Biological Diagnostic and Therapeutic Advances in Alzheimer S Disease Non Pharmacological Therapies For Alzheimer S Disease Ghulam MD Ashraf
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Ghulam Md Ashraf · Athanasios Alexiou
Editors
Biological,
Diagnostic and
Therapeutic
Advances in
Alzheimer’s Disease
Non-Pharmacological Therapies for
Alzheimer’s Disease
Biological, Diagnostic and Therapeutic
Advances in Alzheimer’s Disease
Ghulam Md Ashraf • Athanasios Alexiou
Editors
Biological, Diagnostic
and Therapeutic Advances
in Alzheimer’s Disease
Non-Pharmacological Therapies
for Alzheimer’s Disease
Editors
Ghulam Md Ashraf Athanasios Alexiou
King Fahd Medical Research Center Novel Global Community Educational
King Abdulaziz University Foundation
Jeddah, Saudi Arabia Hebersham, NSW, Australia
Department of Medical Laboratory AFNP Med
Technology, Faculty of Applied Medical Wien, Austria
Sciences
King Abdulaziz University
Jeddah, Saudi Arabia
This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
Preface
Alzheimer’s disease (AD) is still a hardly curable disease with several symptoms of
behavioral and cognitive impairments. Besides the altered protein levels and the
side effects of oxidative stress, it seems that many crucial risk factors play vital
roles, even though it is not yet clear what the etiology is and what the result is. The
reasons why molecular mechanisms cause neurodegeneration in AD are not known.
Alzheimer’s disease is a progressive disorder that leads to dementia and affects
approximately 10% of the population older than 65 years of age. Memory loss is the
first sign of cognitive impairment followed by behavioral disturbances. These symp-
toms are associated with a rigorous neuronal decline and the appearance of two
brain lesions, senile plaques and neurofibrillary tangles, which are mainly com-
posed of Aβ and hyperphosphorylated tau protein, respectively.
While several attempts at reducing AD severity have been presented until now,
targeting mainly the symptomatic treatment, it seems that the early diagnosis or
even the prediction seems to be the most convincing approach. It is also crucial to
mention that in AD, scientists often apply noninvasive therapeutic procedures or
medications like cognitive-behavioral therapy and art therapy within enriched sen-
sorimotor environments in order to engage attention, provide pleasure, and improve
behavior and communication to the patients. Several published studies reveal the
efficacy of applying environmental enrichment in order to increase the effects of
enhanced sensory, cognitive, and motor stimulation on different brain areas of the
patients, which can lead to improved neuronal activation, signaling, and plasticity
between the brain regions.
This book aims to serve as a reference book for those who are interested in the
healthy aging, the non-pharmacological methods on AD, and the importance of
early diagnosis related to risk factors and biomarkers. The editors deeply acknowl-
edge the excellent work of the authors on presenting the challenges against AD
management, in a very unique, interesting, and innovative manner.
Tsagkaris et al. analyze the role of cognitive impairment as a predictive factor of
AD, highly associated with the disease progression and the nonpharmaceutical
management of the disease.
Bano et al. describe the latest studies on causes, symptoms, and preventing meth-
ods of AD, including risk factors and other related comorbidities.
v
vi Preface
Shah et al. analyze the way that dietary interventions can crucially affect the
reduction of neurodegeneration and the various biochemical and genetic alterations
and increase the healthy lifespan among the elderly.
Ashfaq et al. discuss carbon nanostructured material-based biosensors as an
accurate biomarker for AD detection and identification.
Uddin et al. underlie the role of oxidative stress to AD progression in correlation
to mitochondria dysfunction and Aβ- and tau-mediated neurotoxicity.
Alexiou et al. present a set of biologically inspired music algorithms to reveal the
importance of art therapy methods on handling AD patients and increase social
awareness.
Shah et al. investigate the crucial role of structural and functional neuroimaging
on the accurate and efficient AD diagnosis and prognosis.
Ebada et al. demonstrate the role of human gut microbiota in the nervous system
and the way that a variety of disturbances of the intestinal microbiota homeostasis
may affect the gut-brain axis.
Verma et al. describe the approach of applying stem cell therapy for tissue regen-
eration in neurodegeneration and AD.
Srivastava et al. underlie the association and the effects of food, exercise, and
nutrition over aging and AD progression in terms of age-associated cognitive
decline, generation of stress, and neurological fitness.
Zubair presents the most common genetics and neuronal pathways that are asso-
ciated with the AD leading to neuronal death, synaptic failure, and oxidative stress.
Ali et al. describe the most common biotechnological applications including the
BCI and NGS methods, which are involved in the establishment of personalized
tool medicine for gene identification and engineering.
Rizvi et al. present the molecular and cellular mechanisms which are correlated
to the development and progression of AD and can serve as prospective therapeutic
targets.
Hoque et al. reveal the importance of immunotherapy on targeting the senile
plaques with limited side effects and toxicity.
vii
Contents
ix
x Contents
xi
Cognitive Impairment
and Rehabilitation in Alzheimer’s 1
Disease
Abstract
A wealth of evidence emphasizes on the link between Alzheimer’s disease (AD)
and cognitive impairment (CI). CI is generally accepted as a decline in memory,
learning capacity, concentration, or decision-making, leading to functional
impairment. The role of mild cognitive impairment (MCI) as a predictive factor
of AD and the CI linked to the establishment and progression of AD have been
discussed in the context of epidemiology, genetics, pathophysiology, pathology,
and clinical practice. AD-associated CI has been also addressed as a source of
socioeconomic burden urging for the development of therapeutic interventions.
