By H. Samuel. Fairmont State College.
However permethrin 30gm otc skin79 skin care, he was asked to use the toilet and interact with staff and other patients in Pridmore S discount permethrin 30 gm on-line skin care unlimited. Over some weeks order permethrin 30gm on-line acne yahoo answers, however buy cheap permethrin 30gm acne description, his condition improved and he was able to use the toilet. Mrs E benefited from the rest and was happy to continue to support her husband at home. This case illustrates the paradox of some OCD patients who are concerned about cleanliness, but who are themselves, quite unclean. It seems that their concerns and the anxiety are so great and preoccupying that they are unaware of the facts of their actual situation. Case history, 3 Mr F was a 54-year-old divorced, unemployed former clerk, living alone in a Housing Department unit. His marriage had ended 20 years previously and he one child, a daughter living in a distant part of the country. He stated that he would not have been able to come alone because leaving his home was anxiety provoking. He had two friends from the distant past and had maintained contact with them by telephone. He reported that there had been a problem with his kitchen tap and he had not been able to turn it on for 7 years. Mr F could afford a plumber, but the stress of having another person in his flat was too much to contemplate. He had tried a vast range of medications over the years. He said that none had helped in the slightest and he had experienced severe side effects with most of them. His reluctance to leave the house appeared to be agoraphobia. He was disabled by an obsession that he may lose letters from his letter-box. When he approached his letter-box he first searched the small, concrete front drive (about the size of a room) to make sure that the post-man had not dropped a letter before putting it into the box. This searching of a blank flat surface could take half an hour. Mr F would then slowly open the door of his letter-box by one or two centimetres and peep in over the top to see if there were any letters. Irrespective, he would then open the door completely, take out any letters and then feel around inside the box for some minutes to make sure there were no letters left. The most difficult stage then followed: he would again have to search the concrete drive to make sure that no letters had dropped out when he had opened the door. The process of checking his letter-box could take one hour or more. He knew that he was behaving illogically, and this caused him distress. At the time of presentation he had given up all resistance. He said it was less anxiety provoking to comply with this compulsion than to resist, and he would not co-operate with ERP or any other form of behaviour therapy. Mr F believed he may get some help from a particular SSRI and asked for it to be prescribed. Supportive psychotherapy was provided and attempts were made (unsuccessful) to encourage Mr F to participate in pleasurable activities. He appeared to enjoy his meetings with the psychiatrist and would always bring word and number puzzles. After one year Mr F described what may have been a depressive episode which lasted a month. He was already taking a sufficient dose of an effective antidepressant and as change was almost impossible, Mr F and his psychiatrist decided to wait for natural remission. He began bringing the psychiatrist up to 4 plastic shopping bags of old belongings, old magazines and broken electrical equipment. The opinion was formed that Mr F had been hoarding for years and that with the assistance of medication and supportive therapy he was now able to discard some of this material. Mr F was aware that the psychiatrist would probably discard these belongings, he did not object, he seemed unable to do so himself. After 4 years Mr F telephoned his psychiatrist that he was again feeling depressed. He said he could not come to an earlier appointment, and would not accept hospitalization. He did not arrive at his next appointment and was found in his unit of an overdose. Yale-Brown obsessive-compulsive scale (YBOCS) The YBOCS (Goodman et al, 1989) is the most commonly used OCD scale. However, it is protected by copyright an only the flavour can be here presented. There are two parts, 1) a symptom check list, and 2) a severity rating scale. The symptom check list has questions similar to the following: 1. Do you worry excessively about speaking or acting in a manner that you think is harmful, violent, sexually inappropriate, immoral, or sacrilegious? Do you repeatedly ruminate about unwanted thoughts in an effort to prove to yourself that you will not act in a manner that you think