Levodopa-Carbidopa Intestinal Gel Injection for Patient with Severe Parkinson's Disease Followed by Total Hip Arthroplasty: A Case Report and Literature Review.

BACKGROUND: Patients with Parkinson's disease have a high dislocation rate after total hip arthroplasty (THA). This study describes a case with severe Parkinson's disease who developed rapidly destructive coxarthrosis (RDC) and underwent THA using a dual mobility cup after a levodopa-carbidopa intestinal gel (LCIG) infusion. CASE PRESENTATION: The patient is a 59-year-old female with a ten-year history of Parkinson's disease, which was first treated with oral levodopa. The patient developed RDC of the right hip joint. However, THA was difficult owing to Parkinson's disease and its treatment side effects, such as wearing-off, dyskinesia, and freezing of the gait, Thus, LCIG was initiated, and improvement in wearing-off and dyskinesia was observed. Two months after the LCIG therapy, the disease was controlled well. THA was subsequently performed using a dual mobility cup to prevent postoperative dislocation. Postoperatively, LCIG therapy was continuously administered to carefully manage the disease, which was controlled well with no increase in wearing-off and dyskinesia after surgery. At 1 year after surgery, the walking speed, stride length, and the Harris hip score improved compared to preoperatively. The UPDRS III motor score improved to eight without signs of wearing-off or dyskinesia. The Hoehn-Yahr scale was II in the "on" period and remained unchanged 1 year after surgery. The patient could walk without a cane and had satisfactory functional outcomes. CONCLUSION: This case proved that LCIG treatment performed preoperatively, followed by THA using a dual mobility cup, and strict management of Parkinson's disease could result in a satisfactory clinical course without recurrence of wearing-off and dyskinesia. Similar procedures may benefit other patients with Parkinson's disease who have previously been deemed unsuitable for THA.

Direct Enhancement Effect of Hippocampal Cholinergic Neurostimulating Peptide on Cholinergic Activity in the Hippocampus.

The cholinergic efferent network from the medial septal nucleus to the hippocampus is crucial for learning and memory. This study aimed to clarify whether hippocampal cholinergic neurostimulating peptide (HCNP) has a rescue function in the cholinergic dysfunction of HCNP precursor protein (HCNP-pp) conditional knockout (cKO). Chemically synthesized HCNP or a vehicle were continuously administered into the cerebral ventricle of HCNP-pp cKO mice and littermate floxed (control) mice for two weeks via osmotic pumps. We immunohistochemically measured the cholinergic axon volume in the stratum oriens and functionally evaluated the local field potential in the CA1. Furthermore, choline acetyltransferase (ChAT) and nerve growth factor (NGF) receptor (TrkA and p75NTR) abundances were quantified in wild-type (WT) mice administered HCNP or the vehicle. As a result, HCNP administration morphologically increased the cholinergic axonal volume and electrophysiological theta power in HCNP-pp cKO and control mice. Following the administration of HCNP to WT mice, TrkA and p75NTR levels also decreased significantly. These data suggest that extrinsic HCNP may compensate for the reduced cholinergic axonal volume and theta power in HCNP-pp cKO mice. HCNP may function complementarily to NGF in the cholinergic network in vivo. HCNP may represent a therapeutic candidate for neurological diseases with cholinergic dysfunction, e.g., Alzheimer's disease and Lewy body dementia.

Reduction of glutamatergic activity through cholinergic dysfunction in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice.

Cholinergic activation can enhance glutamatergic activity in the hippocampus under pathologic conditions, such as Alzheimer's disease. The aim of the present study was to elucidate the relationship between glutamatergic neural functional decline and cholinergic neural dysfunction in the hippocampus. We report the importance of hippocampal cholinergic neurostimulating peptide (HCNP) in inducing acetylcholine synthesis in the medial septal nucleus. Here, we demonstrate that HCNP-precursor protein (pp) knockout (KO) mice electrophysiologically presented with glutamatergic dysfunction in the hippocampus with age. The impairment of cholinergic function via a decrease in vesicular acetylcholine transporter in the pre-synapse with reactive upregulation of the muscarinic M1 receptor may be partly involved in glutamatergic dysfunction in the hippocampus of HCNP-pp KO mice. The results, in combination with our previous reports that show the reduction of hippocampal theta power through a decrease of a region-specific choline acetyltransferase in the stratum oriens of CA1 and the decrease of acetylcholine concentration in the hippocampus, may indicate the defined cholinergic dysfunction in HCNP-pp KO mice. This may also support that HCNP-pp KO mice are appropriate genetic models for cholinergic functional impairment in septo-hippocampal interactions. Therefore, according to the cholinergic hypothesis, the model mice might are potential partial pathological animal models for Alzheimer's disease.

