Early-stage cognitive impairment in Parkinson's disease and the influence of dopamine replacement therapy.

BACKGROUND AND PURPOSE: The aim of this study was to establish the cognitive profile of newly diagnosed untreated (de novo) patients with Parkinson's disease (PD) and more advanced, treated patients, and to determine the effects of dopamine (DA) replacement therapy. METHODS: A cohort of 23 de novo patients, 55 mild to moderately advanced, medicated PD patients and 21 healthy controls participated. Cognitive tests included the Cambridge Examination for Mental Disorders and a battery of neuropsychological tests taken from the Cambridge Neuropsychological Test Automated Battery and the Vienna Test System. RESULTS: De novo patients with PD were more impaired in working memory strategy use than healthy controls and treated patients with PD. Furthermore, the generation of random motor behaviour was more impaired in both de novo and treated PD patients than in healthy controls. Correlation analysis revealed that in treated patients with PD, ascending doses of dopaminergic medication were associated with poorer performance on a pattern recognition task. CONCLUSION: Selective impairments in strategy use and the generation of random motor behaviour are a very early feature of PD and might be of predictive value in further frontal cognitive deterioration. Furthermore, DA replacement therapy seems to improve frontal lobe function (strategy use) and worsen temporal lobe function (visual memory).

Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat.

AIMS/HYPOTHESIS: The abnormal intrauterine milieu of intrauterine growth retardation (IUGR) permanently alters gene expression and function of pancreatic beta cells leading to the development of diabetes in adulthood. Expression of the pancreatic homeobox transcription factor Pdx1 is permanently reduced in IUGR islets suggesting an epigenetic mechanism. Exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) analogue, given in the newborn period increases Pdx1 expression and prevents the development of diabetes in the IUGR rat. METHODS: IUGR was induced by bilateral uterine artery ligation in fetal life. Ex-4 was given on postnatal days 1-6 of life. Islets were isolated at 1 week and at 3-12 months. Histone modifications, PCAF, USF1 and DNA methyltransferase (Dnmt) 1 binding were assessed by chromatin immunoprecipitation (ChIP) assays and DNA methylation was quantified by pyrosequencing. RESULTS: Phosphorylation of USF1 was markedly increased in IUGR islets in Ex-4 treated animals. This resulted in increased USF1 and PCAF association at the proximal promoter of Pdx1, thereby increasing histone acetyl transferase (HAT) activity. Histone H3 acetylation and trimethylation of H3K4 were permanently increased, whereas Dnmt1 binding and subsequent DNA methylation were prevented at the proximal promoter of Pdx1 in IUGR islets. Normalisation of these epigenetic modifications reversed silencing of Pdx1 in islets of IUGR animals. CONCLUSIONS/INTERPRETATION: These studies demonstrate a novel mechanism whereby a short treatment course of Ex-4 in the newborn period permanently increases HAT activity by recruiting USF1 and PCAF to the proximal promoter of Pdx1 which restores chromatin structure at the Pdx1 promoter and prevents DNA methylation, thus preserving Pdx1 transcription.

Contrasting gray and white matter changes in preclinical Huntington disease: an MRI study.

BACKGROUND: In Huntington disease (HD), substantial striatal atrophy precedes clinical motor symptoms. Accordingly, neuroprotection should prevent major cell loss before such symptoms arise. To evaluate neuroprotection, biomarkers such as MRI measures are needed. This requires first establishing the best imaging approach. METHODS: Using a cross-sectional design, we acquired T1-weighted and diffusion-weighted scans in 39 preclinical (pre-HD) individuals and 25 age-matched controls. T1-weighted scans were analyzed with gross whole-brain segmentation and voxel-based morphometry. Analysis of diffusion-weighted scans used skeleton-based tractography. For all imaging measures, we compared pre-HD and control groups and within the pre-HD group we examined correlations with estimated years to clinical onset. RESULTS: Pre-HD individuals had lower gross gray matter (GM) and white matter (WM) volume. Voxel-wise analysis demonstrated local GM volume loss, most notably in regions consistent with basal ganglia-thalamocortical pathways. By contrast, pre-HD individuals showed widespread reductions in WM integrity, probably due to a loss of axonal barriers. Both GM and WM imaging measures correlated with estimated years to onset. CONCLUSIONS: Using automated, observer-independent methods, we found that GM loss in pre-HD was regionally specific, while WM deterioration was much more general and probably the result of demyelination rather then axonal degeneration. These findings provide important information about the nature, relative staging, and topographic specificity of brain changes in pre-HD and suggest that combining GM and WM imaging may be the best biomarker approach. The empirically derived group difference images from this study are provided as regions-of-interest masks for improved sensitivity in future longitudinal studies.

