Neurodegenerative
Alzheimer disease
Frontotemporal dementia
Dementia with Lewy bodies
Huntington disease
Corticobasal degeneration
Progressive supranuclear palsy
Multisystem atrophy
Argyrophilic brain disease
Wilson disease
Hallevorden–Spatz disease
Mitochondial diseases
Kuf disease
Metachromatic leukodsytrophy
Adrenoleukodystrophy
Vascular
Vascular dementia
Hypoxic/ischemic injury
Post-CABG
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and Leukoencephalopathy
Inflammatory/infectious
Multiple sclerosis
Syphilis
Lyme
HIV
Creutzfeldt–Jakob disease
Primary CNS vasculitis
Vasculitis secondary to other autoimmune disorders (i.e., lupus)
Sarcoid
Chronic meningitis (i.e., tuberculosis, cryptococcus, etc.)
Viral encephalitis (i.e., HSV)
Whipple disease
Systemic lupus erythematosus
Sjögren syndrome
Metabolic/toxins
Hypothyroid
Vitamin B12
Thiamine deficiency (Wernicke–Korsakoff)
Niacin deficiency (pellagra)
Vitamin E deficiency
Uremia/dialysis dementia
Addison/cushing
Chronic hepatic encephalopathy
Heavy metals
Alcohol
Neoplastic
Tumor (depends on location)
Paraneoplastic limbic encephalitis (anti-Hu)
Acute and chronic sequelae of brain radiation (acute and subacute encephalopathy, radiation necrosis, diffuse late brain injury)
Chemotherapy
Lymphomatoid granulomatosis
Alzheimer’s disease (AD) is the most common degenerative dementia and causes a progressive decline in cognitive and functional status. Episodic memory deficits are the predominant initial complaints in most cases. However, deficits in attention, visuospatial processing, naming/language, and executive functions may be present. Over the course of the illness, non-memory cognitive domains become progressively more involved and patients often deteriorate to the point at which they can no longer perform their activities of daily living, recognize family members, and maintain continence. The main pathologic findings of AD are amyloid plaques (an extracellular accumulation of Aβ[beta]), neurofibrillary tangles (intracellular, paired helical structures composed of hyperphosphorylated tau), synaptic loss, and eventually neuronal death. There is a reduction in the availability of acetylcholine (ACh) from loss of cholinergic neurons, which is associated with memory and other cognitive deficits. Other neurotransmitter systems also are disrupted.
Mild cognitive impairment (MCI) is believed to reflect the transition between normal aging and dementia, often due to AD pathology. Originally, MCI was defined in terms of relatively isolated memory deficits in the setting of preserved general cognitive and functional abilities. More recent formulations have categorized the syndrome into amnestic and non-amnestic subtypes, and specified the number of domains involved (single and multiple-domain). The neuropsychiatric aspects of MCI have only recently begun to receive attention. In studies involving specialty memory clinics, patients have tended to convert from MCI to AD at a rate of 10–15 % per year compared to the 1–2 % conversion of age-matched controls. However, in epidemiological studies, the rates of conversion are lower, and 20–40 % of patients may eventually “revert to normal” on subsequent evaluations. At autopsy, many patients who were diagnosed with amnestic-MCI have had neurofibrillary tangles in the hippocampus and entorhinal cortex, with variable findings of amyloid plaques in the neocortex. These findings are felt to be consistent with the idea that MCI often represents a transitional period to AD.
Behavioral variant frontotemporal dementia (bvFTD) is the most frequent form of the set of syndromes under the general rubric of frontotemporal lobar degeneration. Behavioral variant FTD is the second most common cause of neurodegenerative dementia in the presenile years. Patients with bv-FTD exhibit salient changes in personality and behavior that can range from apathy to disinhibition. Patients are frequently inappropriate and lack both insight and empathy. Tests of frontal executive function often are impaired (with relative sparing of memory storage and visuospatial function), but may not be abnormal when the disease is primarily limited to the medial aspects of frontal lobes, sparing the dorsolateral cortices.
Pathologically, tauopathies and TDP-43 proteinopathies make up approximately 90 % of cases of FTD. Taupathies include Pick’s disease, corticobasal syndrome, and progressive supranuclear palsy. In bvFTD, pathology has an early anatomical predilection for medial frontal regions of the brain, including the frontoinsular and orbitofrontal cortices, which likely accounts for the prominent changes in personality and behavior that can occur early in the disease course. Neurochemically, deficiencies have been found in the serotonin and dopamine systems, with relative sparing of the cholinergic and noradrenergic (NA) systems. It remains unclear if these changes reflect the loss of modulatory projection neurons, or a local reduction in synapses that secrete these transmitters. In situ animal models suggest that it is likely a combination of both mechanisms.