Reduction of acetylcholine in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice.

The cholinergic efferent network from the medial septal nucleus to the hippocampus plays an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP), which induces acetylcholine (Ach) synthesis in the medial septal nuclei of an explant culture system, was purified from the soluble fraction of postnatal rat hippocampus. HCNP is processed from the N-terminal region of a 186-amino acid, 21-kDa HCNP precursor protein, also known as Raf kinase inhibitory protein and phosphatidylethanolamine-binding protein 1. Here, we confirmed direct reduction of Ach release in the hippocampus of freely moving HCNP-pp knockout mice under an arousal state by the microdialysis method. The levels of vesicular acetylcholine transporter were also decreased in the hippocampus of these mice in comparison with those in control mice, suggesting there was decreased incorporation of Ach into the synaptic vesicle. These results potently indicate that HCNP may be a cholinergic regulator in the septo-hippocampal network.

Possible correlated variation of GABAA receptor α3 expression with hippocampal cholinergic neurostimulating peptide precursor protein in the hippocampus.

Cholinergic neural activation from the medial septal nucleus to hippocampus plays a crucial role in episodic memory as a regulating system for glutamatergic neural activation in the hippocampus. As a candidate regulating factor for acetylcholine synthesis in the medial septal nucleus, hippocampal cholinergic neurostimulating peptide (HCNP) was purified from the soluble fraction of young adult rat hippocampus. HCNP is released from its precursor protein (HCNP-pp), also referred to as phosphatidylethanolamine-binding protein 1. We recently reported that HCNP-pp conditional knockout (KO) mice, in which the HCNP-pp gene was knocked out at 3 months of age by tamoxifen injection, display no significant behavioral abnormalities, whereas HCNP-pp KO mice have a diminished cholinergic projection to CA1 and a decreased of theta activity in CA1. In this study, to address whether HCNP-pp reduction in early life is associated with behavioral changes, we evaluated the behavior of HCNP-pp KO mice in which HCNP-pp was downregulated from an early phase (postnatal days 14-28). As unexpected, HCNP-pp KO mice had no behavioral deficits. However, a significant positive correlation between HCNP-pp and gamma-aminobutyric acid A (GABAA) receptor α3 subunit mRNA expression was found in individuals. This finding suggests involvement of HCNP-pp in regulating GABAA receptor α3 gene expression.

Reduced Cholinergic Activity in the Hippocampus of Hippocampal Cholinergic Neurostimulating Peptide Precursor Protein Knockout Mice.

The cholinergic efferent network from the medial septal nucleus to the hippocampus has an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to efficiently encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP) induces acetylcholine synthesis in medial septal nuclei. HCNP is processed from the N-terminal region of a 186 amino acid, 21 kD HCNP precursor protein called HCNP-pp (also known as Raf kinase inhibitory protein (RKIP) and phosphatidylethanolamine-binding protein 1 (PEBP1)). In this study, we generated HCNP-pp knockout (KO) mice and assessed their cholinergic septo-hippocampal projection, local field potentials in CA1, and behavioral phenotypes. No significant behavioral phenotype was observed in HCNP-pp KO mice. However, theta power in the CA1 of HCNP-pp KO mice was significantly reduced because of fewer cholineacetyltransferase-positive axons in the CA1 stratum oriens. These observations indicated disruption of cholinergic activity in the septo-hippocampal network. Our study demonstrates that HCNP may be a cholinergic regulator in the septo-hippocampal network.

Anatomical Links between White Matter Hyperintensity and Medial Temporal Atrophy Reveal Impairment of Executive Functions.

Although several studies have demonstrated correlation between white matter hyperintensities (WMH) and impairment of executive functions, the underlying anatomical-functional relationships are not fully understood. The present study sought to investigate the correlations between the volume of WMH and medial temporal lobe atrophy (MTA) using quantitative magnetic resonance image (MRI) and a variety of executive function assessments. A total of 91 patients ranging in age from 58 to 90 years with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or early phase AD were recruited from the outpatient clinic at the Department of Neurology of Nagoya City University Hospital. We administered neuropsychological batteries evaluating verbal memory, orientation, spatial ability, sustained attention, and a variety of executive functions, including verbal fluency, flexibility, inhibition, and working memory. Quantitative MRI analyses were performed using Dr. View/Linux software and a voxel-based specific regional analysis system. Significant correlations were observed between WMH, as well as MTA, and some executive function scores. Regression analysis revealed that MTA was the strongest predictor of flexibility and verbal fluency. These findings provide new insight into the relationship between quantitative MRI analyses and various types of executive dysfunction in elderly people with MCI due to AD and/or early phase AD. When cognitive function is examined in elderly patients with MCI due to AD or early phase AD, it is important to consider the involvement of WMH and MTA, which is indicative of AD pathology in cognitive dysfunction, particularly executive function.

