A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling.

After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.

PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease.

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer's disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical "one-size-fits-all" approach in drug discovery towards biomarker guided "molecularly" tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

Analysing Time to Event Data in Dementia Prevention Trials: The Example of the GuidAge Study of EGb761.

Time-to-event analysis is frequently used in medical research to investigate potential disease-modifying treatments in neurodegenerative diseases. Potential treatment effects are generally evaluated using the logrank test, which has optimal power and sensitivity when the treatment effect (hazard ratio) is constant over time. However, there is generally no prior information as to how the hazard ratio for the event of interest actually evolves. In these cases, the logrank test is not necessarily the most appropriate to use. When the hazard ratio is expected to decrease or increase over time, alternative statistical tests such as the Fleming-Harrington test, provide a better sensitivity. An example of this comes from a large, five-year randomised, placebo-controlled prevention trial (GuidAge) in 2854 community-based subjects making spontaneous memory complaints to their family physicians, which evaluated whether treatment with EGb761 can modify the risk of developing AD. The primary outcome measure was the time to conversion from memory complaint to Alzheimer's type dementia. Although there was no significant difference in the hazard function of conversion between the two treatment groups according to the preplanned logrank test, a significant treatment-by-time interaction for the incidence of AD was observed in a protocol-specified subgroup analysis, suggesting that the hazard ratio is not constant over time. For this reason, additional post hoc analyses were performed using the Fleming-Harrington test to evaluate whether there was a signal of a late effect of EGb761. Applying the Fleming-Harrington test, the hazard function for conversion to dementia in the placebo group was significantly different from that in the EGb761 treatment group (p = 0.0054), suggesting a late effect of EGb761. Since this was a post hoc analysis, no definitive conclusions can be drawn as to the effectiveness of the treatment. This post hoc analysis illustrates the interest of performing another randomised clinical trial of EGb761 explicitly testing the hypothesis of a late treatment effect, as well as of using of better adapted statistical approaches for long term preventive trials when it is expected that prevention cannot have an immediate effect but rather a delayed effect that increases over time.

[Management of hypophosphatemia: a case report]. / Le cas clinique du mois. Prise en charge d'une hypophosphatemia.

Hypophosphatemia is defined by a serum phosphate level lower than 0.8 mmol/l. If hypophosphatemia is chronically maintained, it is associated with muscular, osteous, neurological or cardio-respiratory disorders. We describe a patient with isolated hypophosphatemia, detail the mechanisms of phosphate homeostasis, and envisage the differential diagnosis of hypophosphatemia. Furthermore, we propose a sequential decisional algorithm based on basic biological tests and few complementary investigations. Treatment options are reviewed.

Balneotherapy, prevention of cognitive decline and care the Alzheimer patient and his family: outcome of a multidisciplinary workgroup.

According to the latest forecasts of the INSEE - Institut National de la Statistique et des Etudes Economiques (National Statistics and Economic Studies Institute), ageing of the French population will increase between 2005 and 2050: whereas 20.8% of the population living in continental France reached the age of 60 years or more in 2005, this proportion would be of 30.6% in 2035 and 31.9% in 2050. In 2050, 22.3 million persons will have reached the age of 60 years or more compared to 12.6 million in 2005, increasing by 80% in a 45-year period. In line with the actual age pyramid, ageing is unavoidable, as those who will reach 60 years of age in 2050 are already born (in 1989 or before). This expansion will be most important between 2006 and 2035, when the numerous "baby-boom" generations born between 1946 and 1975, will reach these ages. In future years, lifespan improvement will only emphasize this increase. Even if life expectancy stabilizes at the 2005 level, the number of seniors reaching 60 years or more would still increase to 50% between 2005 and 2050. This issue is identical in all countries of the European Union. Ageing is a major risk factor for dementia that will considerably worsen in the next years, if no curative therapies are found. Today, 25 million persons in the world suffer from Alzheimer's disease (AD). In France, it is estimated that 860,000 persons are affected and that 225,000 news cases are annually diagnosed. After 75 years of age, more than 20% of women and 13% of men are concerned. Forecasts for the coming years are frightening. Considering ageing of the population, the number of Alzheimer's disease cases should raise to 1.3 million in 2020 (20 patients for 1000 inhabitants) ant 2.1 million in 2040 (30 patients for 1000 inhabitants).

