Update on Dementia. Pathophysiology, Diagnosis, and Treatment. DSM-IV versus DSM-V




© Springer International Publishing AG 2017
Pascual Ángel Gargiulo and Humberto Luis Mesones-Arroyo (eds.)Psychiatry and Neuroscience Update – Vol. II10.1007/978-3-319-53126-7_34


34. Update on Dementia. Pathophysiology, Diagnosis, and Treatment. DSM-IV versus DSM-V



Rose E. Nina-Estrella1  


(1)
Department of Pharmacology, School of Physiological Sciences, Faculty of Health Sciences, University Autónoma of Santo Domingo, Santo Domingo, Dominican Republic

 



 

Rose E. Nina-Estrella

Email:


Abstract

Dementia is frequent in the elderly, and advancing age is the strongest risk factor. It includes Alzheimer’s disease (AD), Vascular dementia (VaD), and other neurogenerative disorders such as Lewy body dementia (LBD), and other less-common neurodegenerative dementing diseases, such as frontotemporal dementia (FTD). All this acquired disorder of cognition and the related behavioral impairment interferes with social and occupational functioning. The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) present differences in the description of AD and VaD. The new DSM recognizes the acceptable alternative “neurocognitive disorder” as a newly preferred and more scientific term than “dementia”. This new diagnosis includes both the dementia and amnesic disorder diagnoses from DSM-IV. Furthermore, DSM-V recognizes specific etiologic subtypes of neurocognitive dysfunction, such as Alzheimer’s disease, Parkinson’s disease, HIV infection, Lewy body disease, and Vascular disease. This is a review based on scientific evidence and information concerning the most common dementia, Alzheimer’s disease (AD) and the second most important, Vascular dementia (VaD), and the main differences between the classifications of DSM-IV and DSM-V for both diseases.


Keywords
DementiaAlzheimer’s diseaseVascular dementiaMajor and mild neurocognitive disorderDSM–IVDSM-V



Introduction


According to many specific references such as the World Alzheimer Report 2015, the number of people living with dementia globally is expected to rise from the current 46 million to 131.5 million by 2050. Global costs to treat dementia, estimated at about US$818 billion in 2015, are expected to soar to $1 trillion by 2018 and to $2 trillion by 2030 [1]. Dementia is most common in the elderly. Multiple neuropathologic processes may underlie dementia, including both neurodegenerative diseases and vascular disease. In addition, comorbidity (the presence of more than one disease process) is more common than dementia in elderly persons [2–5].

There are two most important dementias. Alzheimer’s disease (AD) is the most common neurodegenerative disease responsible for dementia. About half of dementia cases result from AD [2, 3]. Many measurable AD pathologic changes occur in most cognitively intact elderly individuals who undergo autopsy. This indicates that AD is a chronic disease with latent and prodromal stages. It suggests that individuals may have varying abilities to compensate, either biologically or functionally, for the presence of pathological changes underlying AD [6].

Vascular dementia is the second most common form of dementia after AD. The condition is not a single disease. It is a group of syndromes related to different vascular mechanisms. Vascular dementia is preventable, but in this dementia early detection and an accurate diagnosis are also important [7].

It is clinically important to use the Hachinski Ischemic Score (HIS) which aims to distinguish Vascular dementia from Alzheimer’s disease [8]. Hachinski’s ischemic scale seems to be reliable approximately in 90% of cases in the differential diagnosis between Vascular and Alzheimer dementias, especially in the multi-infarct group [9]. The presence of 13 clinical symptoms comprises the HIS. It assigns two points to each of the following symptoms: abrupt onset, fluctuating course, history of stroke, focal neurologic signs, and focal neurologic symptoms. It also assigns additional points for stepwise deterioration, nocturnal confusion, preservation of personality, depression, somatic complaints, emotional incontinence, hypertension, and associated atherosclerosis. A score of 7 or higher suggests Vascular dementia, and a score of 4 or less suggests AD.