is harmful, violent, sexually inappropriate, immoral, or sacrilegious? Do you recite prayers or certain phrases in an effort to rid yourself of unwanted thoughts or to ensure that nothing bad happens? Do you often repeat routing, daily activities to ensure that you did not harm someone (e. Do you wash your hands or shower more often or for longer periods of time than most other people? Do you repeatedly visually check to be sure you have properly performed a just-completed task (e. Do you frequently ask others for reassurance that tasks have been properly completed (e. Do you repeatedly ask others for reassurance that you have not done something “wrong”, “bad”, or “harmful”? Do you unnecessarily arrange, order, or tidy the contents of your desk, closet, cabinets, bookshelves, etc, to make them symmetrical or “just right”? Do you unnecessarily straighten common household objects such as window blinds or rugs in an effort to make them symmetrical of “just right”? Do you repeatedly count mundane items that do not really merit counting (e. Do you have great difficulty discarding things that have no practical value and that most other people would consider rubbish (e. The severity rating scale is similar to the following: Item Range 1 Time spent 0 h/day 0-1 h/day 1-3 h/day 3-8 h/day >8 h/day on obsessions 0 1 2 3 4 2 Interference None Mild Definite but Substantial Incapacitating from manageable impairment obsessions 0 1 2 3 4 3 Distress None Little Moderate Severe Near constant, from but disabling obsessions manageable 0 1 2 3 4 4 Resistance Always Much Some Often Completely to resist resistance resistance yields yields obsessions 0 1 2 3 4 5 Control Complete Much Some Little No control over control control control control obsessions 0 1 2 3 4 Obsession subtotal (add items 1-5) _________ Pridmore S. Psychiatric Clinics of North America 2014; 37: 393-413.
Future studies or adolescence is a predictor of the persistence into adult- should determine if components of anxiety syndromes are hood of not only anxiety disorders but other psychiatric controlled by specific genes purchase 30gm permethrin fast delivery skin care 5th avenue peachtree city. The revolution occurring in disorders as well discount 30 gm permethrin otc acne xyl, particularly depression permethrin 30 gm on line skin care gift baskets. It is not known genomics research as a consequence of sequencing the if early effective treatment of childhood and adolescent anxi- 1 human genome and the identification of over 1 ⁄2 million ety disorders will prevent the development of psychiatric single nucleotide polymorphisms (SNPs) should make dis- disorders later in life purchase permethrin 30gm otc acne 60 year old woman. Strategies Important insights into the pathogenesis of anxiety disor- that are complementary to linkage analyses and utilize data ders come from preclinical investigations reviewed by Davis from linkage studies are indicated. The identification of the brain structures and the genotyping of candidate functional SNPs with linkage neural circuits involved in the generation of fear and anxi- and equilibrium mapping in chromosomal regions impli- ety-related behaviors are most noteworthy. The delineation of specific neural pathways mediating conditioned and un- cated in linkage studies. In parallel with the genetic studies, conditioned fear can logically guide the design and conduct enhanced efforts to identify endophenotypic biological vul- of clinical studies investigating the neurobiological mecha- nerability markers are indicated. The studies cited in the nisms of anxiety disorders such as generalized anxiety disor- chapter on temperament, anxiety sensitivity, autonomic reactivity, psychophysiologic function, ventilatory function, neurochemical, and neuroendocrine factors are good exam- Dennis Charney: Mood and Anxiety Disorder Research Program, Na- ples of this approach. Bakshi and Kalin point out in their chapter the advan- 858 Neuropsychopharmacology: The Fifth Generation of Progress tages of using putative animal endophenotypes of stress and the reported neurobiological distinctions between patients anxiety to identify genetic abnormalities associated with and controls is robust enough to be of diagnostic relevance. Rodent and nonhuman primate studies Tallman, Cassella, and Kehne review the mechanism of of mother-infant interactions are particularly compelling, action of anxiolytic drugs and the status of new and novel given the important clinical implications if these interac- therapeutic agents. They highlight the therapeutic potential tions are found to be a critical factor in future fearful disposi- and current status of CRH antagonist drug development. Targeted mutations