- Email: [email protected]
Polydipsia and hippocampal pathology
Correspondence
BIOL PSYCHIATRy 1 9 9 4 " . 3 6 : 7 0 ~ ? 10
Table I. AChE Homospeciflc Activity (U/arb. U), AChE Activity (U/g), AChE humunoreactivity (arb.U/g), and Total Protein (mg/L) in Cerehmspinal Fluid of AD Patients and Controls ~
Pammete~ n
AChE homespecific activity AChE activity AChE immunoreactivity Total protein
c
r
patients
Conlmls
p-
12 0.66 - 0.11 56.1 + 23.5 85.0.4- 33.6 420± 110
19 0.60 ± 0.09 57.9 _ 18.6 97.2 __.30. I 380+_90
NS NS NS NS
• S t u d e m ' s t w o - t ~ l e d test.
709
Rasmussen AG, Adolfsson R, gadsson T (1988): New method specific for acetykholinesterase in ¢~m~xospinalfluid: application to Alzheim~'s disease. Lancet 332"571-572. Schiu. CIL Geula C, Mesulam M (1990): Competitive substrate inhibition in the histuchemistry of cholinesterase activity in Alzheinler's disease. Neurosci Left I 17:56-45I. Siek GC, Katz LS, Ftshman EB, Komsi 'IS, Marquis JK (1990): Molecular forms of acetylchulinestemse in subcortical areas of normal and Alzheimer disease brain. Biol Psychiatry 27:573-580. Sirvii5 J, Riekkinen PJ (1992): Brain and cerebrospinal fluid cholinesterasc in AITheimer's disease, Parkilk~'s disease and aging. A critical review of clinical and experimental studies. J Neural Transm [Park Dis Dement Sect] 4:337-358.
References Appleyard ME, Smith AD, Berman P, et al (1987): Cholinesterase activities in cerebrospinal fluid of patients with senile dementia of Alzbeimer type. Brain 110:1309-1322. Atack JR, Perry EK, Bonham JR, Perry RH (1987): Molecular forms of acetylcholinesterase and butyrylcholineste.rase in human plasma and cerebmspinal fluid. J Neurochem 48: ! 8451850. Bondareff W, Mountjoy CQ, Wischik CM, Hauser DL, LaBree LD, Roth M (1993): Evidence of subtypes of Alzheimer's disease and implications for etiology. Arch Gen Psychiatry 50:350-356. Bonham JR, Gowenlock AH, Timothy JAB (1981): Acetylcholinesterase measurement in the pre-natal detection of neural tube defects and other fetal malformations. Clin Chim Acta 115:163--170. Ellman GL, Courtney KD, Andres V, Featherstone RM (1961): A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88-95. Folstein MF, Folstein SE, Mc Hugh PR (1975 ): Mini Mental State: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189-198. Hammond P, Brimijuin S (1988): Acetylchofinesterase in Huntington's and Alzheimer's diseases: simultaneous enzyme assay and immunoassay of multiple brain re~ons. J Neurochem50:ll 11-1116. d~;m 1" t " t " ~ . . r . ' l ~ n at ql ,"IOG~• ,w, K ~v~tuaiw...l~..s ,t..wavwvuvaa JTE./ a a ~ ~w. ~.s ~ a J o v j .
I[-/.~,C--FII~I
za~i
t ' q a' ,l, ~ l ; n a o ' . ' a ' . , . ~ e . * o ; n
~., •
cerebrospinal fluid. Correlations with clinical measures in Alzheimer's disease. 3 Neurol Sei 72:121-129. lwata J, Nishikaze O (1979): New micro-turbidimetric method of protein in cerebrospinal fluid and urine. Clin Chem 25:13171116. McKhan G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984): Clinical diagnosis of Alzheimer's disease: a report of the NINCDS-ADRDA work-group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34:939-944. Mesulam M-M, Geula C (1990): Shifting patterns of cortical cholinesterases in Alzheimer's disease: Implications for treatment, diagnosis, and pathogenesis. Adv Neurol 51:235-240. Navaratnam DS, Priddle JD, McDonald B, Esiri MM, Robinson JR, Smith AD (1991): Anomalous molecular form of acetylcholinesterase in cerebrospinal fluid in histologically diagnosed Alzheimer's disease. Lancet 337:447-450.
