Neuropsych perspective

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by

cognitive decline, behavioral changes, and neuropathological alterations, including the
accumulation of amyloid plaques and neurofibrillary tangles. This paper provides overviews
of the history and epidemiology of AD, emphasizing the significance of understanding the
neuropsychiatric perspective in comprehensive care and managing the affected individuals.
The neurobiological mechanisms underlying AD, including abnormal neuritic plaques and
neurofibrillary tangles, are discussed, with a particular focus on their association with
neuropsychiatric symptoms (NPS). The paper explores various NPS commonly observed in
AD. The neurobiological causes and factors contributing to each symptom are examined,
highlighting the involvement of specific brain regions and neurotransmitter systems. NPS-
related neuroimaging results are given, highlighting the significance of brain lesion patterns
in comprehending the underlying causes or mechanisms of these neuropsychiatric symptoms.

The Neuropsychiatric Inventory (NPI) and imaging methods like MRI and PET scans are
discussed as useful tools for evaluating and monitoring behavioral changes as well as for
diagnosing neuropathological changes and structural abnormalities linked to NPS.

Pharmacological and Non- Pharmacological interventions for treatment of NPS, are

reviewed, along with their efficacy and safety considerations.

The paper highlights the significance of incorporating the neuropsychiatric perspective into
care plans for individuals with AD. Personalized treatment approaches, including medication,
psychotherapy, environmental modifications, and caregiver support, can be developed.
Recognizing this perspective also encourages future research and innovation in the field of
AD.

HISTORY

Alzheimer's disease is named after Dr. Alois Alzheimer, a German psychiatrist, and
neuropathologist who first identified the condition in 1906. His groundbreaking work
revolutionized our understanding of dementia. Dr. Alzheimer's pivotal moment came when
he examined brain of his patient, Auguste Deter. She displayed severe memory loss,
confusion, and behavioral changes. Dr. Alzheimer discovered unusual protein deposits,
known as amyloid plaques and tangled fibers called neurofibrillary tangles in her brain. These
pathological hallmarks became crucial in recognizing Alzheimer's disease as a distinct form
of dementia, leading to the condition being named after him.

OVERVIEW OF ALZHEIMER’S DISEASE

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects

older individuals. It is characterized by a progressive decline in cognitive abilities and
functioning, often accompanied by behavioral and psychological symptoms. The underlying
neuropathological changes include the accumulation of amyloid-beta plaques and
neurofibrillary tangles composed of hyperphosphorylated tau protein. These
neurophysiological and neurobiological disruptions cause hindrances in communication
between neurons, leading to the degeneration and death of brain cells, particularly in regions
crucial for memory and cognitive processes.

EPIDEMIOLOGY

Alzheimer's disease poses a significant global health challenge, primarily impacting the
elderly population. Currently, it affects approximately 24 million individuals worldwide, with
projections suggesting a four-fold increase by 2050. The economic burden of Alzheimer's is
substantial, with the United States alone spending around $172 billion annually on healthcare
related to the disease. In 2011, there were an estimated 4.5 million individuals aged 65 and
above with clinical Alzheimer's in the United States. The incidence of Alzheimer's disease
doubles every five years after the age of 65, with rates increasing from less than 1% per year
before 65 to 6% per year after 85. Prevalence rates also rise significantly, from 10% after 65
to 40% after 85. Interestingly, the rates of Alzheimer's disease are slightly higher in women,
particularly beyond the age of 85. Understanding the epidemiology of Alzheimer's disease is
vital for effective healthcare planning and developing necessary intervention strategies to
address this growing public health concern.

NEUROPSYCHIATRIC PERSPECTIVE AND ITS SIGNIFICANCE

The Neuropsychiatric perspective of Alzheimer’s disease primarily involves understanding

Neuropsychiatric symptoms and their types including neurobiological mechanisms, causes,
and associated factors.

While the neuropathogenesis of Alzheimer's disease primarily involves neurobiological

factors, the manifestation of neurological and psychiatric symptoms occurs at different stages
of the disease. The Neuropsychiatric perspective of Alzheimer's disease encompasses a deep
understanding of the various Neuropsychiatric symptoms (NPS) that can occur in individuals
with the condition. These symptoms, including depression, psychosis, sleep disturbances,
agitation, anxiety, and more, are crucial to consider due to their complex and multifactorial
nature.

Understanding the underlying neurobiological mechanisms contributing to the progression of

these symptoms is an essential aspect of the Neuropsychiatric perspective. Incorporating the
Neuropsychiatric perspective is crucial for the comprehensive care and management of
individuals with Alzheimer's disease. It allows healthcare professionals to accurately
diagnose NPS, implement improved symptom management strategies, and provide
personalized treatment approaches. This includes a combination of pharmacological
interventions, psychotherapy, environmental modifications, and caregiver support tailored to
address the specific needs of each patient. Furthermore, recognizing the significance of the
Neuropsychiatric perspective paves the way for future research and innovation.