Cognitive rehabilitation (CR) is a complementary non-pharmaceutical treatment
for AD consisting of cognitive stimulation and training methods. Based on the
neuronal plasticity concept, CR aims at increasing AD patients’ functional status
and retarding their mental decline. Although the method has encouraging results
in several studies, there is still controversy as far as its efficacy is concerned and
further research ought to be conducted before incorporating CR in AD’s treat-
ment plan globally. CR drawbacks should be addressed and counteracted in this
context, while the current CR approach may be ameliorated through errorless
learning techniques.
1.1 Introduction
1.3 Cognition
development, whereas it is also deteriorated along with the progression of the dis-
ease. CI may alter the treatment options for AD.
1.5.1 Epidemiology
The majority (>95%) of patients who develop AD disease are over 65 years of age
(also known as late-onset AD), and up to 5% of all people with Alzheimer’s have
early-onset AD, normally appearing in the late four or early five decades of life. The
two forms of AD cannot be easily clinically distinguished but they comply with dif-
ferent patterns of genetic epidemiology (de Souza-Talarico et al. 2016). The early-
onset form displays more severe symptoms and shows higher progression rates than
the late-onset form. The most important risk factor for Alzheimer’s disease is
4 T. Angelopoulos et al.
advanced age. Every 5 years after the age of 65, the risk of suffering from the dis-
ease nearly doubles. Prevalence rates in less developed countries are reduced. In the
USA, where the Hispanic population has a 30% decreased risk than the non-
Hispanic white people, the chance of dying from Alzheimer’s disease is 26% higher
among the non-Hispanic white population than among the non-Hispanic black pop-
ulation (Jicha and Carr 2010; Takizawa et al. 2014).
(APP) after cleavage by beta secretase (first) and gamma secretase (second cleavage
of the β-secretase product) to produce Aβ. The point of cleavage by γ-secretase
determines the kind of aβ produced (Aβ40 or Aβ42). Both b- and γ-secretases are
proteolytic proteins that increase in response to cellular stress such as oxidative
stress, ischemia, and energy loss. β-Secretase1 requires the presence of glycosami-
noglycans for effective cleavage. It is important to note that the function and the
normal biological activity of αβ are not yet fully understood. Both the amyloido-
genic and non-amyloidogenic pathways exist in healthy people, with AD presum-
ably being caused through increased amyloidogenic cleavage or decreased Aβ
turnover. Clots created in the presence of Aβ have an abnormal structure and are
resistant to clearance (Bagyinszky et al. 2016). The amyloid plaques are extracel-
lular deposits found in the brains of AD patients. The plaques are made of a hodge-
podge οf normally fibrillar aggregates known as amyloid fibers, a protein fold
shared by other peptides, for example, the prions linked to protein misfolding dis-
eases (Nicolas et al. 2018; Wu et al. 2012).
1.5.2.4 ApoE
ApoE, one of the principal apolipoproteins in the brain that is expressed in humans
as one of three common isoforms, transports both lipids and Aβ. The three ApoE
variants, ApoE-ε2, ApoE-ε3, and ApoE-ε4, are encoded by three different alleles.
The ApoE-ε2 allele is protective against AD, while ApoE-ε4 allele is the greatest
risk factor. The APOE gene has been associated with late-onset AD and is located in
chromosome 19, belonging in a cluster together with the genes encoding translo-
case of outer mitochondrial membrane 40 (TOMM40), apolipoprotein C1, and apo-
lipoprotein C2. APOE ε4 is responsible for as much as 20–30% of AD risk. The
presence or absence of an APOE ε4 allele determines the risk of AD and the age of
AD onset by approximately 6 years for each allele (Myers et al. 1996; Kurz et al.
1996). The appearance of a single APOE ε4 allele triples the risk of the disease,
while the two copies are associated with a fivefold increase of it. In addition, the
presence of this allele links up with memory impairment, MCI, and progression to
dementia.
ApoE plays a significant role in many potential causes of AD, including Aβ
plaque formation, τ-tangle formation, oxidative stress, lipid homeostasis deregula-
tion, inflammation, synaptic plasticity loss, and cholinergic dysfunction. ApoE-ε4
allele has a low ability to remove Aβ plaques in contrast with ApoE-ε3 and ApoE-ε2
alleles. In patients with AD, ApoE is present in senile plaques (polymorphous
6 T. Angelopoulos et al.
1.5.3 Neuropathology
sensory, motor, and visual cortices that characterize dementia. Additionally, the
presence of several lacunar infarcts in the basal ganglia, cortical microinfarcts, and
demyelination of the periventricular white matter is frequent due to the cerebrovas-
cular disease that is more prevalent in older people and hence is correlated with
cognitive impairment. Ιt is also noteworthy that possible existence of a concurrent
severe cerebral amyloid angiopathy would have a profound effect on brain morphol-
ogy affecting especially the posterior parietal and occipital lobes and causing from
cortical microbleeds to even substantial lobar hemorrhages. AD, dementia, and cog-
nitive impairment are characterized by the death of dopaminergic neurons in sub-
stantia nigra. Only when Lewy bodies are present in the above cases, the substantia
nigra has an abnormal coloration. Finally, the locus coeruleus is noticeably affected
in the early stages of AD (Behrman et al. 2017).