Polydipsiaand ItippocampalPathology To the Editor: I read with great interest the report by Crapanzano et al (Crapanzano et al 1993) of a ease of ictal drinking behavior, Citing their findings and similar reports in the fiterature the authors suggest that hippocampal pathology should be more closely investig~_t_~ in schizophrenic patients with polydipsia with which I can only agree. The fact alone that numerous neuropathological and imaging studies of schizophrenic patients have demonstrated abnormafities of hippocampal structures, especially h i - - u s (Bogerts 1993), makes the hypothesis plausible that they might also be involved in polydipsia in schizophrenic patients. Besides the evidence cited in the report by Dr. Crapanzano and associates, however, there are specific data available that suggest hippocampal pathology might be involved in the disturbed secretion of antidiureric hormone (ADH) patients with polydipsia and hyponatremia. The paravenlricular and supraoptic nuclei, where ADH is produced, get afferents not only from osmoreceptors in the organum vasculosum, but also from limbic structures such as the nucleus accumbens, subiculum and hippocampns (Com'ad and Pfaff 1976; Swanson and Cowan 1975; Woods et al I969). Electrical stimulation of hippocampal structures has been demonstrated to influence the secretionof A D H
(Traczyk and Tomas 1970; Tomas ~t al
1973; Woods et al 1969). Tomas et al found that electrical stimulation with 4 l-Iz of the hippocampus lead to a decreased ADH release; a frequency of 12 Hz was without effect and a frequency of 36141 caused a significant increase of ADH release. Similar observations were made by Hayward and Smith (!963) in ,-nonk~ys, when the amygdala was stimulated. Recently, a study investigating hippocumpal control of hypothalamic adrenocorticotrophic hormone (ACTH) release found that transection of the fomix led to an increased ADH secretion, demonstrating inhibitory control of ADH secretion by afferents from the hippocampus. Interestingly, the increase of ADH secretion could still be overridden by a high feedback signal (in this case serum cortisol) mediated via unknown central nervous system (CNS) areas. In addition, a tight hippocampal regulation of ADH secretion via type H corticosterold receptors was found (Sapolsky et al 1989, 1990).
710
BIOLI~ YCI41ATRY
C~polldeuce
1~4;~:'/0~710
Patients with polydipsia and hyponatremia show a lowered osmotic threshold for ADH release (Goldman et al 1988). Hypersensitive feedback mechanism between osmoreceptors and ADHproducing cells in the hypothalamus could be one explanation for this. in such a case patients with polydipsia/hyponatremia should show a steeper slope of ADH increase with rising osmolality than patients without this disorder. This seems not to be the case (Goldman et al 1988), however, indicating that this basic feedback mechanism functions properly, but is being overridden by abnormal signals from other CNS areas. In view of the data detailed above a possible area where such a signal could originate is the hippocampus. The downward shift of the threshold for ADH release with the maintenance of a normal ADH/osmolality slope could then be explained by either an excessive stimulation of ADH release due to an overactivity of hippocampal efferents---as suggested by the studies of Tortes et al--or a release from inhibition usually exerted by hippocampal afferents as suggested by the studies by Sapolsky et al. in both cases the net result we,'Jd be an increased pituitary ADH release, a left shift of the ADH/osmolality curve and suppression of ADH release only at abnormally low osmolality. This is exactly observed in patients with polydipsia and hyponatremia. If one assumes that this hypothesized hippocampal input fluctuates with the symptoms of psychosis, then such a model could also better explain why patients can develop a worsening of hyponatremia during a psychotic exacerbation, go into sudden hyponatremic crisis and show inappropriately high ADH levels without concomitant polydipsia. In addition, it has also been suggested that hippocampal pathology might be