Changes in Nutritional Status after Deep Brain Stimulation of the Nucleus Basalis of Meynert in Alzheimer's Disease--Results of a Phase I Study.

OBJECTIVE: The progression of Alzheimer's disease (AD) is associated with impaired nutritional status. New methods, such as deep brain stimulation (DBS), are currently being tested to decrease the progression of AD. DBS is an approved method in the treatment of Parkinson's disease, and its suitability for the treatment of AD patients is currently under experimental investigation. To evaluate the advantages and disadvantages of this new treatment, it is important to assess potential side effects of DBS regarding the nucleus basalis of Meynert; this new treatment is thought to positively affect cognition and might counteract the deterioration of nutritional status and progressive weight loss observed in AD. This study aims to assess the nutritional status of patients with AD before receiving DBS of the nucleus basalis of Meynert and after 1 year, and to analyze potential associations between changes in cognition and nutritional status. DESIGN: A 1-year phase I proof-of-concept study. SETTING: The Department of Psychiatry and Psychotherapy at the University of Cologne. PARTICIPANTS: We assessed a consecutive sample of patients with mild to moderate AD (n=6) who fulfilled the inclusion criteria and provided written informed consent. INTERVENTION: Bilateral low-frequency DBS of the nucleus basalis of Meynert. MEASUREMENTS: Nutritional status was assessed using a modified Mini Nutritional Assessment, bioelectrical impedance analysis, a completed 3-day food diary, and analysis of serum levels of vitamin B12 and folate. RESULTS: With a normal body mass index (BMI) at baseline (mean 23.75 kg/m²) and after 1 year (mean 24.59 kg/m²), all but one patient gained body weight during the period of the pilot study (mean 2.38 kg, 3.81% of body weight). This was reflected in a mainly stable or improved body composition, assessed by bioelectrical impedance analysis, in five of the six patients. Mean energy intake increased from 1534 kcal/day (min 1037, max 2370) at baseline to 1736 kcal/day (min 1010, max 2663) after 1 year, leading to the improved fulfillment of energy needs in four patients. The only nutritional factors that were associated with changes in cognition were vitamin B12 level at baseline (Spearman's rho = 0.943, p = 0.005) and changes in vitamin B12 level (Spearman's rho = -0.829, p = 0.042). CONCLUSION: Patients with AD that received DBS of the nucleus basalis of Meynert demonstrated a mainly stable nutritional status within a 1-year period. Whether DBS is causative regarding these observations must be investigated in additional studies.

Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia.

Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological changes of neurotransmission and is observed in Alzheimer's disease. Here we report on six patients with mild to moderate Alzheimer's disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer's Disease Assessment Scale-cognitive subscale as the primary outcome measure. Electroencephalography and [(18)F]-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated.

External trial deep brain stimulation device for the application of desynchronizing stimulation techniques.

In the past decade deep brain stimulation (DBS)-the application of electrical stimulation to specific target structures via implanted depth electrodes-has become the standard treatment for medically refractory Parkinson's disease and essential tremor. These diseases are characterized by pathological synchronized neuronal activity in particular brain areas. We present an external trial DBS device capable of administering effectively desynchronizing stimulation techniques developed with methods from nonlinear dynamics and statistical physics according to a model-based approach. These techniques exploit either stochastic phase resetting principles or complex delayed-feedback mechanisms. We explain how these methods are implemented into a safe and user-friendly device.

Recording the corpus cavernosum electromyogram: principles and problems.

PURPOSE: To apply digital signal acquisition and analyzing techniques to the collection and interpretation of electromyographic data of the cavernous body. MATERIALS AND METHODS: Electromyographic recordings were performed in the cavernous bodies of anesthetized, spontaneously breathing dogs under resting conditions and after intracavernous pharmacostimulation with norepinephrine, angiotensin II, phentolamine/papaverine, diethylether and T61. RESULTS: Resting corpus cavernosum activity was ill-coordinated and provided little information. Signal energy was confined largely to the range below 20 Hz. Pharmacostimulation with norepinephrine or angiotensin increased frequency and amplitude of the potential transients and decreased the random components. Administration of a combination of phentolamine and papaverine made the signals very regular and increased periodicity. Blockade of electrical membrane events with diethylether removed all signal components except for electrical and biological noise. CONCLUSIONS: Our findings indicate that electromyograms from the corpus cavernosum can be recorded even under adverse conditions. Signal properties, however, are such that the application of computer-aided data processing and analysis to the evaluation of these myograms is imperative.