As has been mentioned, dementia includes a group of neurodegenerative disorders characterized by progressive loss of cognitive function and a decrease in the ability to perform daily living activities [10].

There are two American mental disorder classifications that could be used at present for diagnosis criteria of mental disorders: the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), and the fifth edition (DSM-5). We are at a transitional point, discontinuing the use of the DSM-IV and starting use of the new DSM- V. It is true that some doctors have a strong resistance to the use of the DSM-V in respect of the new mental disorders classification. When the DSM-V was published, it led to many controversial medical and psychiatric opinions.

DSM-IV was published in 1994 and DSM-5 was published in 2013. The DSM-V is now the standard classification of mental disorders used by mental health professionals in the United States. It is intended to be used in all clinical settings by clinicians of different theoretical orientations. It can be used by mental health and other health professionals, including psychiatrists and other physicians, psychologists, social workers, nurses, occupational and rehabilitation therapists, and counselors. It can also be used in research in clinical and community populations [11]. We see great differences in the diagnosis of AD and Vascular dementia between the two classifications, and it is the purpose of this chapter to clarify these differences.


Alzheimer’s Disease


Let’s start with the history background of AD.This dementia was first described in 1901 by a German psychiatrist named Alois Alzheimer. He observed a patient at the Frankfurt Asylum named Mrs. Auguste D. This 51-year-old woman suffered from a loss of short-term memory, among other behavioral symptoms that puzzled Dr. Alzheimer [12]. After 5 years, in April 1906, the patient died, and Dr. Alzheimer sent her brain and her medical records to Munich, where he was working in the lab of Dr. Emil Kraepelin. By staining sections of her brain in the laboratory, he was able to identify amyloid plaques and neurofibrillary tangles [12]. The important seminar given by Dr. Alzheimer on November 3, 1906, was the first time that the pathology and the clinical symptoms of the disorder had been presented together. The nosological entity was termed presenile dementia. Alzheimer published his findings in 1907 [13].

In the past 20 years, an effort has been made to understand the neurogenetics and pathophysiology of AD. Four different genes are definitively associated with AD. Other genes that may have a probable role have been identified. The mechanisms by which altered amyloid and tau protein metabolism, inflammation, oxidative stress, and hormonal changes may produce neuronal degeneration in AD are being elucidated, and rational pharmacologic interventions based on these discoveries are being developed [14].


Etiology


The cause of AD is unknown. But there are many possible risk factors to be considered. Many investigators now believe that converging environmental and genetic risk factors trigger a pathophysiologic cascade that, acting over decades, leads to Alzheimer pathology and dementia [15]. A group of risk factors for Alzheimer-type dementia have been identified [16–19]:


  1. (a)


    Advancing age

     

  2. (b)


    Family history

     

  3. (c)


    APOE 4 genotype1

     

  4. (d)


    Obesity

     

  5. (e)


    Insulin resistance

     

  6. (f)


    Vascular factors

     

  7. (g)


    Dyslipidemia

     

  8. (h)


    Hypertension

     

  9. (i)


    Traumatic brain injury

     

  10. (j)


    Inflammatory markers

     

  11. (k)


    Down syndrome

     

Based on evidence, there are some other possible risk factors, like depression. Other important risk factors to consider are the genetic risk factors, which are described below in detail. However, there are also some protective factors, such education and long-term use of nonsteroidal anti-inflammatory drugs [22–24].

With regard to genetic factors, it has been described that in some families an autosomal dominant AD has been observed. It accounts for less than 5% of cases, and is almost exclusively early-onset AD. These cases occur in at least three individuals in two or more generations, with two of the individuals being first-degree relatives [25]. If we follow familial clustering, it represents approximately 15–25% of late-onset AD cases, and most often involves late-onset AD. In familial clustering, at least two of the affected individuals are third-degree relatives or closer [25].

Mutations in the following genes unequivocally cause early-onset autosomal-dominant AD:


  1. 1.


    Amyloid precursor protein ( APP) gene on chromosome 21

     

  2. 2.