involved in the behavior of polydipsia (Luchius 1990). Polydipsia, as seen in schizophrenic patients, can be conceptualized as a stereotypic behavior. It may be comparable to the abnormal "incentive-conditioned" behavior seen in hippocampally lesioned rats characterized by increased motor behavior and stereotypies. In such rats these behaviors are exhibited in association with feeding if the animals are food-det~rived and fed only once a day. It is assumed that in normal rats the hippocampus prevents the association of such conditioning with useless, stereotypic behaviors, but if lesioned fails to do so (for more detail, see Luchius 1990). Applied to ~hizophrenia, this animal data on the neuropathology of stereotypic behavior would strongly implicate hippocampal pathology in the development of bizarre, repetitive behaviors seen in schizophrenic patients such as polydipsia. Studies in patients with polydipsia and hyponatremia carefully matched to nonpolydipsic patients should be undertaken to investigate the hypothesized association between hippocampal pathology and polydipsia/hyponatremia. D. Umbricht Research Fellow Hillside Hospital Glen Oaks, NY 11004
References Bogerts B (1993): Recent advances in the neumpathology of schizophrenia. S c h i z ~ u .Bull 19:431 ~.A.5 Conrad LC, Pfaff DW (1976): Autorediographic tracing of the nucleus accumbeus effereuts in the rat brain. Brain Res 113:589-596 Crapanzano KA, Casanova MF et al (1993): Drinking behavior as a result of fight hippocampal ictal focus. Biol Psychiatry 34:889-92 Goldman MB, Luchins DJ, Robertson GL (1988): Mechanism of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Eng J Mud 3 ! 8:399--403. Hayward JN, Smith WK (1963): Influence of limbic system on neurohypophysis. Arch Neurol 9:171-177 Luchins DJ (1990): A possible role of hippocampal dysfunction in schizophrenic symptomatology. Biol Psychiatry 28:87--91 S~31sky RM, et al (1989): Elevation of hypophyseai portal concentrations of adrenocorticolmpin secretagogues after fomix transection. Endocr/no/ogy 125:2881-2887 Sapolsky RM, et al (! 990): Glucocorticoid feedback inhibition of adrenocorticotmpic hormone secretagogne release. Relationship to corticosteroid receptor occupancy in various limbic sites. Neuroendocrinology 51:328-336. Swanson LW, Cowan WM (1975): Hiplx)car~al-hypothalamic connections: Origin in subicular cortex, not Ammon's horn. Sc/ence !89:303-304 Tomas T, et al (1973): ADH release from cut pituitary stalk and intact pituitary gland during hippocamnal stimulation of various frequencies in rats. Neuroendocrinolosy 11:257-267 Traczyk WZ, Tomas T (1970): The influence of hippocampus on the release of antidiuretic hormone form the pituitary stalk in rats. Bull Acad Pol Sci 18:53-58 Woods WH, et al (1969): Connection of cerebral structures functioning in neurohypophysial hormone release. Brain Res 12:26-46
BIOL PSYCHIATRy 1 9 9 4 " . 3 6 : 7 0 ~ ? 10
Table I. AChE Homospeciflc Activity (U/arb. U), AChE Activity (U/g), AChE humunoreactivity (arb.U/g), and Total Protein (mg/L) in Cerehmspinal Fluid of AD Patients and Controls ~
Pammete~ n
AChE homespecific activity AChE activity AChE immunoreactivity Total protein
c
r
patients
Conlmls
p-
12 0.66 - 0.11 56.1 + 23.5 85.0.4- 33.6 420± 110
19 0.60 ± 0.09 57.9 _ 18.6 97.2 __.30. I 380+_90
NS NS NS NS
• S t u d e m ' s t w o - t ~ l e d test.
709
Rasmussen AG, Adolfsson R, gadsson T (1988): New method specific for acetykholinesterase in ¢~m~xospinalfluid: application to Alzheim~'s disease. Lancet 332"571-572. Schiu. CIL Geula C, Mesulam M (1990): Competitive substrate inhibition in the histuchemistry of cholinesterase activity in Alzheinler's disease. Neurosci Left I 17:56-45I. Siek GC, Katz LS, Ftshman EB, Komsi 'IS, Marquis JK (1990): Molecular forms of acetylchulinestemse in subcortical areas of normal and Alzheimer disease brain. Biol Psychiatry 27:573-580. Sirvii5 J, Riekkinen PJ (1992): Brain and cerebrospinal fluid cholinesterasc in AITheimer's disease, Parkilk~'s disease and aging. A critical review of clinical and experimental studies. J Neural Transm [Park Dis Dement Sect] 4:337-358.