The neurofibrillary tangles (NFTs) are formed in the perikaryal region of pyramidal
neurons. The NFTs are principally produced by paired helical filaments (PHFs) that
are fibrils of ≈ 10 nm in diameter that outline pairs with a helical tridimensional
conformation according to a standard repetitive pattern. A small number of fibrils in
the NFTs remain unpaired and form straight filaments, a different kind of abnormal
filament (Dos Santos Picanço et al. 2016). There are cases where filaments in NFTs
include transition between a paired helical and a straight segment. Leaving struc-
tural units aside, the main component of NFTs is tau protein that has become defec-
tive. This protein normally stabilizes microtubules and is plentiful in neurons and
less common in astrocytes and oligodendrocytes of CNS. Cognitive impairment,
dementia, and AD are often characterized by microtubule instability secondary to
tau protein deficiency. The abnormal tau protein originates from the pathological
phosphorylation of tau and has the effect of the transformation of normal adult tau
into PHF (paired helical filament)-tau and NFTs. Generally, the stabilization of the
microtubules requires the effective interaction οf tau protein isoforms with tubulin
via phosphorylation (Jeong 2017). Lastly, the primarily responsible hyperphosphor-
ylated tau isoforms are often caused by mutations affecting tau function and expres-
sion or even perhaps by increased protease action or interplay between polyanions
and tau protein (Takahashi et al. 2017; Bagyinszky et al. 2016; Bloom 2014; Goedert
2015; Reitz et al. 2011).
Recent studies show that NFT formation is directly proportional to molecular
and conformational changes in the tau protein before and during NFT development
and maturation. The pathologic expansion of the NFTs from the MTL to the neocor-
tex is defined by the Braaks. The topographic spread involves six stages according
to the current location and the severity of the damaged neurons (transentorhinal
stages I–II, clinically silent cases; limbic stages III–IV, incipient AD; neocortical
stages V–VI, fully developed AD). Patients with CI as well as individuals without
1 Cognitive Impairment and Rehabilitation in Alzheimer’s Disease 9
CI demonstrate many potential Braak staging scores from stage 0 that shows total
nonexistence of NFTs to stages V–VI indicating AD. Τhe use of the Braak staging
criteria seems not to clearly differentiate the normal and the CI brains. Nevertheless,
a study suggests that Braak scores are very effective in categorizing amnestic MCI
from non-amnestic MCI (ref) (Takahashi et al. 2017; Mufson et al. 2016; Behrman
et al. 2017).
1.7.1 Diet
Although diets higher in antioxidants and polyunsaturated fatty acids (PUFAs) have
been shown in several studies to lead to decreases in the risks of dementia and AD,
age-related cognitive decline, and MCI (more PUFA, less disease) (Yehuda et al.
n.d.), other studies discovered no clear relationship between dietary PUFAs and
cognitive impairment (Chiu et al. 2008). PUFAs are mostly found in vegetables,
fish, and fruit. In some other studies, individuals with high levels of vitamins E and
C were less susceptible to develop dementia than those with low levels of these
vitamins. Antioxidants like vitamin C can prevent cell damage by oxidation, and
vitamin C may help to revive other antioxidants, such as vitamin E (Engelhart et al.
2002; Morris et al. 2002). However, larger studies have not been able to determine
such associations (Laurin et al. 2004).
Currently, clinical trials concerning dietary supplementation with omega-3
PUFAs have found no complete consequence on cognition in patients with MCI or
AD. On the other hand, docosahexaenoic acid supplementation has a benign effect
on cognitive function in patients harboring the APOE ε4 allele and in the beginning
of the AD.
A Mediterranean-type diet (MeDi) reduced the incidence of AD with the aim of
reducing the risk of MCI and progressing from MCI to AD (Singh et al. 2014). A
2013 systematic review reached similar conclusions, and also found a negative
association with the risk of progressing from mild cognitive impairment to
Alzheimer’s, but acknowledged that only a limited number of studies had been done
on the topic. The principal aspects of this diet include proportionally high consump-
tion of legumes; olive oil as the primary source of monounsaturated fat, unrefined
cereals, fruits, and vegetables; moderate to high intake of fish; moderate consump-
tion of dairy products (mostly as cheese and yogurt); moderate amount of wine
consumption (mostly red); and conservative poor consumption of red non-fish meat
goods. A following cohort study in France showed that Mediterranean-type diet
doesn’t affect the performance on the Isaacs Set Test, the Benton Visual Retention
Test, or the Free and Cued Selective Reminding Test in contrast with high MMSE
scores mentioned (Féart et al. 2009).
Several prospective studies exploring the effect of alcohol on dementia risk con-
cluded that light to moderate alcohol consumption was associated with a reduction
in the risk of AD and dementia (Xu et al. 2017).
10 T. Angelopoulos et al.
Taking part in intellectual activities, such as reading, learning a new hobby, and
playing board games and card games or even using the opposite hand when brush-
ing your teeth, may delay or prevent dementia in older adults, even if these habits
and practices take place in late life, according to the latest research. New researches
suggest, for example, elderly people with greater levels of education had a lower
incidence of dementia than those with no education. Cognitive activity was sug-
gested to decrease the risk of cognitive decline by increasing cognitive reserve.
However, it is important to point out that the exact effect of cognitive exercise on the
risk of dementia remains unclear (Ball et al. 2002; Bidzan et al. 2016; Takizawa
et al. 2014; Acevedo and Loewenstein 2007).
Dementia is one of the major causes of disability and dependency among the elderly.
It is overwhelming not only for the people who have the syndrome but also for their
caregivers and families. There is often a lack of awareness and understanding of
dementia, which results in stigmatization and barriers to diagnosis and care. The
impact of dementia on caregivers, family, and societies can be physical, psychologi-
cal, social, and economic (Dementia 2017).
