14 Book of modern neuroanatomy and capturing a glimpse of the complex eloquent man who carried the banner for neuroanatomical investigation in our times. P.S. Goldman-Rakic Section Neurobiology Yale University School of Medicine 333 Cedar Street, Room C-303 New Haven, CT 06520-8001, USA . Alzkmer Disense: Therapeutic Strategies Ezio Giacobini and Robert Becker (Editors). Birkh&ser, Boston, 1994, ISBN O-8176-3757-5 or 3-7643-3757-5 This book is the latest of three in a series entitled ‘Advances in Alzheimer Disease Therapy’. It is based on presentations given at the ‘International Springfield Symposium on Advances in Alzheimer Therapy.’ The volume comprises of seventeen parts each containing between two to thirteen chapters. Moreover, the introduction contains two chapters, the first of which (by Giacobini) is an overview of the compounds that are discussed in the three volumes. Although I share the optimism of Dr. Giacobini that significant improvement will be made in the cholinomimetic therapy, I doubt that these improvements will come within two to three years. In the second chapter, Amaducci and Fratiglioni deal with the epidemiology of Alxheimers Disease (AD) and its impact on the treatment. The following XVII parts consist of single or multiauthored chapters. The first part is devoted to the neuropathologic and genetic basis of AD treatment. The amyloid cascade hypothesis implies that deposition of the amyloid B-protein is the causative agent of AD pathology and that neurofibrillary pathology, cell loss and dementia follow. Wisniewski and Wegiel indicate that study of the cells that are engaged in amyloid fibril formation (microglia, perivascular cells and myocytes) should be of highest priority in the development of therapeutic strategies to prevent and treat AD. In this respect, they emphasize that drugs affecting &protein amyloidogenesis and b-protein Iibrillogenesis are two areas that should be of high priority in research and development of treatment of AD. Hardy and Duff review the recent advances in understanding the disease and point out some of the problems and deficiences with the cascade hypothesis. The mechanism of Alzheimer neurofibrillary degeneration and a strategy to inhibit this type of degeneration is described by Iqbal and Grundke Iqbal. Olfactory function is severely compromised in the early stages of Alzheimers disease. Struble et al. suggest that using olfactory testing for diagnostic aid in AD may identify early changes. Miklossy describe the presence of spirochetes in the reviews blood, cerebrospinal fluid and brain of 14 AD cases. The characterization of spirochetes found in AD is important since it would enable one to develop serological tests for early detection of the infection. An implication of the observation of Miklossy would be that an appropriate antibiotic treatment could stop the progress of dementia or prevent it. Therapeutic strategies to arrest production and processing of amyloid are discussed in part II. Although no drugs are presented that arrest production and processing of amyloid, several suggestions to study amyloid precursor protein (APP) biogenesis and turnover as well as &A4 production and aggregation in cell free systems and cell culture models are presented. In part III, the choline&z system of human brain is discussed. Mesulam describes the localization as well as the source of butyryl cholinesterase (BChE) in human brain. He suggests that the high density of BChE positive glia in AD brains may play a permissive or causative role in the neuropathology of AD. Soreq et al. establish transgenic models for overexpressing human cholinesterases in cholinergic synapses of Xenopus laevis tadpoles and mice in order to study the role of choline@ neurotransmission in regulating synaptic structure and function. Sihnan et al. describe elegantly the structurefunction relationships in the binding of reversible inhibitors in the active-site gorge of acetylcholinesterase. Taken together, these studies indicate that acetycholinesterase inhibition by eptastigmine is associated with cognitive and clinical improvement. Hupenine-A, a novel anticholinesterase inhibitor, is suggested as a promising candidate for clinical development as a second generation of anticholinesterase in the treatment of AD by Tang et al. From in vitro and in vivo studies in animals, Emmerling et al. predict that CI-1002, a novel inhibitor of acetyl cholinesterase and muscarinic receptors will produce fewer peripheral side effects than other anticholinesterases and should improve patient compliance with treatment. In the next six chapters, the preclinical and/or clinical effects of several anticholinesterases including SDZ ENA 713, MDL 713, 745, galanthamine, velnacrine and tacrine are discussed by several authors. Part IV concludes with two chapters on the preclinical and clinical aspects of second and third generation cholinesterase inhibitors by Giacobini and Caudra, and Becker et al. The first authors have