Hippocampal Cholinergic Neurostimulating Peptide as a Possible Modulating Factor against Glutamatergic Neuronal Disability by Amyloid Oligomers.

Despite having pathological changes in the brain associated with Alzheimer's disease (AD), some patients have preserved cognitive function. A recent epidemiological study has shown that diet, exercise, cognitive training, and vascular risk monitoring interventions may reduce cognitive decline in at-risk elderly people in the general population. However, the details of molecular mechanisms underlying this cognitive function preservation are still unknown. Previous reports have demonstrated that enriched environments prevent the impairment of hippocampal long-term potentiation (LTP) through ß2-adrenergic signals, when LTP is incompletely suppressed by synthetic amyloid-ß (Aß) oligomers. The cholinergic network from the medial septal nucleus (MSN) is also a main modulating system for hippocampal glutamatergic neural activation through nicotinergic and/or muscarinergic acetylcholine receptors. Previously, we reported the importance of a cholinergic regulator gene in the MSN, hippocampal cholinergic neurostimulating peptide (HCNP). By using hippocampal sections from mice, we here demonstrated that the cholinergic neural activation from the MSN enhanced the glutamatergic neuronal activity during unsaturated LTP but not during saturated LTP. Synthetic Aß oligomers suppressed the hippocampal glutamatergic activity in a concentration-dependent manner. Furthermore, HCNP, as well as a cholinergic agonist acting through the muscarinic M1 receptor, prevented the suppression of hippocampal glutamatergic neuronal activity induced by synthetic Aß oligomers. This result suggests that the persisting cholinergic activation might be a potential explanation for the individual differences in cognitive effects of AD pathological changes.

Enhancement of long-term potentiation via muscarinic modulation in the hippocampus of HCNP precursor transgenic mice.

Hippocampal cholinergic neurostimulating peptide (HCNP) regulates acetylcholine synthesis in the septal hippocampus through the quantitative increase of choline acetyltransferase levels in the septal nucleus both in vitro and in vivo. Additionally, HCNP-precursor protein transgenic (HCNP-pp Tg) mice display depressive behavior. To examine the physiological function of HCNP and/or HCNP-pp on hippocampal neural activity, we investigated whether overexpression of HCNP-pp strengthened the efficiency of neural activity in the hippocampus. Long-term potentiation (LTP) of excitatory synaptic transmission was induced by a tetanic stimulation of the Schaffer collateral-commissural fibers (SCs) in mouse hippocampal slices. LTP in HCNP-pp Tg mice was significantly enhanced when compared with wild-type littermate (WT) mice. This facilitation of LTP in HCNP-pp Tg mice was blocked by atropine or pirenzepine, but not by mecamylamine. In contrast, LTP in WT mice was not affected by atropine, but enhanced by carbachol. However, neither difference in the input-output relationship of field excitatory postsynaptic potentials nor in the facilitation ratio in paired-pulse stimulation of the SCs was observed between HCNP-pp Tg and WT mice, indicating that presynaptic glutamate release in HCNP-pp Tg mice is similar to that of WT mice. These results suggest that muscarinic (M1) modulation of glutamatergic postsynaptic function may be involved in strengthening LTP in HCNP-pp Tg mice.

Pleiotrophin promotes functional recovery after neural transplantation in rats.

Pleiotrophin promotes survival of dopaminergic neurons in vitro. To investigate whether pleiotrophin promotes survival of grafted dopaminergic neurons in vivo, donor cells from ventral mesencephalon were treated with pleiotrophin (100 ng/ml) during cell preparation and grafted into striatum of hemi-Parkinson model rats. Functional recovery in methamphetamine-induced rotations was improved, and more tyrosine hydroxylase-positive cells survived in the striatum in the pleiotrophin-treated group. Pleiotrophin addition to cells just before transplantation also resulted in better functional recovery; however, no caspase-3 activation was seen during cell preparation. Interestingly, the effect of pleiotrophin on the survival was additive to that of glial-cell line-derived neutropic factor. These results revealed that pleiotrophin had effects on donor cells in neural transplantation in vivo.