Alzheimer’s
disease is associated with the presence of extracellular ß-amyloid
plaques and intracellular neurofibrillary tangles in the cerebral
cortex and in the subcortical grey matter. These plaques and tangles
cause brain damage and alter cognitive functions in about 16%
of individuals aged over 85 (DeKosky et al., 2001; Evans et al.,
1989; Hendrie et al, 2001; Sloane et al., 2002). One elderly person
on ten presents mild signs of cognitive impairment and is at risk
of Alzheimer’s disease (Unverzagt et al., 2001). Today the
use of acetylcholinesterase inhibitors temporarily delays the
disease’s progress, but an effective interruption of the
pathogenic process, which leads to the expression of symptoms,
is a goal that has still to be achieved. Current studies focus
on biomolecular mechanisms, which lead to the formation of plaques
and tangles; besides 
understanding
such mechanisms opens the way to potential interventions. The
future of pharmacological interventions seems to depend on detailed
knowledge of the pathogenic and molecular cascade, which leads
to Alzheimer’s disease.
This paper will provide some updates on topics related to the
disease’s pathogenic and therapeutic aspects. It will also
study in detail diagnostic evaluations and therapeutic responses
to psychic and behavioural disorders, which are often associated
with Alzheimer’s disease, even at an early stage. The main
goal is to provide a useful easy to grasp update on a topic that
is constantly developing in terms of knowledge and impact on the
National Health Service.
Damaging Processes
Four processes contribute towards the formation of lesions present
in the brain of people suffering from Alzheimer’s disease:
amyloid production, formation of neurofibrillary tangles, inflammation
and neurodegeneration or cell death (Scorer 2001). Each process
contributes both alone and with others towards brain damage.
Amyloid
The effects of the formation of ß-amyloid
plaques in extracellular spaces have been defined after two decades
of research. The presence of ß-amyloid, inflamed cells and
free radicals creates a microenvironment, which leads to the death
of neurones (Olson et al., 2001).
Amyloid and ß-amyloid are the products of the same molecule’s
two catabolic processes but, while the first, present in healthy
people, is soluble and can hence be removed, the second, typical
of Alzheimer’s disease, is insoluble and settles in plaques.
Brains of cognitively unimpaired elderly people often contain
widespread deposits of an amyloid substance but few plaques. In
Alzheimer’s disease plaques form in the temporal and parietal
cortex and in the hippocampus - areas that are associated with
memory and learning functions.
ß-amyloid is formed from a molecule, the Amyloid Precursor
Protein (APP), which is a transmembranous glycoprotein that adheres
to the membrane and keeps it intact. Enzymes present on the membrane
surface cut the APP forming amyloid and other fragments. This
process occurs in all individuals. Amyloid is present in healthy
individuals’ cerebrospinal fluid. The levels of this substance
are considerably higher in people with Alzheimer’s disease.
While y-secretase produces amyloid, the action of y- and y-secretases
produces, starting from APP, the insoluble form (ß-amyloid),
which deposits forming plaque-like aggregates (Selkoe, 2000).
Plaques thus formed activate astrocytes and glial cells to release
cytokines and other acute phase proteins, which trigger the inflammation
cascade with protein hyperphosphorylation, neuronal dysfunction,
loss of synapses and reduced release of neurotransmitters (especially
acetylcholine) and lastly the death of neurones.
Neurofibrillary Tangles
Pathognomonic signs of Alzheimer’s disease are frequent
in the cytoplasm of neurones in the frontal, temporal and parietal
cortex, the hippocampus and the amygdala (Selkoe, 2000). These
tangles are helicoidal filaments formed by intracellular microtubules
and hyperphosphorylated protein . The two kinases (Cdk5 and Csk-3ß),
which cause protein ’s hyperphosphorylation are activated
by ß-amyloid (Maccioni et al., 2001) figures
1 and 2.
 |
Fig.1
Formation of neurofibrillary tangles |
 |
Fig.2
Neurone modifications following neurofibrillary degeneration |
Inflammation
All physiopathological studies confirm the build-up of microglia
around ßamyloid plaques (In t’ Veld et al., 2001).
These cells release cell degradation fibre and products in the
brain, but during this process they also release free radicals
and cytokines, which activate the astrocytes. The latter, the
Central Nervous System’s largest cell population, metabolically
support neurones but they lead to an oxidative reaction, thus
starting the inflammatory cascade (Maccioni 2001).
