recording neural activities and modulating their behavior through electric stimulation. The performance of such systems is thus directly meliorated by advances in electrode technology. We present a new architecture for intracortical electrodes designed to increase the number of recording/stimulation channels for a given set of shank dimensions. The architecture was implemented on silicon using microfabrication process and fabricated 3-mm-long electrode shanks with six relatively large (110 µm ×110 µm) pads in each shank for electrographic signal recording to detect important precursors with potential clinical relevance and electrical stimulation to correct neural behavior with low-power dissipation in an implantable device. Moreover, an electrode mechanical design was developed to increase its stiffness and reduce shank deflection to improve spatial accuracy during an electrode implantation. Furthermore, the pads were post-processed using pulsated low current electroplating and reduced their impedances by ≈ 30 times compared to the traditionally fabricated pads. The paper also presents microfabrication process, electrodes characterization, comparison to the commercial equivalents, and in vitro and in vivo validations.

Hippocampal excitability is increased in aged mice.

Aging is known to be associated with a high risk of developing seizure disorders. Currently, the mechanisms underlying this increased seizure susceptibility are not fully understood. Several previous studies have shown a loss of subgroups of GABAergic inhibitory interneurons in the hippocampus of aged rodents, yet the network excitability intrinsic to the aged hippocampus remains to be elucidated. The aim of this study is to examine age-dependent changes of hippocampal network activities in young adult (3-5 months), aging (16-18 months), and aged (24-28 months) mice. We conducted intracranial electroencephalographic (EEG) recordings in free-moving animals and extracellular recordings in hippocampal slices in vitro. EEG recordings revealed frequent spikes in aging and aged mice but only occasionally in young adults. These EEG spikes were suppressed following diazepam administration. Spontaneous field potentials with large amplitudes were frequently observed in hippocampal slices of aged mice but rarely in slices from young adults. These spontaneous field potentials originated from the CA3 area and their generation was dependent upon the excitatory glutamatergic activity. We therefore postulate that hippocampal network excitability is increased in aged mice and that such hyperactivity may be relevant to the increased seizure susceptibility observed in aged subjects.

Severe hypoglycemia in a juvenile diabetic rat model: presence and severity of seizures are associated with mortality.

It is well accepted that insulin-induced hypoglycemia can result in seizures. However, the effects of the seizures, as well as possible treatment strategies, have yet to be elucidated, particularly in juvenile or insulin-dependent diabetes mellitus (IDDM). Here we establish a model of diabetes in young rats, to examine the consequences of severe hypoglycemia in this age group; particularly seizures and mortality. Diabetes was induced in post-weaned 22-day-old Sprague-Dawley rats by streptozotocin (STZ) administered intraperitoneally (IP). Insulin IP (15 U/kg), in rats fasted (14-16 hours), induced hypoglycemia, defined as <3.5 mM blood glucose (BG), in 68% of diabetic (STZ) and 86% of control rats (CON). Seizures occurred in 86% of STZ and all CON rats that reached hypoglycemic levels with mortality only occurring post-seizure. The fasting BG levels were significantly higher in STZ (12.4 ± 1.3 mM) than in CON rodents (6.3 ± 0.3 mM), resulting in earlier onset of hypoglycemia and seizures in the CON group. However, the BG at seizure onset was statistically similar between STZ (1.8 ± 0.2 mM) and CON animals (1.6 ± 0.1 mM) as well as between those that survived (S+S) and those that died (S+M) post-seizure. Despite this, the S+M group underwent a significantly greater number of seizure events than the S+S group. 25% glucose administered at seizure onset and repeated with recurrent seizures was not sufficient to mitigate these continued convulsions. Combining glucose with diazepam and phenytoin significantly decreased post-treatment seizures, but not mortality. Intracranial electroencephalograms (EEGs) were recorded in 10 CON and 9 STZ animals. Predictive EEG changes were not observed in these animals that underwent seizures. Fluorojade staining revealed damaged cells in non-seizing STZ animals and in STZ and CON animals post-seizure. In summary, this model of hypoglycemia and seizures in juvenile diabetic rats provides a paradigm for further study of underlying mechanisms. Our data demonstrate that severe hypoglycemia (<2.0 mM) is a necessary precondition for seizures, and the increased frequency of these seizures is associated with mortality.

Early suppression of intracranial EEG signals predicts ischemic outcome in adult mice following hypoxia-ischemia.

The objective of this study is to determine whether early alterations in intracranial EEG activity predict overall outcome in non-anesthetized adult mice following hypoxia-ischemia (HI). Adult C57BL/6 mice received surgical implantation of bilateral intracranial EEG electrodes in the hippocampus and cerebral cortex. Animals were subjected to a hypoxic-ischemic (HI) episode consisting of permanent occlusion of the right common carotid artery and subsequent systemic hypoxia (8% O(2) for 30 min). EEG activities were sorted based on the observance of motor seizures, poor physical outcome, brain injury, and mortality. EEG signals were quantified as amplitude, variance, and root mean square, and early alterations in these parameters were compared. Animals with poor-HI outcome exhibited longer and more profound suppression of EEG signals in the hippocampus ipsilateral to the carotid artery occlusion during HI. Of the parameters chosen to quantify EEG activity, root mean square demonstrated the greatest sensitivity in predicting subsequent outcome. Thus, ipsilateral hippocampal EEG signals are a reliable early marker for assessing HI outcome in adult mice, and further characterization of ischemic EEG signals may aid in the development of novel quantitative variables for use in animal models of experimental cerebral ischemia.

iPS cells to model CDKL5-related disorders.