References Appleyard ME, Smith AD, Berman P, et al (1987): Cholinesterase activities in cerebrospinal fluid of patients with senile dementia of Alzbeimer type. Brain 110:1309-1322. Atack JR, Perry EK, Bonham JR, Perry RH (1987): Molecular forms of acetylcholinesterase and butyrylcholineste.rase in human plasma and cerebmspinal fluid. J Neurochem 48: ! 8451850. Bondareff W, Mountjoy CQ, Wischik CM, Hauser DL, LaBree LD, Roth M (1993): Evidence of subtypes of Alzheimer's disease and implications for etiology. Arch Gen Psychiatry 50:350-356. Bonham JR, Gowenlock AH, Timothy JAB (1981): Acetylcholinesterase measurement in the pre-natal detection of neural tube defects and other fetal malformations. Clin Chim Acta 115:163--170. Ellman GL, Courtney KD, Andres V, Featherstone RM (1961): A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88-95. Folstein MF, Folstein SE, Mc Hugh PR (1975 ): Mini Mental State: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189-198. Hammond P, Brimijuin S (1988): Acetylchofinesterase in Huntington's and Alzheimer's diseases: simultaneous enzyme assay and immunoassay of multiple brain re~ons. J Neurochem50:ll 11-1116. d~;m 1" t " t " ~ . . r . ' l ~ n at ql ,"IOG~• ,w, K ~v~tuaiw...l~..s ,t..wavwvuvaa JTE./ a a ~ ~w. ~.s ~ a J o v j .
I[-/.~,C--FII~I
za~i
t ' q a' ,l, ~ l ; n a o ' . ' a ' . , . ~ e . * o ; n
~., •
cerebrospinal fluid. Correlations with clinical measures in Alzheimer's disease. 3 Neurol Sei 72:121-129. lwata J, Nishikaze O (1979): New micro-turbidimetric method of protein in cerebrospinal fluid and urine. Clin Chem 25:13171116. McKhan G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984): Clinical diagnosis of Alzheimer's disease: a report of the NINCDS-ADRDA work-group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34:939-944. Mesulam M-M, Geula C (1990): Shifting patterns of cortical cholinesterases in Alzheimer's disease: Implications for treatment, diagnosis, and pathogenesis. Adv Neurol 51:235-240. Navaratnam DS, Priddle JD, McDonald B, Esiri MM, Robinson JR, Smith AD (1991): Anomalous molecular form of acetylcholinesterase in cerebrospinal fluid in histologically diagnosed Alzheimer's disease. Lancet 337:447-450.
Polydipsiaand ItippocampalPathology To the Editor: I read with great interest the report by Crapanzano et al (Crapanzano et al 1993) of a ease of ictal drinking behavior, Citing their findings and similar reports in the fiterature the authors suggest that hippocampal pathology should be more closely investig~_t_~ in schizophrenic patients with polydipsia with which I can only agree. The fact alone that numerous neuropathological and imaging studies of schizophrenic patients have demonstrated abnormafities of hippocampal structures, especially h i - - u s (Bogerts 1993), makes the hypothesis plausible that they might also be involved in polydipsia in schizophrenic patients. Besides the evidence cited in the report by Dr. Crapanzano and associates, however, there are specific data available that suggest hippocampal pathology might be involved in the disturbed secretion of antidiureric hormone (ADH) patients with polydipsia and hyponatremia. The paravenlricular and supraoptic nuclei, where ADH is produced, get afferents not only from osmoreceptors in the organum vasculosum, but also from limbic structures such as the nucleus accumbens, subiculum and hippocampns (Com'ad and Pfaff 1976; Swanson and Cowan 1975; Woods et al I969). Electrical stimulation of hippocampal structures has been demonstrated to influence the secretionof A D H
(Traczyk and Tomas 1970; Tomas ~t al
1973; Woods et al 1969). Tomas et al found that electrical stimulation with 4 l-Iz of the hippocampus lead to a decreased ADH release; a frequency of 12 Hz was without effect and a frequency of 36141 caused a significant increase of ADH release. Similar observations were made by Hayward and Smith (!963) in ,-nonk~ys, when the amygdala was stimulated. Recently, a study investigating hippocumpal control of hypothalamic adrenocorticotrophic hormone (ACTH) release found that transection of the fomix led to an increased ADH secretion, demonstrating inhibitory control of ADH secretion by afferents from the hippocampus. Interestingly, the increase of ADH secretion could still be overridden by a high feedback signal (in this case serum cortisol) mediated via unknown central nervous system (CNS) areas. In addition, a tight hippocampal regulation of ADH secretion via type H corticosterold receptors was found (Sapolsky et al 1989, 1990).