[Effects of the association of sulbutiamine with an acetylcholinesterase inhibitor in early stage and moderate Alzheimer disease]. / Effets de l'association de la Sulbutiamine à un inhibiteur de l'acétylcholinestérase dans les formes légères à modérées de la maladie d'Alzheimer.

The efficacy of the inhibitors of acetylcholinesterase in Alzheimer's Disease (AD) is moderated and some patients do not respond to these treatments. Sulbutiamine potentializes cholinergic and glutamatergic transmissions, mainly in hippocampus and prefrontal cortex. This multicentric, randomized and double-blind trial evaluates the effects of the association of sulbutiamine to an anticholinesterasic drug in cognitive functions in patients with AD at an early stage (episodic memory, working memory, executive functions, attention). Patients had first donepezil (D) or sulbutiamine (S) during three months. During this period, only attention improved in both groups. During the three following months, a placebo (P) in patients D and donepezil in patients S were added. Compared to entry results, episodic memory decreased in group D + P but improved in group S + D. At the same time the improvement of attention persisted in both groups. Daylife activities only improved in group S + D. In conclusion sulbutiamine can be an adjuvant to treatment in early stage and moderate AD by anticholinesterasic drugs.

Control of cell proliferation by cell volume alterations in rat C6 glioma cells.

K+ and Cl- channels are involved in regulating the proliferation of a number of cell types. Two main hypotheses have been proposed to explain the mechanism by which these channels influence cell proliferation: regulation of membrane potential and regulation of cell volume. In order to test these hypotheses, we measured, under different experimental conditions, the volume, membrane potential and rate of proliferation of C6 glioma cells. Cells cultured in control medium for 1-4 days were compared with cells cultured for the same period of time in the presence of broad spectrum channel blockers: tetraethylammonium, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and Cs+, in hypertonic media (29% increased osmolarity with NaCl, KCl or sucrose), in hypotonic medium (23% decreased osmolarity with H2O) or in the presence of the specific channel blockers, i.e. mast cell degranulating peptide, charybdotoxin or chlorotoxin. In all of these conditions, we observed a close correspondence between the rate of proliferation and the mean cell volume. The proliferation decreased when volume increased. Moreover, whereas control cells were flattened, spindle-shaped, bipolar or multipolar, cells cultured in media supplemented with NPPB, KCl or CsCl were round with few processes. Of the agents tested, only KCl and Cs+ depolarized the cells. These results show that alterations of the rate of proliferation by K+ and Cl- channel blockers or anisotonia are closely related with changes in cell volume or form but are not correlated with changes in membrane potential.

The mental representation of hand movements after parietal cortex damage.

Recent neuroimagery findings showed that the patterns of cerebral activation during the mental rehearsal of a motor act are similar to those produced by its actual execution. This concurs with the notion that part of the distributed neural activity taking place during movement involves internal simulations, but it is not yet clear what specific contribution the different brain areas involved bring to this process. Here, patients with lesions restricted to the parietal cortex were found to be impaired selectively at predicting, through mental imagery, the time necessary to perform differentiated finger movements and visually guided pointing gestures, in comparison to normal individuals and to a patient with damage to the primary motor area. These results suggest that the parietal cortex is important for the ability to generate mental movement representations.

Cognitive deficits in non-Alzheimer's degenerative diseases.