Many anti-inflammatory approaches have been studied to treat Alzheimer’s
disease. Cortisone-based drugs have not proved effective; Celecoxib,
a selective oxygenase cycle inhibitor, has not been associated
with interruptions in the disease’s progress, but as other
nonsteroidal anti-inflammatory drugs (NSAIDS) it has been associated
with a protective effect on the disease’s progress (Scorer
2001).
Current Drug Trends
Neurodegeneration and the loss of dendrites caused by the presence
of ß-amyloid plaques reduce the production of acetylcholine.
A 60-90% loss in cholinergic activity causes cognitive deficit
and memory loss. In Alzheimer’s disease we also notice a
50-70% reduction in serotonin activity, 40-60% reduction in somatostatin
activity and 30-70% reduction in norepinephrine (Cummings et al.,
2001). Symptomatic treatment of Alzheimer’s disease focuses
on enhancing neurotransmission by increasing cholinergic reserves.
Blocking acetylcholinesterase, the enzyme, which removes acetylcholine
from synapses, has proved to be the most successful intervention.
Tacrin, Donepezil, Rivastigmine and Galanthamine, all acetylcholinesterase
inhibitors, have proved effective in delaying the disease’s
progress.
Drug Research
Many research trends are experimenting with substances, which
can block y-amyloid producing y and y secretases or substances
that can activate y secretase, which produces the soluble amyloid
and hence is not implied in pathological processes (Jhee et al.,
2001).
The intervention’s other possible target is the inhibition
of protein y phosphorylation, which forms microtubular tangles,
but kinase Cdk5 plays an essential role in neurone development,
in synaptic release and in the dopamine metabolism.
This enzyme’s selective inhibition with Lithium did not
lead - in cell culture - to the results sought. Besides recent
studies have strengthened the role of ß-amyloid in the formation
of microfibrillary tangles (Scorer, 2001), marking out its formation
as the decisive pathogenic moment for interventions to alter the
disease’s progress.
Genetics and Screening Tests
Much research in recent years has focused on understanding genetic
processes that develop Alzheimer’s disease. Schematically
listed below are some of the most significant results. Only 10-20%
of cases of Alzheimer’s disease can be traced back to the
disease’s hereditary nature, but the study of phenotypes
produced by various mutations has improve understanding of the
disorder’s physiopathological processes.
Mutations in four genes have been studied concerning this disorder’s
expression (Retz et al. 2001): The APP gene (the precursor of
amyloid) is present on chromosome 21, whose mutation increases
this protein’s production. This data justifies the extremely
high prevalence of Alzheimer’s disease in Down’s Syndrome
(trisomy 21 syndrome) (Esler et al., 2001).
The Presenilin 1 gene is located on chromosome 14, whose mutation
increases y and y secretase activity causing 4% of early cases
of the disease (with an onset age between 28 and 50 years).
The Presenilin 2 gene, present on chromosome 1, causes 1% of cases
with an onset age between 40 and 50 years (Athan et al., 2001).
Presenilin mutations increase y secretase levels and are associated
with an aggressive hereditary form of Alzheimer’s disease.
The fourth and most common hereditary form is associated with
one of the many mutations of apolipoprotein allels located on
chromosome 19. Such mutations can increase amyloid aggregation,
thus decreasing the elimination process of the same. Its degree
of expression can vary, but these changes should cause about 50%
of cases with an early onset and 20% with a late onset.
To close this section we deem it useful to enlarge on the topic
of genetic tests and especially to highlight their usefulness
in clinical practice. Genetic tests can be conducted in 70% of
families with an autosomic dominant pattern of Alzheimer’s
disease. In first degree relations the lifetime risk (onset before
90 years) is 3-4 times higher than in control individuals (Liddel
et al., 2001).
Individuals’ response to the test has not been studied in
detail - the test envisages costs, limited information on the
risk of developing the disease and emotional impact on individuals
leading in some cases to neglect of personal health and in some
countries to the risk of problems in maintaining a health insurance.
There is little clinical evidence to support the use of the test
to explain the disease’s clinical onset and no evidence,
at the current stage of research, for its use as a screening tool
on extensive populations. Such considerations should guide clinical
practice on a topic which every physician will be increasingly
called to face.
Early Diagnosis
A frequently heard request in current clinical practice is to
mark out individuals who present the risk of developing the disease
and to develop strategies, which can alter the progressive expression
of symptoms.
Known risk factors for the disease’s development comprise
advanced age, conditions of malnutrition, reduced dimensions of
the brain, past brain traumas and female sex. The reduction in
sensory alertness with special focus on sight and hearing can
lead individuals to lose relational skills and to depression with
an increased risk of dementia. Reports on unsatisfactory general
health conditions are associated with a 5 times larger risk of
developing Alzheimer’s disease (Weisen et al., 1999). Many
individuals present mild signs of cognitive impairment but they
use compensative strategies in daily activities. Only 20% of these
individuals will develop dementia (Wolf et al., 1998). A standardised
assessment, which can provide special specifications on the development
of Alzheimer’s disease, has yet to be found.