710
BIOLI~ YCI41ATRY
C~polldeuce
1~4;~:'/0~710
Patients with polydipsia and hyponatremia show a lowered osmotic threshold for ADH release (Goldman et al 1988). Hypersensitive feedback mechanism between osmoreceptors and ADHproducing cells in the hypothalamus could be one explanation for this. in such a case patients with polydipsia/hyponatremia should show a steeper slope of ADH increase with rising osmolality than patients without this disorder. This seems not to be the case (Goldman et al 1988), however, indicating that this basic feedback mechanism functions properly, but is being overridden by abnormal signals from other CNS areas. In view of the data detailed above a possible area where such a signal could originate is the hippocampus. The downward shift of the threshold for ADH release with the maintenance of a normal ADH/osmolality slope could then be explained by either an excessive stimulation of ADH release due to an overactivity of hippocampal efferents---as suggested by the studies of Tortes et al--or a release from inhibition usually exerted by hippocampal afferents as suggested by the studies by Sapolsky et al. in both cases the net result we,'Jd be an increased pituitary ADH release, a left shift of the ADH/osmolality curve and suppression of ADH release only at abnormally low osmolality. This is exactly observed in patients with polydipsia and hyponatremia. If one assumes that this hypothesized hippocampal input fluctuates with the symptoms of psychosis, then such a model could also better explain why patients can develop a worsening of hyponatremia during a psychotic exacerbation, go into sudden hyponatremic crisis and show inappropriately high ADH levels without concomitant polydipsia. In addition, it has also been suggested that hippocampal pathology might be involved in the behavior of polydipsia (Luchius 1990). Polydipsia, as seen in schizophrenic patients, can be conceptualized as a stereotypic behavior. It may be comparable to the abnormal "incentive-conditioned" behavior seen in hippocampally lesioned rats characterized by increased motor behavior and stereotypies. In such rats these behaviors are exhibited in association with feeding if the animals are food-det~rived and fed only once a day. It is assumed that in normal rats the hippocampus prevents the association of such conditioning with useless, stereotypic behaviors, but if lesioned fails to do so (for more detail, see Luchius 1990). Applied to ~hizophrenia, this animal data on the neuropathology of stereotypic behavior would strongly implicate hippocampal pathology in the development of bizarre, repetitive behaviors seen in schizophrenic patients such as polydipsia. Studies in patients with polydipsia and hyponatremia carefully matched to nonpolydipsic patients should be undertaken to investigate the hypothesized association between hippocampal pathology and polydipsia/hyponatremia. D. Umbricht Research Fellow Hillside Hospital Glen Oaks, NY 11004
References Bogerts B (1993): Recent advances in the neumpathology of schizophrenia. S c h i z ~ u .Bull 19:431 ~.A.5 Conrad LC, Pfaff DW (1976): Autorediographic tracing of the nucleus accumbeus effereuts in the rat brain. Brain Res 113:589-596 Crapanzano KA, Casanova MF et al (1993): Drinking behavior as a result of fight hippocampal ictal focus. Biol Psychiatry 34:889-92 Goldman MB, Luchins DJ, Robertson GL (1988): Mechanism of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Eng J Mud 3 ! 8:399--403. Hayward JN, Smith WK (1963): Influence of limbic system on neurohypophysis. Arch Neurol 9:171-177 Luchins DJ (1990): A possible role of hippocampal dysfunction in schizophrenic symptomatology. Biol Psychiatry 28:87--91 S~31sky RM, et al (1989): Elevation of hypophyseai portal concentrations of adrenocorticolmpin secretagogues after fomix transection. Endocr/no/ogy 125:2881-2887 Sapolsky RM, et al (! 990): Glucocorticoid feedback inhibition of adrenocorticotmpic hormone secretagogne release. Relationship to corticosteroid receptor occupancy in various limbic sites. Neuroendocrinology 51:328-336. Swanson LW, Cowan WM (1975): Hiplx)car~al-hypothalamic connections: Origin in subicular cortex, not Ammon's horn. Sc/ence !89:303-304 Tomas T, et al (1973): ADH release from cut pituitary stalk and intact pituitary gland during hippocamnal stimulation of various frequencies in rats. Neuroendocrinolosy 11:257-267 Traczyk WZ, Tomas T (1970): The influence of hippocampus on the release of antidiuretic hormone form the pituitary stalk in rats. Bull Acad Pol Sci 18:53-58 Woods WH, et al (1969): Connection of cerebral structures functioning in neurohypophysial hormone release. Brain Res 12:26-46