NEUROBIOLOGICAL MECHANISM OF AD

As mentioned earlier the cause of Alzheimer’s Disease is neurobiological in nature. There are
two main characteristic features of the neuropathology of Alzheimer’s disease: Abnormal
neuritic plaques and Neurofibrillary tangles.

Neuritic plaques are spherical microscopic lesions in the brain of Alzheimer’s patients, the
core of which is made from Aβ (amyloid beta) which is found outside of brain cells. The Aβ
is of two forms called Aβ40 and Aβ42. The amyloid beta-peptide is derived from the
breakdown of a transmembrane protein called amyloid precursor protein (APP). The APP is
cleaved by enzymes called alpha and beta-secretase which produce harmless fragments.

During Alzheimer’s, there is a sequential cleavage of Amyloid beta by beta and gamma-
secretase which leads to the overproduction of amyloid beta 42 that leads to aggregation of
amyloid and forms plaques. This causes neuronal toxicity and neuronal death. Among them,
Aβ42 is more abundant in neuritic plaques because of its higher tendency to become
insoluble and form clumps.

The deposition of amyloid plaques doesn’t have any specific patterns of aggregation however
it generally initiates from the isocortex. The amyloid or neuritic plaques have a less severe
effect on the entorhinal cortex and hippocampus involved in memory than neurofibrillary
tangles.

Neurofibrillary tangles are intracytoplasmic structures that are made by a protein called Tau.
During normal functioning, Tau proteins are responsible for stabilizing axonal microtubules
which is important in intracellular transport within neurons. However, when there is an
abnormal accumulation of amyloid beta it leads to hyperphosphorylation of tau. This causes
tau to form twisted pairs of filaments, known as neurofibrillary tangles. The formation of
neurofibrillary or tau tangles initiates in the entorhinal cortex and hippocampus and then
spreads to other regions of the brain. The severity of symptoms associated with Alzheimer’s
disease is more correlated to tau neurofibrillary tangles rather than Neuritic plaques.

NEUROIMAGING FINDINGS OF NPS

The Pattern of brain lesions in Apathy

The Pattern of brain lesions in Depression

The Pattern of brain lesions in Anxiety

The pattern of brain lesions in other NPS of AD

NEUROPSYCHIATRIC SYMPTOMS

Neuropsychiatric symptoms or NPS are groups of symptoms that include changes in mood,
behavior, and thinking. This is common in neurodegenerative diseases like Alzheimer’s
which can cause distress to both the patient and caregivers.
The occurrence of NPS in AD is explained in three ways; Firstly, NPS is an epiphenomenon
of neurodegenerative processes. Secondly, NPS represent biologically different subtypes of
AD. Third, genetic factors become significant after a certain period of degeneration in the
development of NPS.

To develop better therapies for NPS it’s important to acknowledge the neurological
mechanisms associated with NPS. While most studies on the neuropathology of AD have
focused on the cortex, research shows that NPS can have different neurobiological causes.

Clinical Features and factor analysis on AD have shown that NPS and cognitive decline in
AD may originate from different neurobiological systems. In addition to this, neuroimaging
studies have also supported the same idea that there is no strong connection between NPS and
the neurodegenerative mechanism of AD. Although there is no connection between NPS and
cognitive decline, there are some specific types of cognitive impairments that can trigger the
onset or causes of specific NPS.

From the Neurobiological aspect, there is significantly less association between NPS and
cognitive impairment. However, in individuals with normal cognitive NPS like depression,
agitation, and apathy, can act as a predictor of Mild cognitive impairment (MCI) and Mild
behavioral impairment (MBI) which is considered a risky state of dementia.

MECHANISMS LINKING NPS WITH AD

There are four possible mechanisms connecting Neuropsychiatric Symptoms (NPS) to Mild
Cognitive Impairment (MCI) or Dementia of the Alzheimer's type (DAT).

Etiologic Pathway: According to it NPS is seen as a part of a chain of reactions that led to the
development of symptomatic AD. The symptoms themselves reflect an underlying cause that
is associated with the progression of AD and its associated cognitive decline.

Confounding: In this theory, NPS is linked with AD/MCI but not as a direct cause. Instead,
there is a third factor that is responsible for the development of both NPS and AD/MCI. For
example, Brain vascular disease or white matter changes can act as a confounder that is
responsible for both NPS and AD/MCI.

Reverse Causality or Psychological Reaction: Here, cognitive decline is directly associated

with AD and can lead to the manifestation of Neuropsychiatric symptoms. Additionally, NPS
can also be a direct result of the neurodegenerative disease affecting brain areas involved in
behavior, emotion, or perception.