Renin-producing renal cell carcinomas--clinical and experimental investigations on a special form of renal hypertension.

The pathogenetic relationship between tumour and hypertension was investigated in 129 patients with renal cell carcinoma, of whom 41 (31.8%) were hypertensive. Of these 41 patients with renal tumours and hypertension, 6 (14.6%) were found to have primary reninism. In these patients the plasma renin activity in blood from the renal veins showed a tumour kidney to contralateral kidney ratio of between 4 and 7, and 2 patients also had secondary hyperaldosteronism. In the same 6 cases the renin content in the renal tumour tissue was significantly higher than that in tissue from the adjacent tumour-free renal cortex of the ipsilateral kidney. Immunohistochemical demonstration of renin in the tumour was only possible in these 6 cases. In 5 of these patients blood pressure returned to normal following nephrectomy; in the 6th case there was a drop in blood pressure after nephrectomy. In 3 renin-positive tumours examined, autonomous renin production was demonstrated in cell culture. Renin-producing renal cell carcinomas are an uncommon cause of renal hypertension. The differential diagnosis of hypertension should therefore also include renal tumour.

Differential effect of neuropeptide-Y on membrane potential of cells in renal arterioles of the hydronephrotic mouse.

1. The effects of neuropeptide-Y (NPY) on the membrane potential of vascular smooth muscle cells were studied in renal arterioles of hydronephrotic mouse kidneys. 2. Kidney vessels are only weakly coupled with length constants of less than 10 microns and are most probably 'multiunit' vessels. 3. The vasoconstrictor peptide NPY reversibly depolarizes only smooth muscle cells in arterioles at distances greater than 200 microns from the glomerulus, whereas no changes of the membrane potential can be evoked close to the glomerulus (distance less than 50 microns). 4. The depolarizations, when present, are dose dependent. 5. Regardless of distance from the glomerulus cells respond uniformly to application of the vasoconstrictor angiotensin II.

Influence of pulsatile perfusion upon renin release from the isolated perfused rat kidney.

It is well established that renin release from the juxtaglomerular epithelioid cells in the media of the afferent arteriole strongly depends on the mean renal perfusion pressure, whereas a possible influence of the pulsation of blood pressure on renin release has only occasionally been investigated, and the results are contradictory. Such an influence on renin release cannot be excluded because pulsation is known to modulate arterial baroreceptors and vascular tone in some resistance vessels. In the isolated perfused rat kidney, we found a pulsation amplitude-dependent inhibition of renin release that could be blocked either by vasodilatation or by calcium channel blockade. The inhibition occurred at perfusion pressures between 85 and 125 mm Hg. The underlying pulsation pressure-sensitive mechanism has to be ascribed integrating properties, because a constant-flow pressure rise to the "systolic" value of pulsatile perfusion resulted in virtually the same inhibition of renin release. Moreover, a reduced urine flow during pulsatile perfusion provides evidence for preglomerular constriction under these conditions. It is concluded that, besides pathological changes of renal perfusion pressure, variations of the pulse amplitudes, e.g. resulting from renal artery stenosis or atherosclerosis, may also influence renin release and contribute to renovascular hypertension.

Renin-producing renal cell carcinoma.

The pathogenetic relationship between tumor and hypertension was investigated in 40 patients with renal cell carcinoma. 15 of 40 patients were hypertensive. Four of these 15 patients with renal tumors and hypertension (26.7%) were found to have primary reninism. In these patients the plasma renin activity in blood from the renal veins showed a tumor kidney to contralateral kidney ratio of between 6 and 7. In the same 4 cases the renin content in the renal tumor tissue was significantly higher than that in tissue from the adjacent tumor-free renal cortex of the ipsilateral kidney. Immunocytochemical demonstration of renin in the tumor was only possible in these 4 cases. In 3 of these patients blood pressure returned to normal following nephrectomy; in the 4th case there was a drop in blood pressure after nephrectomy. Renin-producing renal cell carcinomas are an uncommon cause of renal hypertension. The differential diagnosis of hypertension should therefore also include renal tumor.

Tachyphylaxis of juxtaglomerular epithelioid cells to angiotensin II. Differences between the electrical membrane response and renin secretion.