Cholinergic modulation of MEG resting-state oscillatory activity in Parkinson's disease related dementia.

OBJECTIVE: EEG and MEG studies in Parkinson's disease (PD) related dementia (PDD) have shown a slowing of resting-state, oscillatory activity compared to non demented PD. Aim of the present MEG study was to determine whether treatment with the cholinesterase inhibitor rivastigmine would reverse this slowing of resting-state activity in PDD patients. METHODS: In eight PDD patients, whole head MEG was recorded in a resting-state condition before and after treatment with rivastigmine. Relative spectral power was calculated in the delta, theta, alpha, beta and gamma frequency bands in fronto-central, parieto-occipital and temporal regions. RESULTS: After treatment with rivastigmine, PDD patients demonstrated an increase in relative power in the alpha range in parieto-occipital and temporal regions together with a diffuse increase in beta power. Furthermore, a decrease of delta power in fronto-central and parieto-occipital regions was found. CONCLUSIONS: Treatment with the cholinesterase inhibitor rivastigmine at least partly counteracts the slowing of resting-state brain activity that is known to occur in PD related dementia. SIGNIFICANCE: Our observations emphasize the prominent role of degeneration of the cholinergic system in the pathophysiology of dementia in PD. In the future, MEG might contribute to the selection of PD patients who may optimally benefit from cholinergic treatment.

MEG resting state functional connectivity in Parkinson's disease related dementia.

Parkinson's disease (PD) related dementia (PDD) develops in up to 60% of patients, but the pathophysiology is far from being elucidated. Abnormalities of resting state functional connectivity have been reported in Alzheimer's disease (AD). The present study was performed to determine whether PDD is likewise characterized by changes in resting state functional connectivity. MEG recordings were obtained in 13 demented and 13 non-demented PD patients. The synchronization likelihood (SL) was calculated within and between cortical areas in six frequency bands. Compared to non-demented PD, PDD was characterized by lower fronto-temporal SL in the alpha range, lower intertemporal SL in delta, theta and alpha1 bands as well as decreased centro-parietal gamma band synchronization. In addition, higher parieto-occipital synchronization in the alpha2 and beta bands was found in PDD. The observed changes in functional connectivity are reminiscent of changes in AD, and may reflect reduced cholinergic activity and/or loss of cortico-cortical anatomical connections in PDD.

Exendin-4 does not promote Beta-cell proliferation or survival during the early post-islet transplant period in mice.

Current pancreatic islet transplantation protocols achieve remarkable short-term success, but long-term insulin independence remains elusive. Hypoxic and inflammatory insults cause substantial early posttransplant graft loss while allo/autoimmunity and immunosuppressive drug toxicity threaten long-term graft mass and function. Exendin-4 (Ex4) is a GLP-1 receptor agonist that promotes beta-cell proliferation, survival, and differentiation. To determine whether Ex-4 displays potential as a graft-supportive agent, we transplanted 500 murine islets under the kidney capsule of syngeneic or allogeneic streptozocin-treated recipient mice and immediately initiated daily treatment with vehicle or Ex4. Graft beta-cell proliferation, death, and vascularity were assessed at 1, 3, and 10 days after syngeneic islet transplantation. For allogeneic recipients, blood glucose and body weight were assessed until glycemic deterioration. Ex-4 did not promote graft beta-cell proliferation, reduce beta-cell death, or enhance graft vascularity over the first 10 days after syngeneic islet transplantation. A trend toward prolongation of posttransplant euglycemia was observed with Ex4 treatment in nonimmune-suppressed allograft recipients, but its use in this setting was associated with frequent, severe hypoglycemia over the first 2 posttransplant days. Our findings do not support a beneficial effect of Ex-4 on islet grafts during the critical early posttransplant period, further, they demonstrate a significant hypoglycemic potential of Ex-4 in the first days after islet transplantation in mice. Optimal application of GLP-1 receptor agonists for long-term proliferative and survival benefits in transplantation may require earlier intervention prior to and/or during islet isolation for peri-transplant cytoprotection and administration beyond the period of engraftment.