Before evaluating the cost of AD, cost terminology should be defined. The costs
of dementia to society come from all goods and services that are given up to antici-
pate, diagnose, heal, or in other respects cope with dementia. Individuals, families,
and carers are affected both economically and in terms of quality of life. Alzheimer’s
disease (AD) – the most common cause of dementia – is associated with a valuated
health-care cost of US$172 billion annually (Alzheimer’s Association 2010). The
basic Alzheimer’s disease (AD) symptoms including progressive cognitive, behav-
ioral, and functional impairment have a direct influence on the patients, families,
and the public health system. AD affects both indirect and direct costs. During the
1 Cognitive Impairment and Rehabilitation in Alzheimer’s Disease 11
early stages of AD and for the community-dwelling patients, indirect costs (such as
the serious adverse impact on patients and family members’ financial situation) are
the highest costs. The evolution of the disease leads to an increase of the direct costs
(equally medical treatment and social services) when the patient is hospitalized or
services of a caregiver are required. Although the drug therapies increase the direct
costs they can reduce, other expenses are also involved. A number of studies have
shown that there are total economic benefits to society while using drug therapies,
and all related cost are considered, where results rely on specific patient and care
setting characteristics. Indicatively, direct medical costs per year for mild AD
ranged from €5476 in France to €27,380 in Spain. A good health system should take
greater account of dementia, and governments must prepare a plan to tackle AD
based on treatment options that are proportionate to the burden of the disease
(Marešová and Zahálková 2016; Takizawa et al. 2014).
1.10.1 Diagnostics
1.10.1.1 Intro
When an individual has symptoms of dementia, a physician must conduct tests to
identify the underlying brain disease or other condition that is causing these symp-
toms. Different types of dementia are associated with distinct symptom patterns and
brain abnormalities (Langa and Levine 2014).
12 T. Angelopoulos et al.
Table 1.1 Normal aging vs. mild and major neurocognitive disorder
Normal aging Mild neurocognitive disorder Major neurocognitive disorder
Primarily intact Inefficiency in daily activities Needs help with daily
cognition activities
Subtle processing speed Decline from lifelong abilities in Substantial decline in one or
is decreased one or more areas of thinking more cognitive abilities
Less efficient attention a
ADLs progressively decreased ADLs severely decreased and
and executive reasoning and bIADLs decreased IADLs not feasible
a
Basic activities of daily living (ADLs): bathing, dressing, eating, transferring from bed to chair,
continence, toileting
b
Instrumental activities of daily living (IADLs): transportation, shopping, cooking, using the tele-
phone, managing money, taking medications, housecleaning, laundry
Table 1.2 Overview- approach to evaluating a patient with dementia: routine evaluation and
optional diagnostic tests
Routine evaluation Optional focus tests Occasionally helpful tests
History Psychometric testing EEG
Physical examination Chest X-ray Parathyroid function
CT/MRI Lumbar puncture Adrenal function
Laboratory tests: thyroid Other tests: liver function, Other tests: urine heavy metals,
function (TSH), vitamin renal function, urine toxin lab screen for autoantibodies, RBC
B12, complete blood screen, HIV, apolipoprotein sedimentation rate, angiogram,
count, electrolytes E, RPR or VRDL brain biopsy, SPECT, PET
Abbreviations: CT computed tomography, EEG electroencephalogram, MRI magnetic resonance
imaging, PET positron emission tomography, RBC red blood cell, RPR rapid plasma reagin (test),
SPECT single-photon emission computed tomography, TSH thyroid-stimulating hormone, VDRL
Venereal Disease Research Laboratory (test for syphilis)
Source: Casper et al. (2015)
Table 1.3 Overview- approach to evaluating a patient with dementia: diagnostic categories
Reversible causes Irreversible/degenerative dementias Psychiatric disorders
Examples: Examples: Examples:
Hypothyroidism Alzheimer’s disease Depression
Thiamine deficiency Frontotemporal dementia Schizophrenia
Vitamin B12 deficiency Huntington’s Conversion reaction
Normal pressure Dementia with Lewy bodies
hydrocephalus Vascular dementia
Subdural hematoma Leukoencephalopathies
Chronic infection Parkinson’s disease
Brain tumor
Drug intoxication
Autoimmune encephalopathy
1.10.3 History
The history begins by asking the patients to describe, in their own words, the reason
for seeking medical care (Table 1.5). Although patients may have many reasons for
initiating a visit to the physician, they should be encouraged to select the most
important or top two most important concerns they have and state them. The physi-
cian should reassure the patient that other concerns will not be ignored but that it’s
important to understand what is the most concerning to the patient at that moment.
The history should concentrate on the onset, duration, and tempo of progression
when it comes to dementia and AD. For example, an acute or subacute onset of con-
fusion may be due to a different cause like delirium and should trigger the search for
intoxication, infection, or metabolic derangement. An elderly person with slowly
progressive memory loss over several years is likely to suffer from AD. Nearly 75%
of patients with AD begin with memory symptoms, but other early symptoms include
difficulty with managing money, shopping, driving, following instructions, navigat-
ing, or finding words. The latter symptoms are really important in the frame of CI.
1 Cognitive Impairment and Rehabilitation in Alzheimer’s Disease 15
The history should be taken in a stepwise manner, and the spoken approach
should also be taken into consideration. We should begin with acquiring the history
of the present illness or concern at large. Open-ended questions produce a descrip-
tion of the patient’s concerns in the patient’s own words, whereas specific questions
fill in gaps and help clarify significant points. These questions should be asked in an
order lead by the story the patient tells and targeted to fit the individual problem.
Important questions to consider include description of onset and chronology, loca-
tion of symptoms, quality (character) of symptoms, intensity, and precipitating,
aggravating, and relieving factors. Ask if this problem or similar problems occurred
before and, if so, whether a diagnosis was established at the time.