    Presenilin-1 (PS1) gene on chromosome 14

     

  3. 3.


    Presenilin-2 (PS2) gene on chromosome 1

     

All three of these genes lead to a relative excess in the production of the stickier 42-amino acid form of the Ab peptide over the less sticky 40-amino-acid form [25].

It has been postulated that beta-pleated peptide has neurotoxic properties, and that it leads to a cascade of events. These events are not well understood, and result in neuronal death, synapse loss, and the formation of neurofibrillary tangles (NFTs) and senile plaques (SPs), between other lesions. However, mutations that have been found to date only make it possible to explain less than half of the cases of early-onset AD [26]. Familial Alzheimer’s disease is caused by any one of a number of different single-gene mutations, such as mutations on chromosome 21, which cause the formation of abnormal amyloid precursor protein (APP). Afterwards, several mis-sense genetic mutations within the APP gene were identified in these familial AD kindreds. These mutations resulted in amino acid substitutions in APP that appear to alter the previously described proteolytic processing of APP, generating amyloidogenic forms of Ab [26]. Approximately 50–70% of early-onset autosomal-dominant AD cases appear to be associated with a locus (AD3) mapped by genetic linkage to the long arm of chromosome 14 (14q24.3). Numerous mis-sense mutations have been identified on a strong candidate gene called PS1 [26].

There is another important gene. The gene encoding the cholesterol-carrying apolipoprotein E (APOE) on chromosome 19 has been linked to increased risk for AD, principally late-onset but also some early-onset cases. This gene is inherited as an autosomal codominant trait with three alleles. The APOE E2 allele, the least prevalent of the three common APOE alleles, is associated with the lowest risk of developing AD, with a lower rate of annual hippocampal atrophy, higher cerebrospinal fluid Aβ and lower phosphor-tau, suggesting less AD pathology [27, 28].

APOE E4 gene “dose” is correlated with increased risk and earlier onset of AD [29]. Blood pressure is very important in those individuals who are genetically predisposed to AD. They are advised to closely control their blood pressure. Hypertension has been shown to interact with APOE E4 genotype to increase amyloid deposition in cognitively healthy middle-aged and older adults. Controlling hypertension may significantly decrease the risk of developing amyloid deposits, even in those with genetic risk [30, 31].

Although research supports the relationship between the APOE ε4 variant and the occurrence of late-onset AD, the full mechanism of action and the pathophysiology are not known [20, 21].

There are also other genome-wide association studies that have identified additional susceptibility loci. They are the following: clusterin (CLU) gene, phosphatidylinositol-binding clathrin assembly protein (PICALM) gene, complement receptor 1 (CR1) gene, ATP-binding cassette sub-family A member 7 gene (ABCA7), membrane-spanning gene cluster (MS4A6A/MS4A4E), ephrin receptor A1 ( EPHA1), CD33, CD2AP [26].

It is important to note that many APOE E4 carriers do not develop AD, and many patients with AD do not have this allele. The presence of an APOE E4 allele does not secure the diagnosis of AD, but instead, the APOE E4 allele acts as a biologic risk factor for the disease, especially in those younger than 70 years [14].

Other risk factor to describe is depression. Depression has been identified as a risk factor for AD and other dementias. Recent Framingham data have helped to bolster the epidemiological association. The study showed a 50% increase in AD and dementia in those who were depressed at baseline. During a 17-year follow-up period, a total of 21.6% of participants who were depressed at baseline developed dementia, as compared with 16.6% of those who were not depressed [32].


Pathophysiology


In the pathophysiology of normal aging and in AD, the pathologic hallmarks of AD are the same that occur in the brains of cognitively intact persons. In AD, tau is changed chemically. If we describes what happen it begins to pair with other threads of tau, which become tangled together. When this happens, the microtubules disintegrate, collapsing the neuron transport system. The formation of these neurofibrillary tangles (NFTs) may result first in communication malfunctions between neurons and later in the death of the cells. This is called apoptosis. In addition to NFTs, the anatomic pathology of AD includes senile plaques (SPs), also known as beta-amyloid plaques. They may be observed at the microscopic level, and cerebrocortical atrophy at the macroscopic level. The hippocampus and medial temporal lobe are the initial sites of tangle deposition and structure atrophy. This can be seen on brain magnetic resonance imaging early in AD and helps supporting a clinical diagnosis [33].