leading to anxiety-like endophe- They also note the potential of developing targets for the notypes in transgenic mice have suggested roles for CRF-2 receptor and other peptides, such as vasoactive intes- serotonin receptor subtype 1A (5-HT1A), corticotropin- tinal peptide (VIP), involved in the regulation of stress. In releasing hormone (CRH), GABA, neuropeptide Y, chole- regard to benzodiazepine drug development, they note an cystokinin, and substance P neural systems in the generation ideal drug might have limited effects on the 1 subtype on anxiety-fear behaviors. These studies provide clues for with increased responsiveness at 2 and 3 subunits. Glu- the discovery of new medications and pharmacogenomic tamate receptor agonists and modulators are proposed as approaches to treatment. Accelerated drug development ef- viable targets for anxiety disorders. For example, point forts focusing on corticotropin-releasing factor 1 (CRF-1) mutations in the glycine-binding site of the NR1 subunit receptor antagonists and benzodiazepine agonists with an result in mice that have reduced glycine affinity and anxioselective subunit profile are indicated. Group II metabotrophic glutamate of pharmacogenomic investigations designed to evaluate the agonists are in early clinical development for the treatment relationships among functional polymorphisms of the of anxiety disorders. Other novel drug targets include 5-HT1A receptor, benzodiazepine receptor, and GABA syn- antagonists of AMPA receptors and antagonists of strych- thesis enzymes and therapeutic responses to specific drugs nine-sensitive glycine site, both of which show anxiolytic should be explored. It is imperative that these findings from the preclinical Ultimately, the goal of research on the neurobiological studies of anxiety and fear states be translated into increased underpinnings of anxiety disorders is to lead to more effec- knowledge of the neural circuits and associated neural tive, more rapidly acting treatments, to achieve a more com- mechanisms that can account for the signs and symptoms plete response, and to be able to predict responses to specific in patients with anxiety disorders. In their review, Gorman, Kent, and Coplan the neuroimaging findings relevant to anxiety and stress highlight the extremely broad spectrum of action of norepi- disorders. Their chapter emphasizes the areas of congruence nephrine and serotonin transport inhibitors in anxiety disor- between animal studies and clinical neuroimaging investiga- ders. These drugs are limited by a delayed onset and in- tions. For example, imaging studies in healthy subjects sup- complete response in many patients. This suggests that port a role for the amygdala in fear conditioning and the norepinephrine and serotonin have broad modulatory ef- frontal cortex in extinction. In the imaging studies of pa- fects on other neuronal systems, which are more primarily tients with anxiety disorders, progress has been made in related to the pathogenesis of anxiety disorders. Functional relationships In summary, a reading of these chapters reveals that there among the amygdala, hippocampus, and medial prefrontal have not been fundamental advances in our ability to diag- cortex have been reported in patients with posttraumatic nose anxiety disorders based on known etiology. The imaging findings in patients stay of medication treatment continues to be classes of medi- with obsessive-compulsive disorder (OCD) are consistent cations that have existed for decades. There are major gaps with 'pathology' in cortico-striatal-thalamo-cortical circui- in our knowledge of anxiety disorders in children. Unfortunately, a critical gap in knowledge exists regard- mechanisms responsible for the occurrence of anxiety disor- ing the relevant neural circuits involved in panic disorder, ders in childhood and adolescence leading to increased risk social anxiety disorder, and generalized anxiety disorder. The neurochemical systems associated with anxiety and fear However, the potential for progress is great. A multidiscipli- circuits are reviewed in the chapter by Charney and Drevets. However, most of the findings reviewed should be genomics, and novel drug design and testing will be a deemed preliminary, and they require replication. LANG This chapter traces the course and trajectory of anxiety dis- risk of development of childhood anxiety. The chapter discusses these disor- tion (EE), which is an interactional style composed of emo- ders in three age groups: (a) childhood, (b) young adulthood tional overinvolvement and high levels of criticism, has been to middle age, and (c) older adulthood. The There are a number of factors that relate to the development answer