Cognitive tests proposed on a nonselected elderly population produce
many false positive results due to cultural differences, education
and the individual’s mood (O’Connor et al., 1990).
It is currently believed that individuals who present the risk
of developing the disease should undergo cognitive assessments
such as the Mini-Mental Status Examination or the Clock Drawing
Test every 6-12 months (Suderland et al., 1989) figure
3. If one notices a 3- point decline between one
assessment and another, the person must be considered at risk
of the disease’s onset and must hence be assessed for treatment
(Petersen et al., 2001).
 |
Fig.3
Clock drawing test The patient is requested to draw a clock
that points at 2:45. This simple test has proved sensitive
and specific for an early diagnosis of Alzheimer's disease. |
Investigational Diagnostics
Correct laboratory evaluation goals consist in performing an accurate
diagnosis and in discovering and correcting any other causes of
the dementia picture. Two research studies on the topic observed
that precise and complete laboratory evaluation led to a change
in the treatment plan in 13% of cases (Chui & Zhang, 1997).
The evaluation must comprise complete haemochrome and electrolytes
tests, a complete metabolic picture, thyroid function, serology
for syphilis, beside B12 and folic acid levels.
HIV tests, drug screening and chest Xrays are recommended depending
on the case history or on the physical examination. Many studies
are investigating the possibility of highlighting special diagnostic
markers for Alzheimer’s disease: ß-amyloid specific
antibodies, melanotransferrin produced by microglia activated
by ß-amyloid plaques, high levels of ß-amyloid and
protein y in the cerebrospinal fluid. None of these markers can
be applied in clinical practice to date.
Concerning image diagnostics, readers must be informed that a
reduction in the volume of the hippocampus is reported in 50-70%
of individuals who will later develop Alzheimer’s disease
(Dickerson et al., 2001). PET provides useful information on ß-amyloid
deposits in cerebral regions with memory functions.
To conclude clinical suspicion and longterm patient monitoring,
confirmed by targeted clinical and laboratory evaluation, are
the best course for early recognition of Alzheimer’s disease
and to formulate accurate differential diagnoses figure
4. Intervention Strategies figure 5
General Conditions of Health and Lifestyle. The most effective
method to reduce the impact of Alzheimer’s disease on the
population is to maintain good general health conditions in the
elderly.
An adequate diet and physical exercise compatible with the individual’s
age and physical conditions are goals to be achieved to influence
the disease’s progress.
Later interventions will hence first focus on attenuating risk
factors: intervening on hypertension or cholesterol produces a
dual series of results, both on the cardiovascular system and
on the Central Nervous System’s symptoms (Peters, 2001).
Stimulation of intellectual activity is a relevant factor in improving
brain function and in slowing down the progress of clinical symptoms
(Stern et al., 2000). Medication Cholinesterase inhibitors induce
a mild improvement in cognitive functions for a limited time.
Recommended in the disease’s mild and moderate conditions,
they have no neuroprotective functions and offer few clinical
improvements when the Mini-Mental Status Examination drops below
12 points (O’Brian, 2001).
Targeted treatment focused on reducing ß-amyloid production
by inhibiting certain secretases is still at a trial stage. Immunotherapy
studies focused on creating antibodies against ß-amyloid,
which can increase cerebral clearance, are at an experimental
stage too.
Intervening on Inflammatory Events Vitamin E - a liposoluble antioxidant
vitamin - removes free radicals present in ß-amyloid plaques.
In studies on animals it reduces neurone degeneration in the hippocampus.
In studies on humans it has proved to slow down the progress of
Alzheimer’s disease. The dosage proposed in such studies
ranges from 400 to 1000 IU twice a day (Sano et al., 1997). Other
antioxidants such as ginko biloba, vitamin C, selegiline (a monoaminoxidase
inhibitor with antioxidant effects) have produced inconsistent
results, which vary from no effect at all to minimum effects on
the disease’s progress.
Oestrogens present a mild antioxidant effect. Men transform testosterone
into oestrogens in the brain and a deficiency of this hormone
is not frequent at a late age. Results concerning the administration
of oestrogens were not decisive. A recent meta-analysis suggests
possible cognitive advantages in the use of oestrogens in women
with Alzheimer’s disease but its use is only recommended
in women undergoing other hormone replacement treatment (LeBlanc
et al., 2001). A recent longitudinal study stressed that hormone
replacement therapy can be useful only if it is protracted for
a long period prior to the onset of the disease (Zandi et al.,
2002). The use of non-steroidal anti-inflammatory drugs is associated
with a slower progress of the disease only if the treatment is
begun at a preclinical stage and protracted for at least 2 years.