SPs and NFTs were described by Alois Alzheimer in his original report on the disorder in 1907 [13]. They are now universally accepted as the pathological hallmark of the disease. Although NFTs and SPs are characteristic of AD, they are not pathognomonic. NFTs are found in several other neurodegenerative disorders. SPs may occur in normal aging. The only presence of these lesions is not sufficient to support the diagnosis of AD. It is important that symptoms and lesions must be present together in sufficient numbers and in a characteristic topographic distribution to fulfill the current histopathologic criteria for AD.

For example, in a study in which neuropathologists were blinded to clinical data, they identified 76% of brains of cognitively intact elderly patients as demonstrating AD [33]. The accumulation of SPs primarily precedes the clinical onset of AD. NFTs, loss of neurons, and loss of synapses accompany the progression of cognitive decline [34].


Diagnosis


Patients with Alzheimer’s disease (AD) most commonly present insidiously progressive memory loss. Other spheres of cognitive impairment are added over several years. This loss may be associated with slowly progressive behavioral changes. After memory loss occurs, there are others symptoms that appear: language disorders (e.g., anomia) and impairment in their visuospatial skills and executive functions [14].

The diagnosis of Alzheimer’s disease should include: signs and symptoms, with the diagnosis criteria as guidelines, biomarkers which confirm the diagnosis,blood test, imaging,neuoropsychological test and pathophysiology.

The symptoms of AD can be classified into the following stages:


  1. (a)


    Preclinical

     

  2. (b)


    Mild

     

  3. (c)


    Moderate

     

  4. (d)


    Severe

     


Preclinical Alzheimer’s Disease


The pathologic changes begin in the entorhinal cortex, which is near the hippocampus and directly connected to it. AD then proceeds to the hippocampus, which is the structure that is essential to the formation of short-term and long-term memories. Affected regions begin to atrophy [14]. These brain changes probably start 10–20 years before any visible signs or symptoms appear. They could start in a silent way after 40 years of age. Memory loss, the first visible sign, is the main feature of amnestic mild cognitive impairment (MCI). Many scientists think MCI is often an initial, transitional clinical phase between normal brain aging and AD. A patient with preclinical AD may appear completely normal on physical examination and mental status testing. At this stage, there is normally no alteration in judgment or the ability to perform activities of daily living [14].


Mild Alzheimer’s Disease


In the mild stage we can observe that the cerebral cortex is affected, memory loss continues and impairment of other cognitive abilities are also present. Later in the disease, physical abilities decline. The clinical diagnosis of AD is usually made during this stage. Signs and symptoms of mild AD can include the following:



  • Memory loss


  • Confusion about the location of familiar places (getting lost begins to occur)


  • Compromised judgment often leading to bad decisions


  • Taking longer to accomplish normal daily tasks


  • Trouble handling money and paying bills


  • Compromised judgment often leading to bad decisions


  • Loss of spontaneity and sense of initiative


  • Mood and personality changes


  • Increased anxiety

The growing number of plaques and tangles first damage areas of the brain that control memory, language, and reasoning. In mild AD, a person seems to be healthy but is actually having more and more trouble making sense of the world around him or her. The realization that something is wrong often comes gradually, because the early signs can be confused with changes that can happen normally with aging. For example: in many cases, the family has a more difficult time handling the diagnosis than the patient does, some patients do not seem emotionally affected, probably because of the sense of apathy, a feeling which occurs in AD. In other cases, following the initial diagnosis, patients should be carefully monitored for a depressed mood. Although it is common for patients with early AD to be depressed about the diagnosis, they rarely become suicidal [14].