After taking the history of the present illness, we should ask about past medical
and surgical history, a list of current medications including prescriptions, herbal
drugs, over-the-counter medications, and vitamins. Next, we may attempt to assess
social and occupational history, along with risk factors. Social history can help us
understand the patient’s values and support systems. Information that can influence
risk factors for disease should be gathered including occupational history, substance
abuse, and sexual history. Marital status and the living situation of the patient are as
important as risk factors for disease and help determine how to provide the best care
for the patient.
An intelligent physician is aware that patients may not report all their problems
because they may have forgotten or simply may not want to discuss them.
The family history is never diagnostic, but it allows risk stratification and it may
indicate signs of CI which will not be mentioned by the patient (Goldman and
Schafer 2012). Studies of family history say that if you have a close relative who has
been diagnosed with AD, your risk increases by 30%. This is a relative risk increase,
meaning a 30% rise in your existing risk. This means your risk may be higher, but
not that much higher, if you consider the absolute numbers. The risk of being diag-
nosed with AD is 2% per year if you are over the age of 65. Family history then
raises this 2% by 30%, to about 2.6% per year. Age raises the chances of AD more
than family history considering that people above the age of 70 have a 5% chance
of being diagnosed. Family history would again raise this by 30%, making 5% go to
6.5%. Nevertheless, a positive family history of AD should always be taken into
consideration. The review of systems is the structural assessment of each of the
major organ systems and can help elicit symptoms or signs that are not covered or
may be overlooked in the history of the present illness (Table 1.6).
1.10.4 Screening
must also be two hands present, one pointing to eleven (11) and one pointing to two
(2). Hand length is not scored in the Mini-Cog algorithm.
Typical AD spares the motor systems until later on in the course, whereas fron-
totemporal dementia (FTD) patients usually develop axial rigidity, supranuclear
gaze palsy, or a motor neuron disease reminiscent of amyotrophic lateral sclerosis
(ALS). In dementia with Lewy bodies (DLB), the initial symptoms may include the
new onset of a parkinsonian syndrome (resting tremor, cogwheel rigidity, bradyki-
nesia, festinating gait), but DLB most often starts with visual hallucinations or
dementia. Creutzfeldt–Jakob disease (CJD) is advocated by the presence of an
akinetic-mute state, diffuse rigidity, and prominent, startle-sensitive myoclonus.
There are no definitive laboratory tests available that will positively diagnose AD
during life. Currently, the only definite diagnosis of AD is to microscopically exam-
ine a section of the person’s brain tissue after death. Histopathologists will look for
senile plaques and neurofibrillary tangles which are characteristic of AD. Since
plaque and tangle formation are also seen in the normal aging process, the sample
must be compared to a control sample of normal, non-AD brain tissue from a person
of the same age.
A physician may use a range of traditional laboratory tests to rule out other con-
ditions and deficiencies that could be affecting the patient’s memory. They may also
look for overmedication and may use imaging tools such as computed tomography
(CT) and magnetic resonance imaging (MRI) scans in order to look for evidence of
tumors, trauma, or stroke that could cause dementia symptoms. Imaging can also
help look for brain atrophy or shrinkage that may be seen later in the AD progres-
sion. The American Academy of Neurology recommends the routine measurement
of a complete blood count, electrolytes, renal and thyroid function, a vitamin B12
level, and neuroimaging studies (CT or MRI).
Common causes of dementia include Alzheimer’s disease, which is the number one
cause. Vascular dementia, alcoholism, and drug/medication intoxication are other
common causes. Less common causes of dementia include vitamin deficiencies,
endocrine and other organ failure, other psychiatric disorders, degenerative disor-
ders, chronic infections, head trauma and diffuse brain damage, intracranial hypo-
tension, neoplasm, toxic disorders, and others.
Differential diagnosis should always be in mind when the physician is taking a
history. Personality change, disinhibition, and weight gain or compulsive eating
suggest frontotemporal dementia (FTD), for example, and not AD. Early visual hal-
lucinations, parkinsonism, and rapid eye movement (REM) behavior disorder
(RBD; the loss of skeletal muscle paralysis while dreaming) may suggest diagnosis
of dementia with Lewy bodies (DLB). Rapid progression with motor rigidity and
myoclonus suggests Creutzfeldt–Jakob disease (CJD). Seizures may indicate
1 Cognitive Impairment and Rehabilitation in Alzheimer’s Disease 19
The treatment options for MCI and CI are either pharmacological or psychological.
Currently, the FDA has not approved any medication for MCI treatment since AD
medication has not been proved effective as far as preventing or delaying the dete-
rioration of MCI is concerned. Several psychological or occupational interventions
have shown encouraging results; however, most of them should be personalized,
while their efficacy depends on the experience of the therapist, the compliance of
the patient, and the support of the carers.
CI in AD patients is treated with pharmacological agents on the grounds of CI’s
pathophysiology knowledge. More specifically cholinesterase inhibitors (ChEIs)
and N-methyl-D-aspartate (NMDA) antagonists are considered as the first-line ther-
apy for global cognitive impairment. Several studies indicate the benefits of psycho-
logical approaches in combination with pharmaceutical treatment. In this frame
several approaches have been developed. To name just a few, we may shortlist cog-
nitive behavioral therapy, stimulation training, cognitive training, cognitive stimula-
tion, and cognitive rehabilitation. The latter consists of both stimulation and training
techniques and focuses on cognitive aspects of the patient’s disorder.