Although observed in various brain disorders, dementia is particularly frequent in neurodegenerative diseases. Alzheimer's disease is characterized by the association of progressive amnesia with either instrumental (aphasia, apraxia, agnosia) or behavioral (apathy, indifference, anosognosia) disorders, depending upon the location of the underlying neuronal lesions. By contrast, memory, linguistic, praxic, visuo-spatial or comportemental impairments are dissociated in more focal "lobar" atrophies, while planning and retrieval deficits predominate in movement disorders with dementia. Alzheimer's and non-Alzheimer's neurodegenerative diseases can therefore be distinguished insofar as the severity and location of the associated neuronal lesions differ. Dementia may be observed in various brain diseases, either vascular, metabolic, demyelinating, traumatic, infectious, inflammatory, neoplastic or hydrocephalus (Chui, 1989). It is particularly frequent in neurodegenerative diseases. The recent clinical description of focal lobar atrophies (Weintraub and Mesulam, 1993) and the analysis of cognitive impairment observed in diseases with movement disorders (Cummings and Benson, 1984) have changed the conception of dementia, that may no more be defined as a global deterioration of higher cortical functions. The relative specificity of the cognitive picture of each disease depends on the location of the underlying neuronal lesions. Together with other tools, such as the neurological examination or the functional imagery, the neuropsychological exam may contribute to characterize the clinical picture of a patient with non-Alzheimer's degenerative disease and therefore to determine a clinical diagnosis, that remains probable till the neuropathological confrontation.

Congruent unilateral impairments for real and imagined hand movements.

The chronometry of imagined and actual movements was investigated in a patient with a unilateral lesion of the motor cortex. Motor imagery generated highly accurate estimates of motor performance in a variety of situations, reflecting the hypokinesia of the contralesional hand. There were parallel increases in mental and actual movement times from proximal to distal limb segments. Bimanual movements adopted the slower speed of the impaired hand in both conditions. Imagined motor sequences to the beat of a metronome predicted the maximum speed reached in actual performance. Finally, visually guided pointing showed the same target-size effects in the imagery and movement conditions. The results are in agreement with the hypothesis that common cerebral motor representations are activated when imaging and planning voluntary movements.

Photodynamic therapy of squamous cell carcinoma. An evaluation of a new photosensitizing agent, benzoporphyrin derivative and new photoimmunoconjugate.

Photodynamic therapy for cancer depends on the relatively selective distribution of photosensitizing agents to malignant as compared with normal tissues, rendering the malignant cells more susceptible to light-mediated damage. Photodynamic therapy has been used with only moderate success to date. The purpose of this study was to compare a new photosensitizing agent, benzoporphyrin derivative (BPD), to the standard agent presently in use, photofrin II, in a hamster cheek pouch model of squamous cell carcinoma. As well we have investigated the potential of using a tumour-specific monoclonal antibody-BPD conjugate to improve the tumour localizing properties of BPD. Treatment consisted of photodynamic therapy with either photofrin II, BPD, or a tumour-specific anti-epidermal growth factor receptor-BPD conjugate. Control groups of light alone, anti-EGFr, tumour non-specific MoAb, and tumour non-specific MoAb-BPD conjugate were included with the contralateral cheek pouch of each animal acting as a dark control. An assessment of differential delivery of BPD to tumour and to normal mucosa was undertaken using a spectrophotometric assay. Parametric statistical analysis included Student's t-tests and linear regression while non-parametric analysis was undertaken using Fisher's exact test. Animals receiving BPD alone demonstrated tumour-to-tissue levels of approximately 2:1 while animals receiving the tumour-specific anti-EGFr-BPD conjugate had significantly better tumour:tissue ratios of 26:1 (P < 0.005). Animals treated with photofrin II had a 1 month cancer-free survival of 27% while animals treated with BPD had an improved survival of 67% (P = 0.03). The group treated with the tumour-specific anti-EGFr-BPD conjugate at a twentieth the total dose of BPD had an 80% 1 month cancer-free survival which was not statistically different from the group treated with BPD alone. Benzoporphyrin appears to be a more effective photosensitizing agent than Photofrin II and its tumour selectivity can be improved using a tumour specific monoclonal antibody conjugate.