Moderate Alzheimer’s Disease


After the mild stage, the moderate stage starts; damage continues to affect the cerebral cortex that controls language, reasoning, sensory processing, and conscious thought. Affected regions continue to atrophy, and signs and symptoms of the disease become more pronounced. Behavioral symptoms, such as wandering and agitation, can occur. More intensive supervision and care become necessary, and this can be difficult for many spouses and families.

The symptoms of this stage can include the following:



  • Increasing memory loss, confusion, and shortened attention span


  • Problems recognizing friends and family members


  • Repetitive statements or movement; occasional muscle twitches


  • Hallucinations, delusions, suspiciousness or paranoia, irritability


  • Difficulty with language; problems with reading, writing, working with numbers


  • Difficulty organizing thoughts and thinking logically


  • Inability to learn new things or to cope with new or unexpected situations


  • Restlessness, agitation, anxiety, tearfulness, wandering, especially in the late afternoon or at night


  • Loss of impulse control (shown through behavior, such as undressing at inappropriate times or places, or vulgar language)


  • Perceptual-motor problems (such as trouble getting out of a chair or setting the table)

Anger is a primary emotion that can mask underlying confusion and anxiety. Also, the risk of violent and homicidal behavior is highest at this stage of disease progression. Patients should be carefully monitored for any behavior that may compromise the safety of those around them. Since it is the case of a person who cannot remember the past or anticipate the future, the world around them can be strange and frightening. Staying close to a trusted and familiar caregiver may be the only thing that makes sense and provides security. The individual may constantly follow his or her caregiver and feel lost when the person is out of sight. Judgment and impulse control continue to decline at this stage [14].


Severe Alzheimer’s Disease


In the last stage, illness severity is perceived. Plaques and tangles are widespread throughout the brain, and areas of the brain have been atrophied. Patients cannot recognize family and loved ones or communicate in any way. This is a burden for the families. They are completely dependent on others for care. All sense of self seems to disappear.

There are other symptoms:



  • Weight loss


  • Seizures, skin infections, difficulty swallowing


  • Groaning, moaning, or grunting


  • Increased sleeping


  • Lack of bladder and bowel control

In end-stage AD, patients may be in bed much or all of the time. Death is often the result of other illnesses, frequently aspiration pneumonia.

Clinical guidelines for the diagnosis of AD have been formulated by the National Institutes of Health–Alzheimer’s Disease and Related Disorders Association (NIH-ADRDA); the American Psychiatric Association, in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V); and the Consortium to Establish a Registry in Alzheimer’s disease (CERAD). In 2011, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) workgroup released new research and clinical diagnostic criteria for AD [35]. The NIH–ADRDA criteria for the diagnosis of AD require the finding of a slowly progressive memory loss of insidious onset in a fully conscious patient. AD cannot be diagnosed in patients with clouded consciousness or delirium [35]. The focus of the 2011 NIA-AA criteria is the need to create a more accurate diagnosis of preclinical disease so that treatment can begin before neurons are significantly damaged, while they are more likely to respond. The report includes criteria for diagnosis of the following:



  • Asymptomatic, preclinical AD (for purposes of research, not clinical diagnosis) [36].


  • Mild cognitive impairment (MCI), an early symptomatic but predementia phase of AD [37]


  • AD dementia [38]

The diagnosis of AD also needs laboratory tests and biomarkers, imaging and neuropsychological tests. Alzheimer disease (AD) is a clinical diagnosis. But as we have mentioned, imaging studies and laboratory tests may be used. Used imaging studies are computed tomography [CT], magnetic resonance imaging [MRI] and, in selected cases, single-photon emission CT [SPECT] or positron-emission tomography [PET].

These tests help exclude other possible causes for dementia (e.g., cerebrovascular disease, cobalamin [vitamin B12] deficiency, syphilis, thyroid disease [37]). Brain scanning with SPECT or PET is not recommended for the routine workup of patients with typical presentations of AD. These modalities may be useful in atypical cases, or when a form of frontotemporal dementia is a more likely diagnosis [39].