1.13.1 Introduction
Malheur à celui qui, faisant le mal, s’imagine que son crime restera
toujours caché ! Alors que tous le tairaient, l’air et la terre elle-même
où est ensevelie sa victime le crieraient tout autour de lui. Et Dieu
fait souvent que le péché pousse le pécheur à le rendre lui-même
fortuitement manifeste, sans qu’il en soit accusé par personne, ou
après qu’il en a été absous.
Le misérable Polinesso avait cru cacher à tout jamais son crime
en faisant disparaître Dalinda qui le connaissait et pouvait seule le
dénoncer. En ajoutant un second crime au premier, il avança le
châtiment qu’il pouvait différer et éviter peut-être. Mais sa propre
précipitation le fit courir à la mort.
Et il perdit d’un seul coup ses amis, sa vie, son rang et, ce qui fut
bien pis encore, l’honneur. J’ai dit plus haut que le chevalier dont on
ne sait pas encore le nom fut longtemps prié de se faire connaître. Il
ôte enfin son casque, et montre aux yeux des assistants un visage
aimé et qu’ils ont vu plus d’une fois ; et il fit voir qu’il était Ariodant,
que l’Écosse entière pleurait ;
Ariodant, que Ginevra avait pleuré comme mort, que son frère
avait également pleuré, ainsi que le roi, la cour et tout le peuple, et
qui venait de faire éclater tant de bonté et de valeur. On vit alors que
le voyageur n’avait pas dit vrai dans ce qu’il avait raconté à son
sujet. Et pourtant il l’avait véritablement vu se jeter tête baissée dans
la mer du haut du rocher.
Mais — comme il arrive souvent au désespéré qui, de loin,
appelle et désire la mort, et la repousse quand il la voit près de lui,
tant elle lui paraît amère et cruelle — à peine Ariodant s’est-il
précipité dans la mer, qu’il se repent d’avoir voulu mourir. Et comme
il était fort, adroit et plus audacieux que n’importe qui, il se mit à
nager et regagna le rivage.
Et, traitant de folie le désir qu’il avait eu d’abandonner la vie, il se
mit en route, les vêtements imprégnés et amollis par l’eau, et arriva
à la demeure d’un ermite. Il y demeura secrètement, attendant de
savoir quel effet la nouvelle de sa mort avait fait sur Ginevra ; si elle
s’en était réjouie, ou si elle en avait été triste et affligée.
Il apprit d’abord que, dans sa grande douleur, elle avait failli
mourir — le bruit s’en était répandu rapidement dans toute l’île —
résultat tout à fait contraire à ce qu’il attendait, d’après ce que, à son
extrême chagrin, il croyait avoir vu. Il sut ensuite comment Lurcanio
avait accusé Ginevra auprès de son père.
Il ressentit autant de colère contre son frère, qu’il avait eu jadis
d’amour pour Ginevra. Cette action lui paraît trop impie et trop
cruelle, encore qu’elle ait été faite pour lui. Enfin il fut informé
qu’aucun chevalier ne s’était présenté pour défendre Ginevra, car
Lurcanio était si fort et si vaillant, que personne n’avait garde de se
mesurer à lui.
Et puis il était connu pour un homme discret, et si sage et si avisé
que, si ce qu’il avait raconté n’eût pas été vrai, il ne se serait pas
exposé à la mort pour le soutenir. C’est pourquoi la plupart hésitaient
à défendre une cause peut-être mauvaise. Ayant appris cela,
Ariodant, après s’être tenu à lui-même de grands discours, se
résolut à relever l’accusation de son frère.
« — Hélas ! je ne pourrais — disait-il en lui-même — la laisser
périr à cause de moi. Ma mort serait trop amère et trop misérable si,
avant moi, je la voyais mourir. Elle est toujours ma dame, ma
déesse ; elle est la lumière même de mes yeux. Je dois, qu’elle soit
innocente ou coupable, entreprendre de la délivrer et mourir sur le
champ du combat.
« Si j’entreprends une cause mauvaise, c’est à elle qu’en sera la
faute, et moi j’en mourrai ; et cela ne me décourage pas, car je sais
que ma mort entraînera la mort d’une si belle dame. Une seule
pensée me consolera en mourant, c’est qu’elle aura pu voir que ce
Polinesso, à qui elle a donné son amour, ne s’est pas même
présenté pour la défendre.
« Et moi qu’elle a si grandement offensé, elle m’aura vu courir à
la mort pour la sauver. Je me serai aussi par là vengé de mon frère
qui a allumé un tel feu. Et je le ferai gémir sur le résultat de sa
cruelle entreprise, quand il saura qu’en croyant venger son frère, il
lui a donné la mort de sa propre main. — »
Dès qu’il eut arrêté cela dans son esprit, il se procura de
nouvelles armes, un nouveau cheval, choisit une cotte de mailles et
un écu noirs, bordés de vert et de jaune. Et, ayant par aventure
trouvé un écuyer étranger au pays, il l’emmena avec lui. C’est alors
que, sans être connu, il se présenta, comme je l’ai déjà dit, contre
son frère qui attendait tout armé.
Je vous ai raconté l’issue du combat, et comment Ariodant fut
reconnu. Le roi n’en eut pas une moindre joie que lorsqu’il avait vu
sa fille délivrée. Il pensa en lui-même qu’elle ne pourrait jamais
trouver un plus fidèle, un plus sincère amant, puisqu’il l’avait
défendue contre son propre frère, après en avoir reçu une si grande
offense.
Et autant de sa propre inclination, car il l’aimait beaucoup, que
sur les prières de toute la cour et de Renaud, qui insistait plus que
les autres, il en fit l’époux de sa charmante fille. La duché d’Albanie,
qui retournait au roi après la mort de Polinesso, ne pouvait pas se
trouver vacante en meilleure circonstance ; c’est pourquoi il la donna
en dot à sa fille.