A study has been made of desensitization of the depolarizing response to angiotensin II of juxtaglomerular epithelioid and vascular smooth muscle cells in the mouse kidney afferent arteriole, of media cells from the mesenteric artery as well as of cultured smooth muscle and mesangial cells. In all cell types, desensitization to this effect of angiotensin II was observed. There was no cross-desensitization between angiotensin II and other depolarizing agonists. Hence, it is concluded that this desensitization is specific, i.e. of the tachyphylaxis type. Substances interfering with receptor recycling, such as chloroquine and monensin, did not block the recovery of the cells from desensitization after removal of the octapeptide. Desensitization to the action of angiotensin II was also observed with respect to its vasoconstrictor effect in the isolated perfused rat kidney. In contrast there was no desensitization of renin secretion in the isolated perfused rat kidney, nor in isolated hydronephrotic mouse tissue, nor in microdissected rat glomeruli.

Myosin content and vasoconstrictive ability of the proximal and distal (renin-positive) segments of the preglomerular arteriole.

The PAP-technique and antibodies to myosin were used to demonstrate the prerequisites for vasoconstriction in the juxtaglomerular part of the preglomerular arteriole as compared with its proximal segment in rats and mice. In contrast with the myosin-positive/renin-negative proximal part of the afferent arteriole no myosin-like activity could be demonstrated in its distal, renin-positive part. In accordance, no thick myofilaments were found in fully differentiated juxtaglomerular epithelioid cells replete with mature secretory granules. Stimulation of the renin-angiotensin system was followed by an increase of the renin-positive/myosin-negative portions of the preglomerular arteriole. Marked interspecies and internephron variations in the length of this vessel segment under control and stimulated conditions were observed. The juxtaglomerular part of the preglomerular arteriole close to the macula densa seems therefore to have only limited capabilities for vasoconstriction. This finding may be of importance regarding the tubulo-glomerular feedback, a mechanism allegedly triggered by the so-called 'macula densa-signal'. It is suggested that this non-contractile segment of the afferent arteriole may represent the renal vascular receptor responsible for the increase of renin secretion during pressure reduction. Unlike the afferent arterioles, most of the efferent arterioles showed the highest level of their weak but distinct myosin-like immunoreactivity in the juxtaglomerular region, indicating some efferent juxtaglomerular vasoconstrictive ability.

Intrarenal generation of angiotensin II evaluated by an electrophysiological technique.

Angiotensin II (ANG II) reversibly depolarizes renin-containing juxtaglomerular epithelioid cells (JGECs) of the hydronephrotic mouse kidney afferent arteriole. This depolarizing response was utilized to assess changes in ANG II concentration in the vicinity of JGECs in order to test whether ANG II is generated from ANG I and artificial renin substrate (ARS) in this preparation. Depolarizations were also produced by the application of ANG I and ARS in the superfusing medium. These responses to ANG I and ARS were completely blocked by saralasin. Hence, our findings are indicative for an intrarenal, local generation of ANG II. As opposed to saralasin, several converting enzyme and renin inhibitors only diminished but generally did not abolish the actions of ANG I and ARS, respectively. These results suggest an alternative, nonrenin and non-converting enzyme-dependent pathway of ANG II generation in renal tissue.

The mesangial cell culture: a tool for the study of the electrophysiological and pharmacological properties of the glomerular mesangial cell.

Cultured rat glomerular mesangial cells (MC) were evaluated as a tool for reliable electrophysiological measurements as well as for fluorimetric determinations of intracellular Ca++. They had a resting potential similar to that observed in cultured vascular smooth muscle cells (VSMCs), in VSMCs of mouse kidney arterioles, or in glomerular--presumably mesangial--cells of kidney slices. The comparison with the other cell types was carried out in order to look for features distinguishing them from these cells, e.g., active and passive electrical membrane properties or electrical membrane responses to vasoactive pharmacological agents. In MCs, as well as in the other cell types, the average membrane potential was approx. -50 mV. The vasoconstrictor peptides angiotensin II (ANG II) and arginine-vasopressin (AVP) caused depolarizations that could be blocked by the respective specific inhibitors of these compounds. The agonist-induced depolarizations have to be attributed, at least in part, to a Ca++ inward current. Norepinephrine, if any, had only a weak action upon MCs, whereas isoproterenol either did not influence the membrane potential or hyperpolarized the cells. Other substances tested, which had no influences upon the membrane potential, were neuropeptide Y and atriopeptin 3. As to their resting electrical properties and their responses to pharmacological agents, cultured mesangial cells did not differ from glomerular, i.e., most probably mesangial, cells in the kidney slice. The difference between mesangial cells and VSMCs consists in their reaction to noradrenaline. Whereas VSMCs respond with a marked depolarization, the noradrenaline effect upon MCs in culture and in the kidney slice is either absent or very weak. Repeated passage of the cells (more than six passages) led to a gradual loss of their responsiveness to the agonists, indicating reduced receptor expression which may be interpreted as dedifferentiation. This held for both cultured MCs and VSMCs. Fluorimetric measurements using the Ca++-specific indicators quin-2 and fura-2 were performed with a purpose-developed, ultrasensitive photon-counting microspectrofluorimeter. Individual MCs as well as isolated glomeruli responded to the vasoconstrictors ANG II and AVP with an increase in Ca++-dependent fluorescence indicating that these agents indeed depolarize the cells partly via a Ca++ influx and increase cytosolic free Ca++.(ABSTRACT TRUNCATED AT 400 WORDS)