Increased cortico-cortical functional connectivity in early-stage Parkinson's disease: an MEG study.

We set out to determine whether changes in resting-state cortico-cortical functional connectivity are a feature of early-stage Parkinson's disease (PD), explore how functional coupling might evolve over the course of the disease and establish its relationship with clinical deficits. Whole-head magnetoencephalography was performed in an eyes-closed resting-state condition in 70 PD patients with varying disease duration (including 18 recently diagnosed, drug-naive patients) in an "OFF" medication state and 21 controls. Neuropsychological testing was performed in all subjects. Data analysis involved calculation of three synchronization likelihood (SL, a general measure of linear and non-linear temporal correlations between time series) measures which reflect functional connectivity within (local) and between (intrahemispheric and interhemispheric) ten major cortical regions in five frequency bands. Recently diagnosed, drug-naive patients showed an overall increase in alpha1 SL relative to controls. Cross-sectional analysis in all patients revealed that disease duration was positively associated with alpha2 and beta SL measures, while severity of parkinsonism was positively associated with theta and beta SL measures. Moderately advanced patients had increases in theta, alpha1, alpha2 and beta SL, particularly with regard to local SL. In recently diagnosed patients, cognitive perseveration was associated with increased interhemispheric alpha1 SL. Increased resting-state cortico-cortical functional connectivity in the 8-10 Hz alpha range is a feature of PD from the earliest clinical stages onward. With disease progression, neighboring frequency bands become increasingly involved. These findings suggest that changes in functional coupling over the course of PD may be linked to the topographical progression of pathology over the brain.

Loss of thalamic serotonin transporters in early drug-naïve Parkinson's disease patients is associated with tremor: an [(123)I]beta-CIT SPECT study.

In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinson's disease (PD). Yet, few studies investigated thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [(123)I]beta-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naïve PD patients and 13 controls with SPECT. Twenty-six patients were examined twice (17 months apart). Based on UPDRS scores, we identified subgroups of patients with moderate/severe tremor (PD(T)) and without tremor (PD(WT)) at the time of clinical diagnosis. Additionally, depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at baseline. Mean thalamic specific to non-specific [(123)I]beta-CIT binding ratio was lower in patients when compared to controls, and further decreased during follow-up. At baseline, average thalamic ratio was significantly lower in the PD(T) than in the PD(WT) subgroup. No correlation was found between BDI scores and thalamic binding ratios. Our findings show decline of [(123)I]beta-CIT binding to thalamic 5-HTT in PD and its possible contribution to tremor onset.

Observations on the cortical silent period in Parkinson's disease.

Transcranial magnetic stimulation is a tool in the neurosciences to study motor functions and nervous disorders, amongst others. Single pulses of TMS applied over the primary motor cortex lead to a so-called cortical silent period in the recording from the corresponding muscle, i.e. a period of approximately 100ms with no muscle activity. We here show that in Parkinson's disease (PD), this cortical silent period in some cases is interrupted by short bursts of EMG activity. We describe in detail these interruptions in two patients with PD. These interruptions may number up to 3 per cortical silent period and show a consistent frequency across trials and hemispheres within a given patient; the two patients described here do differ, however, in the time-delay of the interruptions and hence the induced frequency. For one patient, the frequency of the interruptions proved to be around 13 Hz, the other patient showed a frequency of around 17 Hz. The results corroborate earlier findings of cortical oscillations elicited by pulses of TMS and may be related to abnormal oscillatory activity found in the cortical-subcortical motor system in PD.

Slowing of oscillatory brain activity is a stable characteristic of Parkinson's disease without dementia.

