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AD is characterized by multiple deficits including alterations to the cholinergic system (a major target in the neurotransmitter research because it is central to the cognitive changes observed in AD), the noradrenergic system, the serotonergic system and the dopaminergic system. According to the cholinergic hypothesis, the impairment of cognitive function and the behavioral disturbances that affect patients with AD are mainly due to cortical deficiencies in cholinergic neurotransmission. Deficiencies in the cholinergic system may also be involved in the formation of amyloid plaques and NFTs.

Behavioral and psychological symptoms of dementia cause premature institutionalization and significant loss of quality of life for the patient and his/her family and caregivers. An imbalance of different neurotransmitters (ACh, dopamine, noradrenaline, serotonin) has been proposed as the neurochemical correlate of these neuropsychiatric symptoms. The significant decrease in cholinergic activity may result in a relative increase in monoaminergic activities, leading to hypomanic or manic symptoms and behavior including delusions, hallucinations and physical aggression (Folstein, 1997). Conversely, AChE inhibitors have shown to be able to reduce neuropsychiatric severity (see Table 13.1).

AD and other types of dementias are associated with many problematic behaviors. Noncognitive feature is a terminology that draws the distinction between cognitive loss and the heterogeneous group of symptoms that include psychiatric symptoms such as depression, hallucinations, delusions and misidentifications. This term also includes behavioral disturbances such as aggression, agitation, pacing and eating disorders (Burns et al., 1990). An alternative expression is neuropsychiatric features (Cummings et al., 1994). The term “Behavioral and Psychological Symptoms of Dementia” (BPSD) has also been defined as “symptoms of disturbed perception, thought content, mood and behavior that frequently occur in patients with dementia” (Consensus Conference on the Behavioral Disturbances of Dementia, 1996). Noncognitive disorders can cause distress both to patients and carers. Such changes are often a determinant for institutional care. A study reported that psychotic symptoms (e.g., hallucinations and delusions) were present in about 50% of patients with dementia and disruptive behavior (e.g., physical violence, hiding things, wandering, demanding or critical behavior) in up to 70% (Rabins et al., 1982). These include hitting, yelling, grabbing people, wandering, hoarding, and repetitive gestures and questioning (Moak & Fisher, 1990; Reisberg et al., 1987). All of these problematic behaviors are often grouped together as “agitation” or “agitated behavior”.

Because functional impairment is one of the main consequences of the dementing process, patients are no longer able to engage in meaningful activities on their own. Demented patients cannot pursue hobbies because of apraxia; they cannot read because of comprehension difficulties and they cannot engage in social activities because of aphasia. Meaningful activities may improve depression, diminish agitation, apathy, insomnia and repetitive vocalization and should be attempted. Meaningful activities are important at all stages of dementing illnesses. Individuals with advanced dementia need stimulation with appropriate activities because few, if any, patients with AD progress to the persistent vegetative state (Volicer et al., 1997).

Since the ACh deficit associated with AD was recognized in the mid-1970s, there has been a systematic attempt to increase CNS cholinergic activity by pharmacological manipulations. The main classes of drugs tested so far include ACh precursors, releasing agents, cholinesterase inhibitors (CI) and muscarinic agonists. The expectations were that cholinergic enhancement would improve symptoms of AD in a way similar to dopamine enhancement in Parkinson’s disease.

The most important cognitive deficit of AD is the progressive loss of memory that is manifested according to the traditional classification in both STM and LTM tasks (see Tables 8.1, 8.2 and 8.3). The earliest and most prominent symptom in AD is a profound impairment in the ability to acquire and remember new information whether tested by recall or recognition (Grady et al., 1988; Welsh et al., 1991). Many patients have purely episodic memory impairment for a number of years (Perry & Hodges, 2000; Perry et al., 2000). Semantic memory, the database of conceptual knowledge that gives meaning to sensory experience, is eventually affected in AD, but early in the disease patients show mild and variable impairment of semantic memory. Written language deficits are frequently noted and occur at early beginning of the disease (Eustache & Lambert, 1996). They initially take the form of a lexical agraphia: the characteristic symptom is the production of errors so called “de regulation” (of regulation) occurring during the writing of words with irregular orthography (e.g. femme > fame). On the contrary, deficits of phonological type often appear with the progression of the dementia.