Interaction: This model suggests that there exists synergistic interaction between NPS and a
biological factor that leads to the development of MCI or DAT. For example, research has
shown that individuals with depression have more risk of developing MCI. However, when
depression occurs together with a specific genetic factor called apolipoprotein E ε4 carrier
status, the risk of developing MCI is even higher.

A- Etiologic Pathway Mechanism

B- Confounding Mechanism

C- Reverse Causality Mechanism

D- Interaction Mechanism

TYPES OF NPS; UNDERLYING MECHANISM, CAUSES, AND FACTORS

PSYCHOSIS

Psychosis is a complex behavioral symptom of AD which manifests as hallucinations and

delusions. Delusions in AD are further classified into two types; Persecutory and
Misidentification delusions. Delusions encompass manifestations like phantom border
syndrome, inability to recognize oneself, perception of the caregiver as an imposter, etc.
Whereas, Hallucinations in AD are majorly visual however auditory hallucinations can also
manifest.

The progression of psychosis is a result of multiple brain abnormalities. Dysfunction in the

Anterior cingulate cortex (ACC) and dysfunction in the dorsolateral and medial regions of the
frontal cortex is related to psychosis. Superior temporal pathology is associated with auditory
hallucination. Increased neurofibrillary tangles in the neocortex, disrupted serotonin
signaling, and decreased neuronal density are the main etiology of psychosis. When
considering the genetic factors, the serotonin 2A receptor single-nucleotide polymorphism
(SNP) appears to have a stronger relationship with the occurrence of delusions in AD
psychosis.

AGITATION

Agitation in AD is characterized as dysfunction in verbal, vocal, or motor activities. It can

manifest as aggressive verbal and nonverbal or non-aggressive verbal and nonverbal
behaviors. Agitation in AD patients causes difficulty in handling and managing them.

Studies have found that there exists a correlation between agitation and neurofibrillary
tangles in the orbitofrontal cortex and ACC. Additionally, the frontal region and limbic
system are also implicated in the pathophysiology of agitation in AD.

APATHY

Apathy is a noncognitive symptom of AD that manifests as demotivation or lack of

enthusiasm, and reduced physical activity. It becomes more prevalent when the disease
progresses and can predict the conversion of normal cognitive function to Mild Cognitive
Impairment (MCI) and then to dementia.

Neuroimaging Studies have shown that apathy is associated with dysfunction in prefrontal
cortex, ACC, amygdala, and basal ganglia. Apathy is also linked to abnormalities in
acetylcholine, GABA, and dopamine, and elevated levels of phosphorylated tau in CSF.

DEPRESSION
Depression in AD consists of various emotional symptoms like sadness, crying, anxiety, loss
of interest, etc. It also involves behavioral, cognitive, and somatic symptoms.

The part of the prefrontal cortex involved in depression is part of a larger system called the
default system which includes other brain regions like the cingulate cortex, parahippocampal,
and entorhinal cortex. They are connected to the limbic system and involved in functions
related to mood, emotions, and visceral reactions to emotional stimuli. Dysfunction in this
system is associated with the pathophysiology of depression. Neuroimaging studies have
shown alterations in gray matter volume and blood flow in brain regions that implicates
depression.

ANXIETY

Anxiety is a neuropsychiatric symptom of AD which represents feelings of fear, dread, and

uneasiness. It can manifest as Generalized anxiety disorder (GAD) and is often associated
with other NPS.

The ACC is involved in fear extinction and emotion regulation, acting as a regulatory point
between the prefrontal cortex and amygdala. Structural changes and abnormalities in these
regions may cause the manifestation of anxiety in AD patients. PET studies show decreased
metabolism in regions of the entorhinal cortex, and parahippocampal gyrus which are
correlated with anxiety.

DISINHIBITION, SLEEP, AND EATING DISORDER

Disinhibition means a lack of restraint and disregard for social norms. Reduced volume of
gray matter in the anterior cingulate cortex (ACC) and right middle frontal gyrus has been
associated with disinhibition. Sleep disorders, specifically disturbances in the sleep-wake
cycle are common in AD because the suprachiasmatic nucleus is affected. Although the exact
neuropathology of sleep disorders is not properly understood, disruptions in circadian rhythm
and the glymphatic system have been implicated in the relationship between sleep disorders
and dementia.

Eating disorders in AD manifest as decreased appetite. Brain structures involved in regulating

appetites like the amygdala, hypothalamus, ACC, and insula may be implicated. Atrophy in
these regions may contribute to altered signals related to appetite and weight loss in AD.