is a qualified yes. The last decade or so of research of anxiety in general. Although this remains a controversial by Jerome Kagan and colleagues has led to the identification area, current evidence suggests that anxiety does not appear of a temperament, 'behavioral inhibition' (BI), that ap- to be specifically heritable; what clusters in families is a pears to be related to the subsequent onset of anxiety disor- more general predisposition to mood or anxiety disorders. BI involves reacting to unfamiliar or novel situations Evidence of this comes from twin studies (1) as well as with behavioral restraint and physiologic arousal (5). When from studies of the incidence of disorders in the families of confronted with an unfamiliar person or object, a BI child anxious patients (2). Specific phobia, however, may be an will withdraw, cling, be reluctant to interact, show emo- exception to this general heritability; family members with tional distress, and stop other activities. BI has also been specific phobias tend to be associated with increased risk associated with physiologic differences, such as high and only for specific phobias (3). These findings have led to the hypothesis that BI is found that parental psychopathology was a risk factor for related to a lowthreshold for arousal in the amygdala and the development of disorder only among the lower socioeco- hypothalamus (8). This characteristic, which appears to be nomic status (STS) portion of their sample. It has been present in 10% to 15% of children, has been identified in suggested that environmental factors play a significant role children as young as 14 months, has been shown to persist in the manifestation of specific psychopathology (1). Anxi- throughout childhood (9), and is more commonly found ety in particular is believed to be related to a combination in offspring of anxious parents (8). The inhibited tempera- of negative affect, a sense of lack of control over situations ment has been associated with risk of developing an anxiety or environments, and attentional self-focus. Early experi- disorder, most commonly social phobia (10). This lack of differentiation appears to be character- istic of younger children, with increased specificity develop- Murray B. Lang: Department of Psychiatry, University ing over time (11,12). At least by middle childhood, there of California–San Diego, San Diego, California. Spence (12) conducted a confirmatory 11 to 16), but that there was a substantial amount of new factor analysis with data from children of 8 to 12 years.
For example permethrin 30gm visa acne topical medications, the relation- tial neurochemical and neuroanatomic abnormalities are re- ship between aggression and antisocial behavior has been viewed order 30 gm permethrin amex acne 40 years. Behavioral and pharmacologic therapies have had suggested in monoamine oxidase A (MAOA) deficiency generic 30 gm permethrin amex acne light therapy. Neuroanatomic studies discount 30gm permethrin with amex acne 40s, brain imaging studies, single large Dutch kindred (21). The affected males differed and continuing investigations of neurotransmitter systems, from unaffected males in that they tested in the borderline endocrine rhythms, and sleep studies may provide informa- range of mental retardation and demonstrated increased im- tion that will be helpful in the future in treatment. Yet a specific psychiatric diagnosis was not made in four affected males who were examined Lesch–Nyhan Disease by psychiatrists. Because MAOA deficiency leads to in- LND is a rare (1:380,000) sex-linked recessive disease creased 5-hydroxytryptamine (5-HT) levels, the aggressive caused by an inborn error of purine nucleotide metabolism. HPRT, which is involved in the purine salvage (purine base suggested that even if a possible association between MAOA recycling) pathway (25). LND is of psychosocial and psychiatric tors noted that genes are essentially simple and code for importance because of the lifelong suffering experienced by proteins, whereas behavior is complex; thus, a direct causal the involved child and his family, the uniqueness of the relationship between a single gene and a specific behavior behavioral phenotype, and the resources needed for lifelong is highly unlikely. In MAOA deficiency, complexity is patient supervision. Moreover, an understanding of the neu- shown by the variability in the behavioral phenotype and robiological basis of this disease may contribute to a better by the highly complex consequences of MAOA deficiency understanding of brain mechanisms involved in self-inju- on neurotransmitter function. Thus, the full pathway from rious and compulsive behaviors. Still, a great deal may be learned