There are two important organizations working in early AD detection. They are the Amyloid Imaging Taskforce (AIT), an assembly of experts from the Alzheimer’s Association, and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). They developed guidelines for the use of amyloid β (Aβ) positron emission tomography (PET) imaging to clarify diagnoses of AD or frontotemporal dementia. It described that, amyloid imaging is appropriate in patients with persistent or progressive unexplained mild cognitive impairment, in those satisfying core clinical criteria for possible AD because of unclear clinical presentation, and in patients with progressive dementia and atypically early age of onset. The committee recommends against imaging in asymptomatic individuals and patients with a clear AD diagnosis with typical age of onset. Scanning cannot be used to stage dementia or determine its severity, and it should not be used in lieu of genotyping for suspected autosomal mutation carriers [40].

There are three imaging agents regularly used for diagnostic. The first one is the florbetapir F 18 (AMYViD). This was approved by the FDA in April 2012 as a diagnostic imaging agent. It is indicated for PET brain imaging of beta-amyloid neuritic plagues in adults. It has been evaluated in Alzheimer’s disease but also in other cognitive declines [41–43].

The second was approved by the FDA in October 2013. It is the 18F–labeled Pittsburgh compound B (PIB) derivative, flutemetamol F18 injection (Vizamyl), for use with PET brain imaging in adults undergoing evaluation for Alzheimer disease and dementia. Like florbetapir F18, flutemetamol F18 attaches to beta-amyloid in the brain and produces a PET image that can be used to assess its presence. A positive scan indicates that there is likely a moderate or greater amount of amyloid in the brain, but it does not establish a diagnosis of Alzheimer’s disease or other dementia. The effectiveness of flutemetamol F18 was established in two clinical studies with 384 participants who had a wide range of cognitive function [44].

The final and third agent, florbetaben F18 (Neuraceq), was approved by the FDA in March 2014. Images may be obtained between 45–130 min following the injected dose. FDA approval was based on safety data from 872 patients who participated in global clinical trials, as well as on three studies that examined images from adults with a range of cognitive function, including 205 end-of-life patients who had agreed to participate in a post-mortem brain donation program. Images were analyzed from 82 subjects with post-mortem confirmation of the presence or absence of beta-amyloid neuritic plaques [45]. Subjects in this study underwent testing of memory and executive function along with fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scanning and amyloid deposition with C 11 Pittsburgh Compound B (PiB PET). The researchers found that amyloid burden and lower FDG metabolism (synaptic dysfunction) independently predicted episodic memory performance. Subjects with worse memory performance had higher PiB deposition and lower FDG metabolism in regions of the brain commonly affected in AD [46].

Cerebral spinal fluid (CSF) is a new biomarker. But routine measurement of cerebral spinal fluid tau and amyloid is not recommended except in research settings. Lumbar puncture for measurement of tau and amyloid may become part of the diagnostic workup when effective therapies that slow the rate of progression of AD have been developed, particularly if the therapies are specific for AD and carry significant morbidity [14]. It is observed in the CSF levels of tau and phosphorylated tau that are often elevated in AD, whereas amyloid levels are usually low. The reason for this is not known, but perhaps amyloid levels are low because the amyloid is deposited in the brain rather than the CSF. By measuring both proteins, sensitivity and specificity of at least 80–90% can be achieved [14].

Another research tool is the genotyping for apolipoprotein E (APOE) alleles. It has been helpful in determining the risk of AD in populations, but until recently it was of little, if any, value in making a clinical diagnosis and developing a management plan in individual patients. Numerous consensus statements have recommended against using APOE genotyping for predicting AD risk [25].

One of the neuropsychological tests used in the assessment of AD is the Mini-Mental State Examination (MMSE). It is often used to assess cognitive status. Health providers are increasingly using an alternative mental status test, the Montreal Cognitive Assessment (MoCA) to screen for cognitive impairment [47, 48].

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