confirmed that central AChE inhibition and ACh levels are not necessarily correlated and report that individual inhibitors affect aminergic systems in different ways. The last authors describe the pharmacology and clinical efficacy of metrifonate. They emphasize the importance of monitoring patients for side effects which might be apparent after months of treatment during long clinical trials. Moreover, they plead to all who are investigating these drugs to undertake a thorough characterization of any patient who shows idiosyncratic responses to these drugs. Book In part V, the role of nicotinic systemin the cognitive disorderof Alzheimerdiseaseis presented.Moreover, nicotinic agonists are proposed as drugs for AD treatment. Muscarmicagonistsare suggestedin part VI, from preclinicaland clinical studies,to havetherapeuticpotentialin AD. Preclinicalstudieswith AF 102B (Fisher et al.), PD 142505(Schwarxet al.), and xanomeline (Shannonet al.) showthat thesemuscarinicagonistsare Ml selective.Clinical trials with AF 102 B show favorableresultsin AD patients.Xanomeline shows favorabletolerability profdein clinical trials. Theseresultsencouragefurther clinical trials to evahtateif Ml agonistsmay be useful in a choline@ replacement treatmentand also in delayingthe progressionof AD. Farber et al. discusscholine metabolismand membranephospholipidin relation to AD, whereasZacxek et al. suggestthepossibilityof a multiple neurotransmitter releaseby linopirdine@UP 996)as an AD therapy in part VII. The threechaptersin part VIII deal with preclinical and clinical aspectsof nootropicdrugs.It is suggested that thesedrugsmight havetherapeuticvalue in AD. However,in my opinion severalprechnical studies shouldbe doneto understandthe mechanismof action of nootropics.Multicenter clinical studiesindicatinga largh populationof patientsare also requiredto confirm i&e preliminarydata. In the fast of the two chaptersof part IX, Cue110 reviewsthe experimental,clinical and histologicaldata of loss of synapsesin AD and proposestrophic factor inducedsynaptogensis in AD. In the secondchapter, Svennerhohnand Toffano describeexperimentaland clinical data of gangliosidesin AD. In part X, the first chapterby OlneyandFarberdeals with excitatorytransmitterneurotoxicityand AD. The secondchapter,by Miller et al., dealswith freeintracellular calciumin agingand AD. The last chapterin this part by Sugayaand MC Kinney dealswith nitric oxide synthase(NOS) in a lesion model of AD. They hypothesizethat certainNOS negativecholine@ neurons may be vulnerablein AD and that part of the neurodegeneration may be causedby induction of cytokineinduciblein the activatedmicroglia in AD. In part XI, two chapters,one by Burlakovaand the otherby Richardsonet al., dealwith antioxidantdrugs. Theseauthorspresentin vitro evidencefor the useof antioxidantsin AD. Burlakovapresentsdata on a hybrid moleculewhich has both anticholinesterase and antioxidantactivity andsuggests that successful application of antioxidantsasneuroprotectors will be achieved by creatinghybrid moleculesand studyingantioxidant action at ultra low doses.Another two chaptersdeal with the immunemechanismin senileplaqueformation (McGeer et al.) and inflammatory pathology in AD (Websterand Rogers).Both chapterssuggestinterven- reviews 75 tion with anti-inflammatoryagents.In a chapterby McLachlanet al., theuseof aluminumchelatorssuchas desferrioxamineto lower brain aluminum concentrations is suggested as therapeutictools in AD. The first two chaptersin part XII deal with behavioural disturbances.In the first, Schneiderreviewsthe managementof agitationand depressionin dementia. Treatmentwith serotonergicdrugsof emotionaldisturbancesin patientswith dementiadisordersis discussed in the secondchapterby Gottfries.The third chapterin this part by Francis et al, deals with glutamate& hypoactivityin AD. Disturbancesof gait in patients with dementiais reviewedby Elble. In part XIII, the first chapterby Hanin reviewsthe centrallycholinodeftcientanimalas a modelof AD. He emphasizes that the advantagesof the availability of a centrallycholinodeficientanimalmodelareseveralfold. In the secondchapter, Neve and Koxlowski show elegantlythe role of the carboxyterminus@APP-ClOO) of the Alxheimer amyloid protein precursorin AD neurodegeneration. They suggestthat the degeneration of the neuronscomesabout by the binding of &APPCl00 to a newlyidentifiedmoleculelocatedon the surfaceof nervecells.However,morework remainsto be doneto characterixethe detailedmechanismby which flAPP-ClOOkills neuronsin or&r to developa potential therapyfor AD. Anothertransgenicmice model,transgeniefor the human 751amino acid form of the /3amyloidprecursor protein,is discussedby Higginsand Cordell. The histological featuresof the @APP751 transgenicmousebrain most closelyresemblesthoseof early AD. Taken together,the studies of Neve and Koxolwski,andHigginsand Cordellshouldprovideincreasedconfidencein transgenesis asa meansto testadditional geneticand environmentalfactorswhich