by considering such path- Genetic and Metabolic Aspects ways in neurogenetic syndromes. The HPRT-encoding gene is located on the X chromosome in the q26-q27 region and is made up of nine exons and eight introns totaling 57 kilobases (kb). The HPRT gene is PREVALENCE transcribed to produce a mRNA of 1. More than 270 With increasing attention to neurogenetic disorders, the mutations throughout the coding regions have been identi- number of identifiable behavioral phenotypes is increasing. Techniques that provide information on the Careful observations of behavior are necessary when consid- three-dimensional structure of the HPRT protein make it ering intervention for neurogenetic disorders. Although possible to correlate structure and function of the enzyme standardized rating scales and personality profiles have been (26). Besides The gene involved in LND is on the X chromosome, so behavioral phenotypes, isolated special abilities that occur the disorder occurs almost entirely in males; occurrence in in genetically based syndromes require assessment. The metabolic abnormality is the include special abilities in calculation and in music (24). This enzyme is normally present in each posed modular organization of the central nervous system. Its absence prevents the normal metabolism of hypoxanthine and results in excessive uric acid production BEHAVIORAL PHENOTYPES OF SPECIFIC and manifestations of gout without specific drug treatment NEURODEVELOPMENTAL DISORDERS (i. The full disease requires the virtual ab- sence of the enzyme. Other syndromes with partial HPRT The sections that follow discuss four syndromes in which deficiency are associated with gout without the neurologic behavioral phenotypes have been identified:LND, PWS/ and behavioral symptoms. Page and Nyhan reported that AS, fragile X syndrome, and WMS. Characteristic behaviors HPRT levels are related to the extent of motor symptoms, Chapter 46: Behavioral Phenotypes of Neurodevelopmental Disorders 629 the presence or absence of self-injury, and possibly the level findings was documented on quantitated neurologic exami- of cognitive function (27). The study of variant cases with motor symptoms but with no self-injurious be- Self-injurious behavior usually is expressed as self-biting; havior suggests that reductions in dopamine receptor den- however, other patterns of self-injurious behavior may sity are not a sufficient explanation of the self-injury. It is not uncommon for self-injury to progress to deliberate self-harm (19,28). Characteristically, ever, these authors found that HPRT level and the extent the fingers, mouth, and buccal mucosa are mutilated. The of motor deficit were correlated with dopamine transporter biting pattern is often asymmetric, so the patient may muti- binding in caudate and putamen in the nine cases. Dopa- late the left or right side of the body and may become anx- mine transporter binding was significantly correlated with ious if he perceives that this side of the body is threatened. Moreover, when the movement Other associated maladaptive behaviors include head or disorder was rated on the Fahn-Marsden dystonia rating limb banging, eye poking, pulling of fingernails, and psy- scale, putamen dopamine transporter density was signifi- chogenic vomiting (28). These findings Self-mutilation in LND is conceptualized as a compul- suggest that dopamine reduction is linked to the extent of sive behavior that the child tries to control but generally the movement disorder, but it may not be a sufficient expla- is unable to resist. With increasing age, the affected child nation for self-injurious behavior, and other neurotransmit- becomes more adept at finding ways to control his self- ters need to be examined. He may enlist the help of others to protect him with levels from 2% to 20% showed cognitive deficit pro- against these impulses or may learn self-restraint. A language pattern that consists of repeated ambivalent Future investigation will need to take into account the statements with anxiety and coprolalia (vulgar speech) is existence of a variety of mutations in the HPRT gene struc- characteristic. Why partial HPRT deficiency does not lead to neuro- aggressive and may inflict injury on others through pinch- logic and behavioral symptoms remains unclear; perhaps ing, grabbing, or using verbal forms of aggression. Fre- neurotrophic factors are active with minute amounts of the quently, he will apologize for this behavior immediately enzyme. It is advisable to study combined drug and behav- afterward and will say that the behavior was out of his con- ioral treatment. As in other inborn errors, continuous Etiologic Factors family support is essential. Harris provides