The variable dosage used in studies makes it difficult to define
a minimum effective dosage. A lower dose than the antiinflammatory
dosage seems effective due to its protective effect (Zandi et
al., 2002; Stewart et al., 1997).
 |
Fig.4
Diagnostic specifications provided by neuroimaging techniques |
 |
Fig.5
Intervention strategies to slow down the progress of Alzheimer’s
disease |
Behavioural and Psychological Symptoms
in Dementia: Diagnosis and Treatment
Individuals suffering from Alzheimer’s disease, besides
impairment of cognitive and functional skills, often present non
cognitive symptoms. During the disorder’s progress about
90% of individuals show behavioural and psychological symptoms
(ranging from depression to psychosis) (Grossberg & Desai
AK, 2003), currently designated with theacronym BPSD (Behavioural
and Psychological Symptoms of Dementia). This scene can be traced
back to widespread damage of the entire cortex though it presents
diversified degrees of severity in each area figure
6.
 |
Fig.5
Cerebral Regions |
Depression
Depressive symptoms during Alzheimer’s disease are associated
with excessive disablement, increased irritability and physical
aggressiveness, besides deterioration in the quality of life and
aggravated cognitive symptoms (Geerlings et al., 2000).
Epidemiological study data provide highly variable results with
a prevalence of depression in individuals with Alzheimer’s
disease ranging from 0 to 97%. Such discordant data seem to result
from different methodological approaches (i.e. the assessment
of a higher or lower degree of depression). In the Chache County
Study 90% of the elderly population in an American State was surveyed
for clinical characteristics. 20% of individuals with Alzheimer’s
disease reported recent dysphoria, 20% reported irritability and
18% reported depressive symptoms (Lyketsos et al., 2000). A clinical
study of individuals with Alzheimer’s disease resident in
homes for the elderly noticed that 20% presented Major Depressive
Disorder and the incidence of depressive symptoms in patients
admitted to homes for the elderly was 17% a year (Payne et al.,
2002).
Dementia and Major Depressive Disorder (MDD) symptoms can be superimposed
especially concerning symptoms that are not directly related to
the mood, such as listlessness, reduced social interest and reduced
psychomotor activity.
An accurate differential diagnosis must keep in mind that mood
symptoms in uncomplicated dementia are generally transitory with
affective lability, which is easily distinguished from the persistent
depression typical of MDD. The differential diagnosis is more
complicated when the mood disorder presents cognitive symptoms,
which are similar to the early forms of dementia. In such cases
we recommend contacting a specialist. A heterogeneous series of
clinical trials supports the theory that depression in individuals
with Alzheimer’s disease can be treated:
In a placebo controlled trial Citalopram (SSRI) proved superior
to the placebo (Nyth et al., 1992).
Sertraline (SSRI) proved superior to the placebo in 12 weeks (Lyketsos
et al., 2003). The partial response was considerably higher, marking
a significant trend towards complete clinical remission.
Other studies performed with Fluoxetine or Sertraline in individuals
with serious forms of Alzheimer’s disease have given a better
response, compared to the placebo even without adding statistical
significance.
In two comparative trials, which compared Paroxetine and Fluoxetine
to tricyclic antidepressants (TCA), SSRI and TCA’s efficacy
was superimposable, while tolerance towards the latter was significantly
lower (Katona et al., 1998; Taragano et al., 1997). To conclude,
data published in specialist literature highlights that the first
choice treatment for depression in individuals with Alzheimer’s
disease is an SRI class antidepressant.
Psychosis and Excitement
The most frequent psychotic symptoms present in Alzheimer’s
disease are delusion and hallucinations, while excitement symptoms
include the inability to sit still, oral or physical aggressiveness,
irritability and failure to closely follow treatment. Such symptoms
appear in more than 50% of individuals. They can interfere with
the treatment and cause fear or tension in caregivers, thus leading
to the person’s admission to an institution. The failure
to closely follow treatment can aggravate the progress of dementia
(Jeste & Finkel, 2000).
Psychiatric evaluation must be conducted together with the evaluation
of general medical conditions and environmental factors in order
to make a correct diagnosis. Pain can for example cause episodes
of excitement, often due to the poor ability of individual’s
suffering from dementia to effectively communicate their health
conditions. Other conditions of disease or drug treatment underway
can lead to the expression of depressive scenes, agitation or
psychosis. An accurate organic and environmental assessment is
hence essential in these patients.