Typical and atypical aspects of renin secretion from juxtaglomerular epithelioid cells.

A survey is given about features of renin synthesis and secretion from juxtaglomerular epithelioid cells that are largely atypical as compared to those of other secretory systems. Renin-producing cells have the capability of reversible metaplastic transformation into vascular smooth muscle cells, their secretory granules are very closely related to lysosomes, and they react paradoxically, i.e. with an inhibition instead of a stimulation of renin secretion, to a rise in intracellular free Ca++. The modes of renin secretion and activation of the enzyme as well as possible mechanisms involved in adjusting the ratio of secreted active to inactive renin to the current needs of the renin-angiotensin system are discussed.

Junctional transmission in renin-containing and smooth muscle cells of the afferent arteriole.

Intracellular recordings were done in renin-containing juxtaglomerular (JG) and vascular smooth muscle (VSM) cells of the mouse kidney afferent arteriole. Both cell types exhibited a membrane potential around -75 mV and spontaneous depolarizing transients resembling spontaneous excitatory junction potentials (SEJPs) in the arterioles of other organs. The amplitude distribution of these randomly occurring transients was skewed in both cell types with a modal value of 1.2-1.9 mV. Activation of presumably postjunctional alpha 1-, P2-, ANG II- and AVP-receptors depolarized JG and VSM cells. Application of the P1-purinoceptor agonist 2-chloroadenosine strongly increased frequency and amplitude of the SEJP-like events, whereas these transients were abolished by the P1-purinoceptor antagonist 8-phenyltheophylline, both substances presumably acting on prejunctional receptors. The SEJP-like events were completely depressed by reserpine treatment, but not abolished by alpha 1-, alpha 2-, and P2-antagonists. At present, it cannot be decided, whether norepinephrine is the sole transmitter in the afferent arteriole, acting on specialized junctional adrenoceptors with the P2-purinoceptors being irrelevant for junctional transmission, or whether both substances are co-transmitters. Except norepinephrine and ATP, all other transmitter candidates tested were ruled out for various reasons.

A piezotranslator with variable movement pattern: experiences with the penetration of very small cells.

Successful recording of intracellular potentials strongly depends on the quality of the impalement of the cells by microelectrodes. A substantial improvement of the penetration process could be obtained by using a piezotranslator which accurately controls the forward and backward movement of the electrode tip. The relevant movement amplitudes and velocities can be adjusted independently. The described piezotranslator was used in experiments with cultured cells of the glomerular mesangium of rat kidney, forming a flat monolayer 1-3 micrometers in height. Many successful impalements and long-term, stable recordings demonstrate the usefulness of the translator.

Epithelioid cells: membrane potential changes induced by substances influencing renin secretion.

Microelectrode recordings were performed in renin-containing epithelioid (JG) and vascular smooth muscle (VSM) cells of the afferent arteriole in the isolated hydronephrotic mouse kidney. Both cell types had a membrane potential of about -75 mV and exhibited small, spontaneous depolarizing transients, probably resulting from random transmitter release by sympathetic axon terminals. Substances depressing renin secretion, such as angiotensin II, arginine-vasopressin, and alpha 1-adrenergic agents reversibly depolarized both JG and VSM cells. On a molar basis, the action of angiotensin II was strongest. Stimulators of renin release, e.g. isoproterenol, histamine, and prostaglandin E2 did not influence the membrane potential of both cell types. VIP and NPY, possible co-transmitters of norepinephrine, as well as AP II, were also without effect. It is proposed that suppression of renin secretion from JG cells is mediated by depolarization and Ca2+ influx, whereas stimulation is triggered independently from membrane potential changes, e.g. by adenylate cyclase activation.