DIAGNOSIS

NEUROPSYCHIATRIC INVENTORY (NPI)

NPI is a tool that is used to assess behavioral changes in Alzheimer’s patients. It's a vital
diagnostic tool used for assessing the psychopathology of patients with neurodegenerative as
neuropsychiatric symptoms serve as an indicator of progression from mild cognitive
impairment to dementia. It helps clinicians identify and monitor these symptoms, leading to
better care for patients. When compared with existing instruments NPI exhibits many
advantages; it measures a wide range of NPS, provides a comprehensive understanding of
behavioral changes and at the same time differentiates between behavior severity and
frequency which is vital for assessing interventions.
The NPI has evolved to meet the demand of clinicians, there have been many versions of NPI
like NPI 10, NPI 12, NPI-Q, NPI-NH, and NPI-C. The need for an expert version led to the
NPI-C, and the desire to assess patients in residential settings with professional caregivers
gave rise to the NPI-NH.

IMAGING STUDIES

Imaging studies are important for diagnosing the underlying neuropathology and structural
changes in NPS. MRI and CT scans are very useful for brain atrophy. For example, MRI
scans can help differentiate between Depressive pseudodementia (DPD) by comparing left
hippocampal volume.

Functional MRI (fMRI) and single-photon emission chromatography (SPECT) scans, which
measure cerebral blood flow, may also aid in AD diagnosis. SPECT scans have shown high
accuracy in distinguishing depression from dementia by comparing cerebral perfusion.

PET scans are the most accurate imaging method for AD diagnosis. They can detect changes
in glucose metabolism and amyloid plaques in the brain.

TREATMENT

PHARMACOLOGICAL INTERVENTIONS

Antipsychotic medications have been found effective to manage psychosis and agitation in
Alzheimer’s patients. However, there are a few safety concerns with associated with
psychosis like the risk of cerebrovascular events and falls. Therefore, antipsychotics are not
recommended for routine treatment of NPS (neuropsychiatric symptoms) in AD. However,
they are very effective in cases where immediate treatment of aggression or psychosis is
required.

Antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs), are thought to

alleviate depression in AD patients. However, overall, antidepressants have not shown
significant clinical benefits for NPS in AD. Among the antidepressants studied, citalopram
has the most evidence supporting its use in AD patients.

Acetylcholinesterase inhibitors (AChE-Is) and memantine are medications that exhibit the
potential in managing neuropsychiatric symptoms in AD. One limitation of AChE-Is is that
their use is indicated for patients with mild-to-moderate AD. Memantine, on the other hand,
is more effective in treating severe AD compared to mild and moderate forms of the disease.

NON PHARMACOLOGICAL INTERVENTIONS

Non-pharmacological interventions are an alternative approach to managing neuropsychiatric

symptoms (NPS) in Alzheimer's disease. These therapies offer potential clinical benefits
without the side effects and risks associated with medications.

Cognitive behavioral therapy (CBT) has been found to reduce depression in patients with
early dementia. CBT involves identifying and changing patterns of negative thoughts and
behaviors that contribute to depression, leading to improved emotional well-being.
Reminiscence therapy is a psychotherapy modality specifically helpful for patients with
dementia. It involves discussions about past activities and events, often using aids like
photographs and music to evoke memories. Reminiscence therapy has shown some benefits
in improving mood and cognition.

Music therapy and Aroma-massage therapy are other non-pharmacological interventions that
have been studied for their therapeutic benefits in treating NPS in AD. They have shown
effectiveness in reducing depression and anxiety in AD patients.

The DICE (Describe, Investigate, Create, Evaluate) approach is a framework developed for
the implementation of non-pharmacological interventions. It involves describing the specific
problem behavior, investigating potential causes and contributors, creating a plan to address
the underlying causes, and evaluating the efficacy of the intervention.

While non-pharmacological therapies hold promise for managing NPS in AD, they are often
underutilized. It requires collaboration between caregivers and healthcare providers to
understand the unique needs and behaviors of the individual with AD.

CONCLUSION

In conclusion, understanding the neuropsychiatric perspective of Alzheimer’s disease is

crucial for the comprehensive care and managing the individuals with this condition. The
diverse range of neuropsychiatric symptoms has different neurobiological mechanisms,
causes, and factors. Thus, research in this area is crucial for accurate diagnosis, targeted
treatment, and the development of preventive strategies. The complex interplay between
neurobiological factors and the manifestation of neuropsychiatric symptoms indicates the
need for a person-centered approach that considers the individual's cognitive, emotional, and
social well-being.

The neuropsychiatric perspective in the diagnostic process allows for a more comprehensive
assessment of AD. Moreover, It helps in developing therapeutic strategies and highlights
multidimensional treatment for both cognitive decline and NPS related to AD. Understanding
the neuropsychiatric perspective also enables targeted support for caregivers, empowering
them to manage challenging behaviors and emotional disturbances associated with AD while
maintaining their well-being.

By embracing this perspective, we can provide personalized, holistic care that enhances
overall well-being and improves the quality of life for individuals living with Alzheimer's
disease.