Renaud obtint la grâce de Dalinda qui, délivrée de sa funeste
erreur, rassasiée du monde, tourna son esprit vers Dieu et se
consacra à lui. Elle alla se faire religieuse en Dace, et quitta
immédiatement l’Écosse. Mais il est temps désormais de retrouver
Roger qui parcourt le ciel sur son léger cheval.
Bien que Roger soit d’un courage indomptable, et qu’il n’ait pas
changé de couleur, je ne puis croire que, dans sa poitrine, son cœur
ne tremble pas plus que la feuille. Il avait dépassé de beaucoup
l’Europe, et était parvenu bien au delà des bornes qu’Hercule avait
jadis imposées aux navigateurs.
L’hippogriffe, grand et étrange oiseau, l’emporte avec une telle
rapidité d’ailes, qu’il aurait laissé bien loin derrière lui le prompt
agent de la foudre. De tous les oiseaux qui vont, légers, par les airs,
aucun ne lui serait égal en vitesse. Je crois que c’est à peine si le
tonnerre et la flèche arrivent du ciel sur terre avec plus de
promptitude.
Après que le cheval-oiseau eut parcouru un grand espace en
ligne droite et sans jamais se détourner, fatigué d’aller dans les airs,
il commença à décrire de larges cercles et s’abattit sur une île. Elle
était semblable à celle où, pour éviter la longue poursuite de son
amant et se dérober à lui, la vierge Aréthuse se fraya en vain sous la
mer un chemin sombre et étrange [43] .
Le chevalier n’avait rien vu d’aussi beau ni d’aussi agréable dans
tout son voyage à travers les airs ; et, s’il avait cherché par le monde
entier, il n’aurait pas vu de plus joli pays que celui où, après avoir
plané un grand moment, le grand oiseau descendit avec Roger. Ce
n’était partout que plaines cultivées, collines charmantes, eaux
claires, rives ombreuses et prés moelleux.
De ravissants bosquets de lauriers odorants, de palmiers, de
myrtes gracieux, de cèdres et d’orangers qui portaient des fruits et
des fleurs et entrelaçaient leurs formes belles et variées, faisaient un
rempart contre les chaleurs ardentes des jours d’été, avec leurs
épaisses ramures en forme d’ombrelles. Et dans leurs rameaux
voltigeaient en sûreté et chantaient les rossignols.
Parmi les roses pourprées et les lis blancs, qu’une tiède brise
conserve toujours frais, on voyait les lièvres et les lapins courir sans
crainte, et les cerfs au front élevé et superbe, sans redouter d’être
pris et tués, paître l’herbe et ruminer en repos. Les daims et les
chèvres, agiles et pleins d’adresse, bondissaient en foule sous ces
bosquets champêtres.
Dès que l’hippogriffe est assez près de terre pour que l’on puisse
sauter sans trop de danger, Roger s’enlève rapidement de l’arçon et
se retrouve sur le gazon émaillé. Il serre toutefois les rênes dans sa
main, car il ne veut pas que le destrier s’envole de nouveau. Il
l’attache sur le rivage à un myrte verdoyant, entre un laurier et un
pin.
Puis, dans un endroit où jaillissait une fontaine couronnée de
cèdres et de palmiers touffus, il pose son écu, ôte son casque du
front, et se désarme les deux mains, Et, tourné tantôt vers la mer,
tantôt vers la montagne, il livre son visage aux brises fraîches et
suaves qui, avec de doux murmures, font trembler les hautes cimes
des hêtres et des sapins.
Il baigne dans l’onde claire et fraîche ses lèvres desséchées ; il
l’agite avec les mains, pour apaiser la chaleur qu’a allumée dans ses
veines le poids de sa cuirasse. Et il ne faut point s’étonner que cette
chaleur soit devenue si grande, car il a été loin de se tenir en une
même place ; au contraire, sans jamais se reposer et couvert de ses
armes, il est allé toujours courant pendant trois mille milles.
Pendant qu’il se repose en cet endroit, le destrier qu’il avait laissé
au plus épais du feuillage sous l’ombre fraîche, se cabre tout à coup,
comme s’il voulait fuir, épouvanté qu’il est par je ne sais quoi de
caché dans les branches. Et il secoue tellement le myrte auquel il
est attaché, qu’il encombre tout autour la terre de ses rameaux. Il
secoue le myrte au point d’en faire tomber les feuilles, mais sans
réussir à s’en détacher.
Comme fait parfois un tronc d’arbre à la moelle rare ou absente,
quand il est mis au feu, et que la grande chaleur consume l’air
humide qui le remplit et le fait résonner en dedans, jusqu’à ce qu’elle
se fraye un chemin au dehors avec un bouillonnement strident, ainsi
murmure, crie et se courrouce ce myrte blessé, et enfin ouvre son
écorce,
D’où, avec une voix triste et plaintive, sortent, distinctes et
claires, ces paroles : « — Si tu es courtois et accessible à la pitié,
comme le montre ta belle physionomie, éloigne cet animal de mon
arbre. Il suffit que je sois affligé de mon propre mal, sans qu’une
autre peine, sans qu’une autre douleur vienne encore du dehors
pour me tourmenter. — »
Au premier son de cette voix, Roger tourne les yeux et se lève
subitement. Et quand il s’aperçoit qu’elle sort de l’arbre, il reste plus
stupéfait que jamais. Il s’empresse d’écarter le destrier, et, la
rougeur sur les joues : « — Qui que tu sois — dit-il — pardonne-
moi, esprit humain ou déesse des bocages.