In clinical practice, the behavioral disturbances seen in patients with dementia are helpful in determining disease severity and the need for support care. In patients with AD, the early appearance of behavioral symptoms is associated with faster disease progression. The first neuropsychological dysfunction in AD is described as a loss of attention capacity, followed by loss of language and visuospatial function (Grady et al., 1988). Behavioral complications of dementing illness are common, adversely affecting the quality of lives of patients and caregivers. They create stress for caregivers, complicate patient management and often precipitate institutionalization. About 70-90% of patients with dementia exhibit behavioral and psychological symptoms at some time during the course of the disease. There has been growing interest in the detection and quantification of the emotional, behavioral, ideational, perceptual and vegetative symptoms that accompany and complicate the lives of persons with AD and their caregivers. The availability of scales to detect and quantify these aspects of the disease is important to clinical investigators seeking effective means of treating these symptoms. Reliable quantification of behavior is desirable to facilitate documentation of symptoms, provide a tool for follow-up of behavioral changes over time and enable researchers to measure the effects of behavioral and pharmacological intervention.

The hypothesis that a cholinergic deficit might be responsible for memory impairment was based on studies showing learning and memory deficits in animals and humans whose cholinergic system was blocked by atropine or scopolamine (Drachman, 1977). Confirmation was sought by animal investigations in which the forebrain cholinergic nuclei were destroyed, initially by electrolytic lesions, then by excitotoxins and finally by the selective immunotoxins 192 IgG-saporin (Wenk et al., 1994). Intracerebroventricular (i.c.v.) injection of 192 Ig-G-saporin brings about a widespread degeneration of cholinergic neurons including the nucleus basalis of Meynert and the septum (Lin et al., 1999). The reversion of the learning and memory deficits induced by nucleus basalis of Meynert lesions has become a classical preclinical test for the screening of drugs aimed to correct the cholinergic hypo-function in AD (see Pepeu, 2000).

Memory is a theoretical construct that may explain current behavior by reference to events that have happened or will happen in the future. Memory may be conceived as a complex, dynamic, recategorising and interactive process based on actual sensory-motor experiences and manifests itself in the behavior of an organism. Repetition in learning is a prerequisite for the formation of accurate and long-lasting memory. Practice is most effective when widely distributed over time, rather than when closely spaced or massed. But even after efficient learning, most memories dissipate with time unless frequently used (Spear, 1978; Spear & Riccio, 1994). Memory always has a subjective and an objective side. The subjective side is observed by the individual’s history (developmental perspective). The objective side is noted by the neural patterns generated by the sensory-motor interactions with the environment. It has been well established by many memory researchers that memory is not a unitary function. This notion is supported by evidence that different brain lesions in patients produce highly specific changes in some aspects of memory functions while sparing other ones. Research has attempted to delineate patterns of impaired and spared memory functions in order to assess whether there is a particular class of processing system that is not functioning while other systems function normally.

AD is a multifactorial disease implicating interactions between environmental and genetic factors. However, there are various genetic defects that may predispose an individual to AD. AD cases can be divided into familial and sporadic cases as well as early onset (EOAD: 65 years) (see Table 4.1). Familial AD (FAD) cases are rare, comprising only 5-10% of all cases. Mutations in several genes have been described as causes of AD: the PS1 gene in chromosome 14, the PS2 gene in chromosome 1, and the APP in chromosome 21 (Sherrington et al., 1995; Levy-Lahad et al., 1995; Goate et al., 1991). All known mutations that predispose a person to EOAD either increase the overall level of Aβ production or increase the ratio of Aβ42 to Aβ40 (Suzuki et al., 1994; Borchelt et al., 1996).

Aging of the brain is accompanied by multiple changes in morphology and functional variations at the cellular and molecular levels of nerve cells. Neuritic plaques, one of the two diagnostic brain lesions observed in Alzheimer’s original patient, are microscopic foci of extracellular amyloid deposition. They are associated with axonal and dendritic injury, and are generally found in large numbers in the limbic and association cortices (Dickson, 1997).