Rett syndrome (RTT) is a progressive neurologic disorder representing one of the most common causes of mental retardation in females. To date mutations in three genes have been associated with this condition. Classic RTT is caused by mutations in the MECP2 gene, whereas variants can be due to mutations in either MECP2 or FOXG1 or CDKL5. Mutations in CDKL5 have been identified both in females with the early onset seizure variant of RTT and in males with X-linked epileptic encephalopathy. CDKL5 is a kinase protein highly expressed in neurons, but its exact function inside the cell is unknown. To address this issue we established a human cellular model for CDKL5-related disease using the recently developed technology of induced pluripotent stem cells (iPSCs). iPSCs can be expanded indefinitely and differentiated in vitro into many different cell types, including neurons. These features make them the ideal tool to study disease mechanisms directly on the primarily affected neuronal cells. We derived iPSCs from fibroblasts of one female with p.Q347X and one male with p.T288I mutation, affected by early onset seizure variant and X-linked epileptic encephalopathy, respectively. We demonstrated that female CDKL5-mutated iPSCs maintain X-chromosome inactivation and clones express either the mutant CDKL5 allele or the wild-type allele that serve as an ideal experimental control. Array CGH indicates normal isogenic molecular karyotypes without detection of de novo CNVs in the CDKL5-mutated iPSCs. Furthermore, the iPS cells can be differentiated into neurons and are thus suitable to model disease pathogenesis in vitro.

Acute postischemic seizures are associated with increased mortality and brain damage in adult mice.

Postischemic seizures are associated with worsened outcome following stroke, but the underlying pathophysiology is poorly understood. Here we examined acute seizures in adult mice following hypoxia-ischemia (HI) via combined behavioral, electrophysiological, and histological assessments. C57BL/6 mice aged 4-9 months received a permanent occlusion of the right common carotid artery and then underwent a systemic hypoxic episode. Generalized motor seizures were observed within 72 h following HI. These seizures occurred nearly exclusively in animals with extensive brain injury in the hemisphere ipsilateral to the carotid occlusion, but their generation was not associated with electroencephalographic discharges in bilateral hippocampal and neocortical recordings. Animals exhibiting these seizures had a high rate of mortality, and post-HI treatments with diazepam and phenytoin greatly suppressed these behavioral seizures and improved post-HI animal survival. Based on these data, we conclude that these seizures are a consequence of HI brain injury, contribute to worsened outcome following HI, and that they originate from deep subcortical structures.

Alterations of cortical and hippocampal EEG activity in MeCP2-deficient mice.

Rett syndrome is a pediatric neurological condition caused by mutations of the gene encoding the transcriptional regulator MECP2. In this study, we examined cortical and hippocampal electroencephalographic (EEG) activity in male and female MeCP2-deficient mice at symptomatic stages during different behavioral states. During acute sleep, MeCP2-deficient mice displayed normal delta-like activity in cortex and sharp-wave activity in hippocampus. However, when the mice were awake but immobile, abnormal spontaneous, rhythmic EEG discharges of 6-9 Hz were readily detected in the somatosensory cortex. During exploratory activity, MeCP2-deficient mice displayed clear theta rhythm activity in hippocampus, but its peak frequency was significantly attenuated compared to wild type. Collectively, these findings indicate that a deficiency in MeCP2 function in mice leads to alterations in EEG activity with similarities to what has been observed clinically in Rett syndrome patients.

Direct-current electrical field guides neuronal stem/progenitor cell migration.

Direct-current electrical fields (EFs) promote nerve growth and axon regeneration. We report here that at physiological strengths, EFs guide the migration of neuronal stem/progenitor cells (NSPCs) toward the cathode. EF-directed NSPC migration requires activation of N-methyl-d-aspartate receptors (NMDARs), which leads to an increased physical association of Rho GTPase Rac1-associated signals to the membrane NMDARs and the intracellular actin cytoskeleton. Thus, this study identifies the EF as a directional guidance cue in controlling NSPC migration and reveals a role of the NMDAR/Rac1/actin signal transduction pathway in mediating EF-induced NSPC migration. These results suggest that as a safe physical approach in clinical application, EFs may be developed as a practical therapeutic strategy for brain repair by directing NSPC migration to the injured brain regions to replace cell loss. Disclosure of potential conflicts of interest is found at the end of this article.

Regional cerebral blood flow in childhood autism: a SPET study with SPM evaluation.