may play a role in thedevelopmentof AD. Takedaet al., in the third chapter,review neurofilamentpathology in animalmodelsfor AD. Usingdifferentkinds of animal models(fluid percussionrat model, cyclosporinA administeredrat model,Alxheimerbt@ coat inoculation model)which weredesignedto representeachspecific aspectof pathogenicprocessof AD, they discussthe aberrationof cytoskeletalproteinsin thesemodels.They speculatethat phosphorylationof neurofdamentprotein inhibits axonal transport and eventuallyleadsto the cytoskeletalpathologyof AD. In anothermodel,Oron et al. studythe role of antineurofdamentantibodiesin neurodegeneration in AD. Their animalmodel (experimental autoimmunedementia)studiesshow that anti NF-H IgG similar to thoseof AD patientsinducespecific neuronalandbehaviouralderangements. In the only chapterdealingwith primatemodels,Walker describes the useof agednon-humanprimatesas modelsof /3amyloidoses. Their studyindicatesthat non-humanprimatesareadvantageous modelsfor studyingthe pathogenesisof senileplaquesand cerebrovascular amyloid 16 Book and for testing strategies for the diagnosis and treatment of 8-amyloidoses. The ditTerent animal models described in this part (XIII) will be valuable in determining disease mechanisms and in assessing potential therapeutics. Part XIV deals with the use of imaging techniques to monitor the effect of drugs in AD treatment. The first two chapters by Nordberg and Tavitian et al. deal with positron emission tomography (PET). The studies by Nordberg indicate that functional changes can be traced in brain after months of tacrine treatment in AD patients with mild dementia. Moreover, patients receiving intraventricular infusion of NGF for three months have consistently shown improvements of [ “C]-nicotine binding in cortical brain regions as well as changes in CBF and glucose metabolism. The studies by Tavitian et al. describe the synthesis and application of two new PET ligands to non-human primates’ brain imaging and suggmt that [ “Cl-methyltacrine appear to bind to the same cerebral sites as tacrine and [“C]-physostigmine shows a distribution highly compatible with that of acetykholinesterase. Taken together, the studies of Nordberg and Tavitian et al. indicate that PET will be important for examining a site of mechanism of action of a certain drug as well as for evaluation of long-term treatments in AD and to select responders to a certain therapy. In a subsequent chapter, Robert et al. discuss the use of single photon emission tomography (SPECT) in early diagnosis and to monitor the effect of drugs in AD. Part XV deals with the clinical testing of efficacy of new drugs in AD. The chapters deal with minimal efficacy criteria, instruments for measuring the efficacy of treatments, psychometric strengths and weaknesses of the AD assessment scale in clinical testing, and validation of informant based cognitive assessment for use in autopsy. In part XVI, the socioeconomic aspects in the treatment of AD is discussed. The costs of treatment and care in general of AD patients is evaluated. Part XVII deals with the future of Alxheimer treat- reviews ment. The first chapter by Whitehouse deals with the biological approaches, international harmonization and ethical issues. Whahmd et al. discuss the use of trophic factors and reducing &amyloid deposition in the second chapter. In the final chapter, Cacabelos discusses new strategies for AD treatment and suggests multifactorial strategies and compounds with pleiotropic activity. Although there has been disappointment with the cholinergic approaches, the fact that the only approved treatment for AD is a cholinesterase inhibitor, and the development of second and third generation choline&erase inhibitors, new selective muscat-ink and nicotinic compounds which are being tested in the clinic indicates that in the last decade tremendous progress has been made in the field of cholinergic therapy. Tharapies to slow the progression of the disease by preventing cell death are now in the early stages of clinical trial, including drugs that act on mitochondrial metabolism, calcium metabolism, free radicals, and neuronal viability. Considerable optimism has been placed on slowing the progression of AD using approaches directed towards the amyloid cascade. However, development of more effective treatments to cure or even prevent the disease depends on an understanding of AD pathogenesis. To summa&e, several chapters include well illustrated and well presented original material, together with excellent summaries of previous work, others only review old work; and, finally, some chapters fall defiitely outside the main objective. However, on balance, the editors of this book have been quite successful. It is certainly a volume that should be accessible to all preclinical and clinical researchers interested in therapeutic strategies of AD. A. A&m Department of Geriatric Medicine Karolinska Institutet Huddinge University Hospital S-141 86 Huddinge Sweden