Treatment Clinical Intervention
Clinical intervention in the management of individuals with Alzheimer’s
disease and psychotic symptoms envisages the need to provide emotional
support to the patient and his/her relations, who often fear the
symptoms. Specifying precise symptoms on such disorders helps
people who live with the patient to avoid expulsion attitudes
that often lead to institutionalization.
A relevant point in these individuals’ treatment consists
in stressing how any change in habit can be poorly tolerated due
to the memory problem and cognitive deficit and how such changes
can aggravate mental confusion, disorientation and psychotic symptoms.
Medication
The basic assumption in treatment strategies for disorders setting
in at a geriatric age is “start low and go slow”.
This approach is also useful when treating psychoses or agitation
in patients suffering from Alzheimer’s disease. It is however
equally important to avoid low dosages. The first consideration
to be made concerns the choice of the most appropriate class of
drugs for the patient’s symptoms, trying to avoid undesired
effects. Treatment must be started with low dosages and increased
gradually till the symptom/s is/are solved or till undesired effects
appear.
Many drugs or substances can aggravate mental agitation and confusion
in people suffering from dementia: anticholinergic, digoxin, theophylline
and caffeine. Benzodiazepines, even with a short half life, should
be avoided in these individuals due both to the risk of increasing
mental confusion and to the risk of falls.
The ideal strategy for effective safe treatment is to change one
drug at a time to better identify benefits and undesired effects.
One study (Liperoti et al., 2003) conducted a trail on 139,714
people resident in 1732 American homes for the elderly. Behavioural
problems were observed in 62% of individuals. 18.2% was treated
with antipsychotic drugs and 11% with atypical antipsychotic drugs.
The use of this diagnostic category was significantly related
to the presence of Alzheimer’s disease. The use of antipsychotic
drugs must be proposed to these individuals with great caution.
Phenothiazines should be avoided due to their anticholinergic
and antiadrenergic effects, which could cause mental confusion,
orthostatic hypotension with falls or events of transitory cerebral
anoxia in individuals with a poor cerebro-cardiovascular balance.
Butyrophenones (haloperidol) envisage a less problematic profile
concerning the abovementioned complications. But the onset of
extrapyramidal symptoms (Parkinsonism), which are hard to correct
with anticholinergic drugs that risk exacerbating a scene of mental
confusion, is frequent in elderly individuals. The following has
been observed concerning atypical antipsychotic drugs: Risperidone
was studied vs. placebo in a sample of 625 patients with severe
forms of dementia. Doses between 1 and 2 mg/day proved to be the
most effective in reducing behavioural symptoms. The dose of 1
mg/day seems the most recommended to avoid the onset of extrapyramidal
effects. A recent analysis of clinical data suggested that this
molecule increases the risk of adverse cerebrovascular events
in individuals suffering from dementia. Hence it must be used
with extreme caution (Katz et al., 1999; Wooltorton, 2002).
Two placebo-controlled trials with Olanzapine performed respectively
on 238 and 206 individuals presenting dementia and psychotic symptoms
suggest this molecule’s efficacy in reducing symptoms (excitement,
aggressiveness, hallucinations and delusion) and tolerance already
at dosages of 5 mg/day (Satterlee et al., 1995; Street et al.,
2000). Concerning this molecule too, like Risperidone, we must
report the increased risk of adverse cerebrovascular events in
individuals suffering from dementia. In this case too we must
stress caution concerning its use on individuals with serious
cardio-cerebrovascular diseases.
Concerning both molecules the Ministry of Health’s Bollettino
d’informazione sui farmaci (No. 1/2004) [Drug Information
Bulletin] focused once again on the dangers of cerebrovascular
events for individuals suffering from dementia, especially for
those whose case history presents stroke or TIA.
Data published in literature concerning Quetiapine has been less
consistent so far. We must however stress how its efficacy and
tolerance profile could be similar to the two abovementioned molecules.
Despite the positive results observed on large clinical trials,
the efficacy of these drugs is still not satisfactory with a response
rate that ranges from 45 to 55% compared to individuals administered
the placebo (30-35%). Hence the need in this field too for studies
focused on identifying molecules that can produce stronger effects
on excitement and psychosis in Alzheimer’s disease and absolute
reliability as they are often used on people suffering from multiple
diseases and treated with multiple drugs.
Claudio Mencacci
Giancarlo Cerveri
Department of Psychiatry
Fatebenefratelli-Oftalmico
Hospital Administration
Milan, Italy