Disappearance of parkinsonian signs after spontaneous vascular 'thalamotomy'.

Disappearance of parkinsonian symptoms was observed in a 57-year-old patient with Parkinson's disease after a contralateral thalamopeduncular infarct. From analysis of stereotaxic data in parkinsonian patients, this may be explained by lesion of the ventro-oral internal nucleus or of Forel's field, both of which are involved in thalamopeduncular infarcts.

Cortical cholinergic projections from the basal forebrain of the rat, with special reference to the prefrontal cortex innervation.

The topographic organization of cells containing choline-acetyltransferase (CAT) and located within the magnocellular nuclei of the basal forebrain was studied by correlating maximum CAT decrease in one or another cortical region with a given localization of the cell lesions. Lesions were made by using ibotenic acid. Lesions affecting the ventral pallidum decreased CAT activity in the antero-medial prefrontal cortex and lesions of the internal and ventral borders of the pallidum decreased CAT activity in sensori-motor and parieto-temporal cortices. None of these lesions produced a decrease of CAT activity in the hippocampus. These results suggest that it is possible to show the presence of a specific cholinergic projection from the basal forebrain to the medial-associative prefrontal cortex of the rat.

Somatostatin and dementia in Parkinson's disease.

The concentrations of somatostatin in the cortex, hippocampus and caudate nucleus of subjects with Parkinson's disease were determined by radioimmunoassay. Somatostatin levels in the frontal cortex were significantly reduced in Parkinsonian subjects who were slightly or severely demented compared to controls and to non-demented Parkinsonians. Significant reductions were also observed in the hippocampus and entorhinal cortex of severely demented subjects.

Pharmacological blockade of the globus palidus-induced inhibitory response of subthalamic cells in the rat.

The aim of the present study was to investigate, with extracellular recording and microiontophoretic techniques, the possibility that gamma-aminobutyric acid (GABA) is the transmitter substance in the pallido-subthalamic (GP-STN) pathway. Experiments were carried out in 94 rats, anesthetized with ketamine. Among the 236 recorded STN neurons, 85 were inhibited by GP stimulation. This inhibition lasted 10--20 msec (mean duration +/- S.E.M. 13.45 +/- 0.5 msec). Control stimulations located either in the internal GP or in the striatum never elicited the same type of response as they did in the STN. STN neurons were inhibited by microiontophoretically applied GABA or muscimol. Iontophoretically applied bicuculline or picrotoxin reversibly blocked the GP-evoked inhibition at doses which blocked the GABA inhibitory responses but not those produced by glycine. The results are consistent with the hypothesis that GABA is the transmitter releasted by the inhibitory pallido-subthalamic pathway, and are in agreement with recent biochemical data. Nevertheless, on a few cells, strychnine blocked the GP-induced inhibition. This results is discussed in relation to the specificty of GABA and glycine antagonists.

Pharmacological properties of acetylcholine-induced excitation of subthalamic nucleus neurones.

1. In 15 rats anaesthetized with ketamine, microiontophoretically applied acetylcholine (ACh) excited all 58 cells studied in the subthalamic nucleus (STN). 2. The ACh-evoked excitation was slow in onset and outlasted the ACh application. There was no sign of desensitization when the ACh application was prolonged or repeated. The excitation was prolonged by a concomitant application of physostigmine. 3. Acetyl-beta-methyl choline and oxotremorine were effective cholinomimetics. Nicotine had no effect. 4. The ACh excitation was antagonized by stropine and scopolamine but not by mecamylamine. 5. It was condluded that STN ACh receptors are muscarinic in character. 6. Since large microiontophoretic applications of Mg2+ did not suppress ACh-evoked excitation, it is suggested that ACh acts postsynaptically. 7. The excitatory response of STN cells to striatal or pallidal stimulation was unaffected by atropine administered either microiontophoretically to single cells or intravenously (3 mg/kg) to the whole animal.