« Je ne savais pas que, sous ta rude écorce, se cachait un esprit
humain ; c’est pourquoi j’ai laissé endommager ton beau feuillage et
insulter à ton myrte vivace. Mais ne tarde pas à m’apprendre qui tu
es, toi qui, en un corps grossier et rugueux, vis et parles comme un
animal doué de raison. Que de l’orage le ciel te préserve toujours !
« Et si, maintenant ou jamais, je puis réparer par quelque service
le mal que je viens de te causer, je te promets, par la belle dame qui
possède la meilleure part de moi-même, de faire de telle sorte, par
mes paroles et par mes actes, que tu aies une juste raison de te
louer de moi. — » A peine Roger eut-il fini de parler, que le myrte
trembla de la tête au pied.
Puis on vit son écorce se couvrir de sueur, comme le bois
fraîchement tiré de la forêt, qui sent la violence du feu après lui avoir
en vain fait toute sorte de résistance. Et il commença : « — Ta
courtoisie me force à te découvrir en même temps qui j’ai d’abord
été, et ce qui m’a changé en myrte sur cette charmante plage.
« Mon nom fut Astolphe, et j’étais un paladin de France très
redouté dans les combats. J’étais cousin de Roland et de
Renaud [44] , dont la renommée n’a pas de bornes. Je devais, après
mon père Othon, régner sur toute l’Angleterre. J’étais si beau et si
bien fait, que plus d’une dame s’enflamma pour moi. Seul je me suis
perdu moi-même.
« Je revenais de ces îles lointaines qu’en Orient baigne la mer
des Indes, où Renaud et quelques autres avec moi avions été
retenus prisonniers dans un obscur et profond cachot, et d’où nous
avait délivrés la suprême vaillance du chevalier de Brava ; me
dirigeant vers le ponant, j’allais le long de la côte qui du vent du nord
éprouve la rage.
« Et comme si le destin cruel et trompeur nous eût poussés sur
ce chemin, nous arrivâmes un matin sur une belle plage où s’élève,
sur le bord de la mer, un château appartenant à la puissante Alcine.
Nous la trouvâmes sortie de son château, et qui se tenait sur le
rivage, attirant sur le bord, sans filets et sans amorce, tous les
poissons qu’elle voulait.
« Les dauphins rapides y accouraient, et les thons énormes à la
bouche ouverte ; les baleines et les veaux marins, troublés dans leur
lourd sommeil ; les mulets, les salpes, les saumons et les barbues
nageaient en troupes le plus vite qu’ils pouvaient. Les physitères, les
orques et les baleines montraient hors de la mer leurs monstrueuses
échines.
« Nous aperçûmes une baleine, la plus grande qui se soit jamais
vue sur toutes les mers. Onze pas et plus émergeaient hors des
ondes ses larges épaules. Et nous tombâmes tous dans une grande
erreur ; car, comme elle se tenait immobile et sans jamais bouger,
nous la prîmes pour une petite île, tellement ses deux extrémités
étaient distantes l’une de l’autre.
« Alcine faisait sortir les poissons de l’eau avec de simples
paroles et de simples enchantements. Avec la fée Morgane elle
reçut le jour ; mais je ne saurais dire si ce fut dans la même couche
ou avant, ou après. Alcine me regarda, et soudain mon aspect lui
plut, comme elle le montra sur son visage. Et il lui vint à la pensée
de m’enlever, par astuce et artifice, à mes compagnons. Son
dessein réussit.
« Elle vint à notre rencontre l’air souriant, avec des gestes
gracieux et prévenants, et dit : « — Chevaliers, qu’il vous plaise de
prendre aujourd’hui vos logements chez moi. Je vous ferai voir, dans
ma pêche, toutes sortes de poissons différents, les uns recouverts
d’écailles, les autres lisses, et d’autres tout poilus, et tous plus
nombreux qu’il n’y a d’étoiles au ciel.
« Et si nous voulons voir une sirène qui apaise la mer par son
doux chant, passons d’ici sur cette autre plage, où, à cette heure,
elle a toujours coutume de retourner. — » Et elle nous montra cette
grande baleine qui, comme je l’ai dit, paraissait être une île. Moi, qui
fus toujours trop entreprenant — et je m’en repens — j’allai sur ce
poisson.
« Renaud me faisait signe, ainsi que Dudon, de ne pas y aller,
mais cela servit peu. La fée Alcine, avec un visage riant, laissa les
deux autres et s’élança derrière moi. La baleine, à lui obéir diligente,
s’en alla, nageant à travers l’onde salée. Je ne tardai pas à me
repentir de ma sottise, mais je me trouvais trop éloigné du rivage.
« Renaud se jeta à la nage pour m’aider et faillit être englouti, car
un furieux vent du sud s’éleva, qui couvrit d’une ombre épaisse le
ciel et la mer. J’ignore ce qui lui est ensuite arrivé. Alcine s’efforçait
de me rassurer, et pendant tout ce jour et la nuit suivante elle me tint
sur ce monstre au milieu de la mer,
« Jusqu’à ce que nous arrivâmes à cette belle île, dont Alcine
possède une grande partie. Elle l’a usurpée sur une de ses sœurs, à
qui leur père l’avait entièrement laissée en héritage parce qu’elle
était sa seule enfant légitime. Les deux autres, à ce que m’a dit
depuis quelqu’un qui en était pleinement instruit, sont nées d’un
inceste.
« Et de même qu’elles sont iniques et pleines de scélératesse et
de vices infâmes, leur sœur, qui vit chaste, a dans son cœur toutes
les vertus. Les deux autres se sont liguées contre elle, et déjà plus