a description of a comprehensive treatment program for LND (19). The cause of the neurologic and behavioral symptoms is not clearly established; however, abnormalities in dopamine function have been demonstrated in three autopsied cases Prader–Willi Syndrome (29). The behavior is not caused by either hyperuricemia PWS is a neurodevelopmental disorder characterized by or by excess hypoxanthine because LND partial variants whose HPRT levels are greater than 2 do have hyperuri- obesity, short stature, cryptorchidism, mental retardation, cemia but they do not self-injure. Moreover, infants treated hyperphagia, learning disability, short stature, hypogonad- for hyperuricemia from birth whose uric acid level is nor- ism, hypotonia, small hands and feet, and dysmorphic fa- malized still develop self-injury despite having normal levels cies. Patients have an increased prevalence of daytime sleepi- of uric acid. Although it is a rare disorder (1 in 10,000 to the self-injurious behavior (30). These authors documented 15,000), its behavioral phenotype has assumed prominence reductions in dopamine transporter density of 68% in puta- in genetics because of its relationship with AS, which has men and 42% in caudate in six patients with classic LNS a different behavioral phenotype, although both disorders and self-injurious behavior. To clarify the relationship be- involve genomic imprinting of the same region of chromo- tween presynaptic dopamine transporter binding in the stri- some 15. In UPD, two copies of the maternal chromo- 630 Neuropsychopharmacology: The Fifth Generation of Progress some are inherited with no paternal contribution (32). Pipes evaluated food-related behavior in the PWS (36). Without the presence of the chromosome donated by the They found that behavioral problems were most commonly father, the normal imprinting of the two maternally donated related to food and included food stealing, foraging for food, chromosomes leads to absence of gene expression in this gorging, and indiscriminate eating with little food selectiv- interval. This results in a functional abnormality that is ity. No special circumstances that resulted in food stealing essentially equivalent to the structural abnormality found or gorging were identified. Moreover, in about 5% of cases, abnormalities with temper tantrums, stubbornness, negativism, skin pick- in the mechanism of imprinting may occur when the im- ing and scratching, and non–food-related obsessions have printing control center itself has a mutation. A questionnaire survey involving 369 cases Several genes are included in the most commonly deleted identified compulsive and impulsive aggressive behavior region in PWS. These authors used the Overt Aggression Scale, the are maternally imprinted (33). Among these, ZNF 127, Yale-Brown Obsessive-Compulsive Disorder Scale, a clini- NDN, SNURF-SMRPN, IPW are paternally imprinted. An- cal global rating, and DSM-III-R criteria to diagnose self- other gene, UBE3A (E6-AP ubiquitin lipase), is maternally stimulation and self-injury, compulsive behavior, and obses- imprinted.
These are the following: NEUROTRANSMITTER ABNORMALITIES 1 buy cheap permethrin 30gm online acne 6dpo. Sixty-five percent of au- topsy-confirmed DLB cases meet the NINCDS/ADRDA Neurochemical activities have been widely investigated in clinical criteria for probable or possible AD (47) buy 30 gm permethrin with visa acne under eyes, which is AD and PD buy generic permethrin 30gm line acne medication, including in some instances PD with dementia discount permethrin 30gm acne queloide, the most frequent clinical misdiagnosis applied to patients but fewer reports are available on DLB. These are summa- with DLB presenting with a primary dementia syndrome. Up to a third of DLB cases Reductions in presynaptic cholinergic activities, particu- are additionally misclassified as vascular dementia on the larly in the cerebral neocortex, are more marked in DLB Hachinski ischemic index by virtue of the fluctuating nature than in AD and are similar to those in PD with dementia and course of the illness. As in PD, the cortical cholinergic deficit appears to neurologic signs are usually absent. The development of reflect neuronal loss in the basal nucleus of Meynert (50). NEUROTRANSMITTER ACTIVITIES IN The cortical cholinergic pathology is independent of the DLB, AD, AND PDa extent of Alzheimer pathology, being equally great in DLB cases with and without this type of pathology (51). Cholin- DLB AD PD ergic deficits in DLB extend beyond the cortex to the stria- I. CHOLINERGIC SYSTEM tum and certain nuclei of the thalamus (52). Also, in con- ChAT trast to AD and similar to PD with dementia, DLB is Cerebral cortex ↓↓ ↓ ↓↓b associated with elevation of the muscarinic receptor subtype Hippocampus Striatum M1 (53), a finding that has recently been confirmed by Thalamus / immunoabsorption studies (54). However, muscarinic M1 AChE receptors are not uncoupled to the same extent as in AD Cortex (52; Perry et al. Changes in nicotinic recep- BUChE tors in the cortex include a loss of the high-affinity agonist Cortex ↓ VAChT binding site (likely to reflect the 4 subunit), but no change Cortex b in the subunit or -bungarotoxin binding (54a). In con- 7 Muscarinic receptors trast, little change in nicotine binding occurs in the thala- M1 b mus, but highly significant reductions in -bungarotoxin Cortex Striatum binding are seen in the reticular nucleus (55). Similar nico- M2 tinic receptor abnormalities occur in AD and (as far as has Cortex ↓ been investigated) in PD, although the loss of nicotine bind- Nicotinic receptors ing in the striatum is greater in PD, in keeping with the α7/αBT binding Cortex more extensive reduction in basal ganglia dopaminergic pro- Thalamus jections (56). Although the loss of high-affinity nicotinic α4/high-affinity receptor binding in AD has been related to synapse loss, agonist site measured by synaptophysin levels (57), synaptophysin loss Cortex Striatum / occurs in DLB only when the pathology includes the Alzhei- Thalamus →/ / mer type (58). MONOAMINERGIC SYSTEMS The involvement of the dopaminergic system is the other DOPAMINERGIC consistent neurochemical feature of DLB (Table 91. Earlier reports that dopamine loss Receptors was in some cases severe despite the absence of neurologic D1 receptorc c symptoms (49), a finding that was interpreted to indicate D2 receptor /↓ c compensatory striatal pathology, need to be replicated in D3 receptor →/ SEROTONINERGIC prospectively assessed cases because symptoms may have Presynaptic been overlooked in psychogeriatric clinics; furthermore, Serotonin neuroleptic medication reduces striatal dopamine. Although Striatum in PD striatal dopamine deficits are more marked in caudal Cortex Serotonin transporter regions, particularly putamen, in DLB the loss of dopamine Cortex transporter is similar at different rostral caudal levels (59). Receptors Whereas in PD dopamine D2 receptors are up-regulated, 5-HT2A receptor at least in earlier stages of the disease, receptors are not Cortex →/ NORADRENERGIC increased in DLB and in particular are not up-regulated as a Noradrenaline result of neuroleptic medication (60). In addition to striatal Striatum dopamine deficits, dopamine losses in cortical areas also Cortex ↓ occur (Table 91. MAO-B ↑ The significance of the serotoninergic, noradrenergic, 5-HT, 5-hydroxytryptamine; AChE, acetylcholinesterase; and neuropeptide (e. The clinical significance of some of the cho- aSummary of neurochemical findings, reviewed Perry et al. Chapter 91: Dementia with Lewy Bodies 1307 GENETICS AD at a similar stage of dementia. The polymorphism caus- ing the K allele in the gene for butyrylcholinesterase has Familial cases of DLB have been reported, although the been reported to be associated with AD, although this find- majority of cases appear to be sporadic. Following the dis- ing has not been replicated by others. In DLB, an increased covery of two separate missense mutations in the -sy- number of butyrylcholinesterase K homozygotes have been nuclein gene on chromosome 4 in a small number of fami- found. It has been suggested that this genotype may partly lies with pathologically confirmed early-onset PD, mutation explain the enhanced responsiveness to cholinesterase inhib- screening was undertaken in this gene in both familial and itors in DLB (73). Although abnormalities in butyrylcho- sporadic cases of DLB (61). These studies failed to reveal linesterase are evident in AD, including elevated enzymatic any nucleotide changes within the exons screened. Such an influence may be via so-called susceptibility genes. Be- CLINICAL–PATHOLOGIC RELATIONSHIPS cause DLB shares pathologic overlap with PD and AD, Cognitive and Neuropsychiatric susceptibility genes of interest for both conditions have been considered in candidate gene approaches. For PD and DLB, In DLB, a consistent gradient of LB density has been noted, allelic frequencies of the cytochrome P-450 gene CYP2D6 as follows: substantia nigra entorhinal cortex cingulate (debrisoquine-4-hydroxylase) have been examined. The re- gyrus insula frontal cortex hippocampus occipital sults of these studies have been conflicting. Paralimbic and neocortical LB densities are highly frequency of the CYP2D6*B allele has been reported in correlated with each other but not with nigral pathology, DLB (62), whereas another study found no association (63). One study of pathologic burden allele in AD and DLB despite an increased frequency in versus clinical severity examined correlations between two PD (64). The current balance of evidence suggests that the simple measures of cognitive ability and a range of lesion CYP2D6*B allele is not a major genetic determinant of counts and neurochemical measures in the midfrontal cor- DLB. Severity of dementia was significantly The 4 type of apolipoprotein E is significantly elevated correlated with LB density, plaque density, and severity of in both DLB and AD, with a concomitant reduction in the cholinergic deficit, but not with neurofibrillary tangle den- E 3 type of apolipoprotein. Interestingly, although the 4 sity or synaptophysin levels. In contrast, in AD cases, tangle allele was associated with an increased risk for the develop- density and synaptophysin levels were most highly corre- ment of DLB, it did not appear to affect the burden of lated with clinical severity. This suggests that the dementias pathology, measured by senile plaque and neurofibrillary of DLB and AD may have different pathologic but similar tangle density in the neocortex (65). Other studies have failed to find is associated with neuronal loss in the substantia nigra (66). Most recently, a significant difference has been reported Neurologic for the allelic distribution of a pentanucleotide repeat within the promoter region of the nitric oxide synthase gene Cell loss in the ventrolateral tier of the substantia nigra is (NOS2A) in a comparison of autopsy-proven DLB cases the dominant pathologic correlate for parkinsonism in both with controls (68). This is associated with gliosis and Lewy body brain as a physiologic neuronal mediator, but excessive pro- formation. Dopaminergic neurons in this area of the sub- duction of nitric oxide (e. The net effect of loss of the modu- sonism, it has been shown that inhibitors of nitric oxide lating effects of dopamine within the putamen is increased synthase may provide protective benefit in the treatment of neuronal activity in the globus pallidus (internal segment). Because output from the globus pallidus (internal segment) Associations between polymorphisms within the 2- is inhibitory to the ventrolateral thalamic nucleus, this leads macroglobulin, 1-antichymotrypsin, and presenilin 1 to excessive inhibition of thalamic activity and thus reduced genes and DLB have not been demonstrated (after account- feedback to the motor cortex. The perturbation in this loop, ing for apolipoprotein E 4 allele frequency) (70–72). Because the presynaptic lesion is similar in the two disorders, the answer As with any patient presenting with cognitive impairment, may therefore lie postsynaptically. Evidence to support this obtaining a full history and performing a mental and physi- notion comes from postmortem neurochemical studies cal examination are essential steps toward making a firm comparing dopaminergic activities in DLB with those in clinical diagnosis. As with suspected cases of AD, the level PD and AD (59). In these studies, dopamine D2 receptor and extent of laboratory investigations vary according to binding was reduced in the caudal putamen and was signifi- the clinical picture, associated comorbidity, and physical cantly lower than in PD at all levels. However, because of the particular Although the increased falls reported in DLB may be associations of DLB with fluctuations in attention and cog- multifactorial, it is likely that more widespread involvement nition and visual hallucinations, both very commonly asso- of brainstem nondopaminergic nuclei is a contributing fac- ciated with a variety of other organic disorders, the investi- tor. Degeneration of the predominantly cholinergic pedun- gation of a suspected case of DLB requires a very careful culopontine nucleus is a likely explanation because neuronal laboratory evaluation. This usually includes routine hema- loss in this structure has been associated with postural insta- tology and biochemistry, determinations of erythrocyte bility (78). In addition, degeneration of the pedunculopon- sedimentation rate and creatine phosphate, thyroid function tine nucleus has been implicated as the pathophysiologic tests, measurements of B12 and folate levels, syphilis serol- basis for REM sleep behavioral disorder, which is also re- ogy, and urinalysis. A chest roentgenogram may also be ported in DLB (79). As in the diag- nosis of AD, neuroimaging investigations are often helpful, Neurochemical both in excluding other intracranial disorders (including As yet, only a few clinical–neurochemical relationships have cerebrovascular disease) that may be responsible for the cog- been identified in DLB.