GAD is defined as anxiety, tension or worry associated with a considerable number of patients displaying a mix of somatic and psychological symptoms. The diagnostic definitions of GAD in various manuals, including ICD-10 and DSM-III/IV, differ in quality, number of symptoms, time frames and exclusion criteria. Consequently, lifetime prevalence rates vary between 1.2 and 6.4% in epidemiological surveys (Wittchen et al., 1994). Although the diagnostic reliability of GAD is comparatively low, the features constituting the diagnostic criteria have been noted to be reliable (Di Nardo et al., 1993). A study that compared the distribution of somatic symptoms associated with GAD in patients with “pure” GAD and patients with GAD plus comorbid current or lifetime psychiatric diagnoses showed that GAD is a distinct disorder that is relatively consistent in presentation in patients with or without other psychiatric disorders (Brawman-Mintzer et al., 1994). The hypothesis of the existence of distinct subtypes of GAD, i.e. a “pure” GAD and a “secondary” type with comorbid disorder, representing possibly a prodromal/residual state or an epiphenomenon associated with another disorder, was therefore not confirmed.

OCD is characterised by recurrent, unpleasant thoughts which enter consciousness against the will of the individual, termed obsessions, and repetitive, unwanted behaviours, which may be ritualistic, termed compulsions, that lead to severe impairment in daily functioning. One of the most common compulsions is cleaning. Some individuals concerned about contamination will spend hours showering or bathing, others will wash their hands almost constantly, and some will spend hours and hours of each day cleaning their home. In addition to cleaning there are a number of other compulsions including checking (e.g., individuals may check hundreds of times if all doors at home are locked), repeating (e.g., some people may wish to ease anxiety by repeating a name or phrase over and over), slowness (being overly meticulous and tidy and spending hours organising and arranging objects and possessions) and fear of contamination (e.g., a person may devote hours of the day to washing their hands and avoids any social contact with others due to the fear of contamination).

The symptoms of “anxiety” are listed under two headings. Subjective ones (i.e. those felt as “psychological” experiences) include fear, emotional worries, feelings of terror, depersonalisation etc., and occasionally mental acts such as obsession-like thoughts concerning the safety of others, fear of dying etc. On the other hand, the “objective” symptoms of anxiety (also called “somatic” and later on “anxiety-equivalents”) include abdominal pain, nausea, vertigo, dizziness, palpitations, dry mouth, hot flushes, hyperventilation, breathlessness, headache, restless legs, and other bodily experiences sometimes indistinguishable from complaints caused by physical disease. At the beginning of the 19th century, Landre-Beauvais (1813) defined “anxiete” as “a certain malaise, restlessness, excessive agitation” suggesting that these states may accompany “acute” and “chronic” diseases. With this approach, anxiety becomes a syndrome with both subjective and somatic components, and which can accompany diverse diseases.

Very little is known about the biological basis of anxiety disorder. Variance in personality traits, including those related to anxiety, is thought to be generated by a complex interaction of environmental and experiential factors with a number of gene products involving distinct brain systems such as the midbrain raphe serotonin (5-hydroxytryptamine, 5-HT) system (Loehlin, 1989; Plomin et al., 1994). Although twin studies have indicated that individual variation in measures of anxiety-related personality traits is 40-60% heritable, none of the relevant genes has yet been identified (Loehlin, 1989).

Because anxiety is a concept that describes a human subjective state, its absolute reproduction in animals is an impossible target. Since animals cannot tell us about the experience of anxiety and fear, a rich source of information that is readily obtained from humans with anxiety disorders may be missed. Therefore, it can only be modelled in animals. A model is an artificial representation of a disease or some aspects of it. Models are often evaluated on a continuum of similarity to the disease (Howard et al., 1989). In theory, the ideal model may reproduce all the features of the phenomenon under investigation and as such would be an exact reproduction rather than a model. In many instances in psychopharmacological research, a model is understood to be a screening method, validated at the standard drug correlational level. Therefore, an animal model of anxiety may be considered as an approach that registers positive for clinically proven anxiolytics and negative for drugs that are thought to be nonanxiolytic in that they usually do not relieve the symptoms of anxiety.

Anxiety disorders tend to be chronic conditions. Women are more prone than men to essentially all anxiety disorders (Bland et al., 1988; Kessler et al., 1994; Offord et al., 1996; Robins & Regier, 1991). Epidemiological studies suggest that women have a 2-to 3-fold increase in the occurrence of PD, PTSD and GAD. Fluctuations in oestrogen and progesterone levels can substantially influence the severity and course of anxiety disorders. Future investigations that focus on gender differences may provide valuable information for effective treatment strategies for women with anxiety disorders.