Extensive changes in resting-state oscillatory brain activity have recently been demonstrated using magnetoencephalography (MEG) in moderately advanced, non-demented Parkinson's disease patients relative to age-matched controls. The aim of the present study was to determine the onset and evolution of these changes over the disease course and their relationship with clinical parameters. In addition, we evaluated the effects of dopaminomimetics on resting-state oscillatory brain activity in levodopa-treated patients. MEG background oscillatory activity was studied in a group of 70 Parkinson's disease patients with varying disease duration and severity (including 18 de novo patients) as well as in 21 controls that were age-matched to the de novo patients. Whole head 151-channel MEG recordings were obtained in an eyes-closed resting-state condition. Levodopa-treated patients (N = 37) were examined both in a practically defined 'OFF' as well as in the 'ON' state. Relative spectral power was calculated for delta, theta, low alpha, high alpha, beta and gamma frequency bands and averaged for 10 cortical regions of interest (ROIs). Additionally, extensive clinical and neuropsychological testing was performed in all subjects. De novo Parkinson's disease patients showed widespread slowing of background MEG activity relative to controls. Changes included a widespread increase in theta and low alpha power, as well as a loss of beta power over all but the frontal ROIs and a loss of gamma power over all but the right occipital ROI. Neuropsychological assessment revealed abnormal perseveration in de novo patients, which was associated with increased low alpha power in centroparietal ROIs. In the whole group of Parkinson's disease patients, longer disease duration was associated with reduced low alpha power in the right temporal and right occipital ROI, but not with any other spectral power measure. No association was found between spectral power and disease stage, disease severity or dose of dopaminomimetics. In patients on levodopa therapy, a change from the 'OFF' to the 'ON' state was associated with decreases in right frontal theta, left occipital beta and left temporal gamma power and an increase in right parietal gamma power. Widespread slowing of oscillatory brain activity is a characteristic of non-demented Parkinson's disease patients from the earliest clinical stages onwards that is (largely) independent of disease duration, stage and severity and hardly influenced by dopaminomimetic treatment. Some early cognitive deficits in Parkinson's disease appear to be associated with increased low alpha power. We postulate a role for hypofunctional non-dopaminergic ascending neurotransmitter systems in spectral power changes in non-demented Parkinson's disease patients.

Resting state oscillatory brain dynamics in Parkinson's disease: an MEG study.

OBJECTIVE: The pathophysiological mechanisms of cognitive dysfunction and dementia in Parkinson's disease (PD) are still poorly understood. Altered resting state oscillatory brain activity may reflect underlying neuropathological changes. The present study using magneto encephalography (MEG) was set up to study differences in the pattern of resting state oscillatory brain activity in groups of demented and non-demented PD patients and healthy, elderly controls. METHODS: The pattern of MEG background oscillatory activity was studied in 13 demented PD patients, 13 non-demented PD patients and 13 healthy controls. Whole head MEG recordings were obtained in the morning in an eyes closed and an eyes open, resting state condition. Relative spectral power was calculated using Fast Fourier Transformation in delta, theta, alpha, beta and gamma frequency bands. RESULTS: In the non-demented PD patients, relative theta power was diffusely increased and beta power concomitantly decreased relative to controls. gamma Power was decreased in central and parietal channels. In the demented PD patients, a diffuse increase in relative delta and to lesser extent theta power and a decrease in relative alpha, beta and to lesser extent gamma power were found in comparison to the non-demented PD group. In addition, reactivity to eye opening was much reduced in the demented PD group. CONCLUSIONS: Parkinson's disease is characterized by a slowing of resting state brain activity involving theta, beta and gamma frequency bands. Dementia in PD is associated with a further slowing of resting state brain activity, additionally involving delta and alpha bands, as well as a reduction in reactivity to eye-opening. SIGNIFICANCE: The differential patterns of slowing of resting state brain activity in demented and non-demented PD patients suggests that, in conjunction with a progression of the pathological changes already present in non-demented patients, additional mechanisms are involved in the development of dementia in PD.

Cognitive dysfunction and dementia in Parkinson's disease.

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder mainly characterized by degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area, in combination with a varying loss of central noradrenergic (locus coeruleus), cholinergic (nucleus basalis of Meynert) and serotonergic (dorsal raphe nuclei) integrity, leading to a multitude of motor and non-motor behavioral disturbances. Apart from the clinical motor hallmarks, in the early stages of disease, subtle cognitive dysfunction might be seen comprising mainly executive dysfunction, with secondary visuospatial and mnemonic disturbances. In about 20-40% of patients, these problems may eventually proceed to dementia, which constitutes an important risk factor for caregiver distress, decreased quality of life and nursing home placement. Dementia in PD is typically characterized by a progressive dysexecutive syndrome with attentional deficits and fluctuating cognition, often accompanied by psychotic symptoms. It is thought to be the result of a combination of both subcortical and cortical changes. PD-related dopaminergic deficiency in the nucleus caudatus and mesocortical areas (due to degeneration of projections from the substantia nigra and ventral tegmental area) and cholinergic deficiency in the cortex (due to degeneration of ascending projections from the nucleus basalis of Meynert), combined with additional Alzheimer-pathology and cortical Lewy bodies, may greatly contribute to dementia. Current treatment of dementia in PD is based on compensation of the profound cholinergic deficiency. Recent studies with the cholinesterase inhibitors galantamine, donepezil and rivastigmine show promising results in improving cognition and ameliorating psychotic symptoms, which must further be confirmed in randomized controlled trials.