AIM: To establish a link between rCBF assessed with Tc-ECD SPET and the clinical manifestation of the disease. METHODS: We performed the study on 11 patients (five girls and six boys; mean age 11.2 years) displaying autistic behaviour and we compared their data with that of an age-matched reference group of eight normal children. A quantitative analysis of rCBF was performed calculating a perfusion index (PI) and an asymmetry index (AI) in each lobe. Images were analysed with statistical parametric mapping software, following the spatial normalization of SPET images for a standard brain. RESULTS: A statistically significant (P=0.003) global reduction of CBF was found in the group of autistic children (PI=1.07+/-0.07) when compared with the reference group (PI=1.25+/-0.12). Moreover, a significant difference was also observed for the right-to-left asymmetry of hemispheric perfusion between the control group and autistic patients (P=0.0085) with a right prevalence greater in autistic (2.90+/-1.68) with respect to normal children (1.12+/-0.49). Our data show a significant decrease of global cerebral perfusion in autistic children in comparison with their normal counterparts and the existence of left-hemispheric dysfunction, especially in the temporo-parietal areas devoted to language and the comprehension of music and sounds. CONCLUSION: We suggest that these abnormal areas are related to the cognitive impairment observed in autistic children, such as language deficits, impairment of cognitive development and object representation, and abnormal perception and responses to sensory stimuli. Tc-ECD SPET seems to be sensitive in revealing brain blood flow alterations and left-to-right asymmetries, when neuroradiological patterns are normal.

Phosphatase PTEN in neuronal injury and brain disorders.

The phosphatase and tensin homologue PTEN was originally identified as a tumor suppressor. In the CNS, mutation or inactivation of PTEN is best known for playing a tumorigenic role in the molecular pathogenesis of glioblastoma. However, recent studies show that PTEN is associated with several brain diseases other than cancer, suggesting a broader role of PTEN in CNS pathophysiology. Here, we review the evidence for the crucial involvement of PTEN in neuronal injury as well as in neurological and psychiatric disorders, and discuss the potential of PTEN as a molecular target for the development of a novel CNS therapeutic strategy.

Ischemic insults direct glutamate receptor subunit 2-lacking AMPA receptors to synaptic sites.

Regulated AMPA receptor (AMPAR) trafficking at excitatory synapses is a mechanism critical to activity-dependent alterations in synaptic efficacy. The role of regulated AMPAR trafficking in insult-induced synaptic remodeling and/or cell death is, however, as yet unclear. Here we show that brief oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia, promotes redistribution of AMPARs at synapses of hippocampal neurons, leading to a switch in AMPAR subunit composition. Ischemic insults promote internalization of glutamate receptor subunit 2 (GluR2)-containing AMPARs from synaptic sites via clathrin-dependent endocytosis and facilitate delivery of GluR2-lacking AMPARs to synaptic sites via soluble N-ethylmaleimide-sensitive factor attachment protein receptor-dependent exocytosis, evident at early times after insult. The OGD-induced switch in receptor subunit composition requires PKC activation, dissociation of GluR2 from AMPA receptor-binding protein, and association with protein interacting with C kinase-1. We further show that AMPARs at synapses of insulted neurons exhibit functional properties of GluR2-lacking AMPARs. AMPAR-mediated miniature EPSCs exhibit increased amplitudes and enhanced sensitivity to subunit-specific blockers of GluR2-lacking AMPARs, evident at 24 h after ischemia. The OGD-induced alterations in synaptic AMPA currents require clathrin-mediated receptor endocytosis and PKC activation. Thus, ischemic insults promote targeting of GluR2-lacking AMPARs to synapses of hippocampal neurons, mechanisms that may be relevant to ischemia-induced synaptic remodeling and/or neuronal death.

Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN.

The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid and protein phosphatase. We report here that PTEN physically associates with the NR1 and NR2B subunits of NMDA receptors (NMDARs) in rat hippocampus. Downregulating the protein expression of PTEN inhibits the function of extrasynaptic NMDARs and decreases NMDAR surface expression, suggesting a crucial role for endogenous PTEN in the modulation of NMDAR-mediated neuronal function. Reducing PTEN expression also enhances Akt/Bad phosphorylation in hippocampal neurons. Importantly, suppressing lipid and protein phosphatase activity of PTEN, respectively, activates Akt and inhibits extrasynaptic NMDAR activity and thereby protects against ischemic neuronal death in vitro and in vivo. Thus, our study reveals a dual neuroprotective mechanism by which Akt/Bad and extrasynaptic NMDARs are regulated via downregulation of two distinct PTEN phosphatase activities and present the possibility of PTEN as a potential therapeutic target for stroke treatment.

Circadian regulation of GABAA receptor function by CKI epsilon-CKI delta in the rat suprachiasmatic nuclei.

The type A GABA receptors are thought to mediate synchronization of clock cell activity within the suprachiasmatic nuclei (SCN). Here we report that casein kinases I epsilon and delta (CKI epsilon and CKI delta), the crucial clock regulators, form a complex with GABA(A) receptors and inhibit the receptors' function within the SCN according to a circadian rhythm. These results indicate that circadian variation of the kinase-receptor association may mediate regulation of GABA(A) receptor function by CKI epsilon-CKI delta in the SCN.