The development of beta-cell mass: recent progress and potential role of GLP-1.

Over the last decade, remarkable strides in incretin hormone biology have laid the foundation for our more recent appreciation that GLP-1 not only regulates mature beta-cell function but also critically regulates beta-cell differentiation, beta-cell proliferation and beta-cell survival. Dysregulated beta-cell growth and function are central to the pathophysiology of both type 1 and type 2 diabetes. Thus, GLP-1 receptor agonists are being intensively developed for the treatment of human diabetes and are likely to become available to clinical use in the near future. A general overview of beta-cell development will be provided, with particular emphasis on recent contributions to our understanding of pancreas and islet development during the embryonic, fetal and neonatal periods. The transcriptional hierarchy and extracellular signals governing events during these periods will be highlighted. Evidence suggesting a role for endogenous GLP-1 and GLP-1 receptor during beta-cell development will be reviewed. Finally, the therapeutic potential for intervention with GLP1 receptor agonists during the neonatal period will be discussed.

Deficits on Corsi's block-tapping task in early stage Parkinson's disease.

Cognitive deficits in Parkinson's disease (PD) include disturbances in working memory. We examined sequential visuo-spatial memory span by means of an adaptation of the Corsi Block-Tapping Task in groups of medicated (n=14) and non-medicated (n=15) patients with early stage PD, and in control subjects (n=22). A deficit in memory span was found in medicated patients with early stage PD relative to controls. There were no differences between non-medicated patients relative to either controls or medicated patients. A decrease in sequential visuo-spatial memory span appears to be a relatively early feature of PD and most likely reflects executive rather than mnemonic dysfunction.

The role of acetylcholine and dopamine in dementia and psychosis in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological disorder in which there is abnormal degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area combined with a varying degree of deterioration of the cholinergic, serotonergic and noradrenergic system, leading to a variety of motor and non-motor abnormalities. Dopamine (DA) depletion in nigrostriatal projections manifests with abnormal spontaneous motor behavior and (subtle) cognitive deficits, whereas more overt cognitive impairment may develop with concomitant DA-deficiency related mesocorticolimbic denervation. In combination with a progressive dysfunction of the ascending neocortical cholinergic (and serotonergic and noradrenergic) projections, mainly due to a loss of cholinergic neurons in the nucleus basalis of Meynert (NbM), these cognitive deficits may proceed into dementia sometimes in combination with psychotic behavior, which might also be associated with dopaminomimetic and/or anticholinergic treatment as well as with cholinergic deficit or dopaminomimetic induced REM sleep disturbances. As these psychiatric symptoms have a substantial negative effect on the patient's quality of life, contribute to caregiver distress and are predictive of nursing home placement, identification and adequate treatment is of great importance. Recent evidence supports a possible role for cholinomimetic therapy in alleviating cognitive dysfunction and psychotic symptoms in PD.

The influence of computer experience on visuo-motor control: implications for visuo-motor testing in Parkinson's disease.

Abnormalities in visuo-motor control have repeatedly been reported in Parkinson's disease (PD) patients. In the more recent studies, tasks measuring visuo-motor performance are usually computerised tasks requiring the use of a mouse-like manipulandum. In healthy subjects, previous computer mouse experience can influence performance in computerised visuo-motor tasks. We, therefore, investigated the potential confounding effect of mouse experience in a visuo-motor task used in PD patients, the visuo-motor testing (VMT) system, and its concurrent usefulness in the diagnosis of PD. Our study population included 49 early PD patients and 31 controls. The VMT system involves moving a pointer over a sinusoidal path displayed on a computer screen by moving an unseen digitiser mouse over a tablet. In both PD patients and controls, subjects with low mouse experience scored worse than subjects with high mouse experience on variables measuring movement accuracy, direction and speed. After correction for mouse experience the aforementioned deficits were still present in PD patients with low mouse experience. However, PD patients with high mouse experience only showed deficits in movement accuracy. It would seem that previous mouse experience can at least partly compensate for deficits in directional control and speed in PD patients, implying a possible role for training in the treatment of functional motor impairments in PD. Future studies using computerised psychomotor tasks should take sufficient precautions to avoid potential confounding effects of mouse experience. The present data further suggest that only accuracy of visuo-motor control might be a useful parameter in the (early) diagnosis of PD.

[Presymptomatic detection of Parkinson's disease]. / Presymptomatische detectie van de ziekte van Parkinson.

Parkinson's disease (PD) is characterized by a progressive degeneration of mesencephalic dopaminergic neurons. More than half of these neurons are lost in a presymptomatic phase of an estimated 4-6 years duration. It is obvious that any type of treatment aimed at slowing down the disease process should preferably be applied in this presymptomatic phase. Presymptomatic detection of PD has therefore become an important goal. In a recent study in a population of 361 asymptomatic first degree relatives of PD patients, we were able to demonstrate that presymptomatic detection is possible by means of a combination of three olfactory processing tasks and [123l] beta-CIT single photon emission computed tomography (SPECT) scanning of the nigrostriatal dopaminergic system. These results are a first step towards the development of a screening strategy that may be applied in the general population. Impairments of olfactory function, however, are not specific to PD but are also associated with other neurodegenerative disorders (e.g. Alzheimer's disease) and certain lifestyle characteristics (e.g. smoking). In the next few years our research efforts will focus on two different approaches to develop a more specific screening strategy. First, olfactory processing tasks will be combined with tasks aimed at detecting subtle (visuo)motor disturbances and early cognitive impairments. In parallel, an effort will be made to define disease-specific patterns of olfactory dysfunction in neurodegenerative disorders.

Motor perseveration is an early sign of Parkinson's disease.

Perseveration in the generation of random motor behavior was examined by means of the Vienna perseverance task in groups of de novo (n = 18) and treated (n = 18) patients with early PD, and in control subjects (n = 18). In comparison with control subjects, both the de novo and treated patients with PD were relatively unable to generate random motor sequences, indicating a decreased ability to switch cortical behavioral programs in PD. An impairment of random motor generation appears to be a very early feature of PD.

Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia.

We have used conditional gene ablation to uncover a dramatic and unpredicted role for the winged-helix transcription factor Foxa2 (formerly HNF-3 beta) in pancreatic beta-cell differentiation and metabolism. Mice that lack Foxa2 specifically in beta cells (Foxa2(loxP/loxP); Ins.Cre mice) are severely hypoglycemic and show dysregulated insulin secretion in response to both glucose and amino acids. This inappropriate hypersecretion of insulin in the face of profound hypoglycemia mimics pathophysiological and molecular aspects of familial hyperinsulinism. We have identified the two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP)), the most frequently mutated genes linked to familial hyperinsulinism, as novel Foxa2 targets in islets. The Foxa2(loxP/loxP); Ins.Cre mice will serve as a unique model to investigate the regulation of insulin secretion by the beta cell and suggest the human FOXA2 as a candidate gene for familial hyperinsulinism.

Improved glucose tolerance and acinar dysmorphogenesis by targeted expression of transcription factor PDX-1 to the exocrine pancreas.

The homeodomain protein PDX-1 is critical for pancreas development and is a key regulator of insulin gene expression. PDX-1 nullizygosity and haploinsufficiency in mice and humans results in pancreatic agenesis and diabetes, respectively. At embryonic day (e) 10.5, PDX-1 is expressed in all pluripotential gut-derived epithelial cells destined to differentiate into the exocrine and endocrine pancreas. At e15, PDX-1 expression is downregulated in exocrine cells, but remains high in endocrine cells. The aim of this study was to determine whether targeted overexpression of PDX-1 to the exocrine compartment of the developing pancreas at e15 would allow for respecification of the exocrine cells. Transgenic (TG) mice were generated in which PDX-1 was expressed in the exocrine pancreas using the exocrine-specific elastase-1 promoter. These mice exhibited a marked dysmorphogenesis of the exocrine pancreas, manifested by increased rates of replication and apoptosis in acinar cells and a progressive fatty infiltration of the exocrine pancreas with age. Interestingly, the TG mice exhibited improved glucose tolerance, but absolute beta-cell mass was not increased. These findings indicate that downregulation of PDX-1 is required for the proper maintenance of the exocrine cell phenotype and that upregulation of PDX-1 in acinar cells affects beta-cell function. The mechanisms underlying these observations remain to be elucidated.