DLB appears to be the second most common form of neurodegenerative dementia in older patients, with Lewy body pathology found in up to 35 % of dementia cases. DLB often presents with fluctuations in cognition, visual hallucinations, and mild extrapyramidal features. The hallucinations tend to be well formed (e.g., animals or people). Cognitive impairments most often involve the realms of executive function, attention, speed of processing, and visuospatial abilities. Memory is disrupted at the level of encoding and retrieval, and tends to be less severe than clinical AD. REM sleep behavior disorder and depression are relatively common. The clinical overlap with Parkinson’s disease associated dementia (PDD) is considerable and differentiating one from the other often is arbitrary. Pathologically, cortical Lewy bodies (spherical, intracytoplasmic, eosinophilic, neuronal inclusions containing α[alpha]-synuclein and ubiquitin proteins) are found in these patients. The temporal cortex and limbic structures are prominently involved. In addition, plaque and tangle pathology often is observed in these patients, with roughly half reaching pathologic criteria for AD. Neurochemically, cholinergic deficits are more pronounced in DLB than AD, which may explain why cholinesterase inhibitors tend to have a greater therapeutic benefit in DLB.
Huntington’s disease (HD) is a fatal neurodegenerative disorder associated with severe BPSD. HD is rare with an estimated prevalence of 4–10/100,000 in Western countries. Symptom onset is early (i.e., 35–45 years) and follows an autosomal dominant pattern of inheritance. Pathologically HD is characterized by an abnormal expansion of CAG repeats in the Huntington’s gene on chromosome four producing a neurotoxic protein. The initial and rapid loss of striatal neurons leads to choreiform movements and severe psychiatric disturbances. As the disease evolves to include the cerebral cortex and other subcortical structures, cognitive impairment may be subtle, typically presenting as a dysexecutive syndrome. Ultimately, multiple cognitive domains are impacted and most patients develop the ‘HD Triad’ of abnormal movements, psychiatric disturbances, and dementia (Walker 2007). Death occurs 15–20 years after symptom onset.
Vascular dementia (VaD) is often cited as the second most common form of dementia, with estimates ranging from 10 % to more than 33 % of all dementia cases. Vascular dementia represents the clinical end-product of vascular injury to the brain from a range of etiologies, including leukoariosis, small-vessel infarcts, multiple cortical strokes, or a single, strategically placed stroke. Multiple lacunar infarcts or significant white matter disease (Binswanger disease) can lead to apathy, frontal network impairment, and corticospinal and bulbar signs. Large-vessel strokes result in syndromes specific to the site of the lesion, such as amnesia, aphasia, agnosia, etc. The coexistence of vascular injury and AD pathology is extremely common (with some reports suggesting occurrence in more than 50 % of cases diagnosed with vascular dementia). Often, such cases are labeled as a “mixed dementia”. Particularly pertinent is the observation that vascular events seem to hasten the onset and increase the severity of clinical AD, which makes it very difficult to accurately estimate the actual prevalence of vascular dementia. Not surprisingly, the risk factors for vascular dementia are believed to be the same as those for stroke, including hypertension, diabetes, high cholesterol, and atherosclerosis.
13.4 Spectrum of Neuropsychiatric Symptoms in Neurodegenerative Diseases
Recently (2012), the International Psychogeriatric Association (IPA) published the ‘The IPA Complete Guide to Behavioral and Psychological Symptoms of Dementia’ for academic and clinical specialists who manage and study BPSD. Aside from defining roles that clinicians play in the management of BPSD, these guidelines highlight the diversity of BPSD and review currently accepted, evidenced-based approaches to treatment. Notwithstanding, there remain several challenges and disagreements currently encountered in the literature regarding the neuropsychiatric and behavioral symptoms seen in dementia. For example, can BPSD be divided into syndromes that cluster as psychosis, agitation, and mood disorders? Should clinicians group together disparate symptoms if patients present with many different ones that have various underlying etiologies? An important issue is that clinicians and nursing home providers often lack formal screening batteries to appropriately identify the symptoms. Regardless of where one stands on these debates, there is clear evidence that BPSD increase the rate of institutionalization, caregiver distress, and the cost of care.
The study of BPSD has been challenging, as researchers have had difficulty accurately quantifying symptoms in trials. Dividing by subtypes of dementia has had limited benefit. For example, research comparing AD and VaD has found that behavioral dysregulation did not differ by subtype of dementia but rather by severity of the disease process. The majority of well-controlled studies on pharmacologic management of BPSD have been conducted on cohorts of AD patients. In some cases (e.g., PDD and DLB) the underlying neurobiology of BPSD is likely quite different from that of AD. Nevertheless, at this point it is most useful to extrapolate from the available data to make evidence-based treatment decisions, regardless of the underlying neurodegenerative process. There are exceptions to this approach, which will be discussed below.
There is frequently dissociation between the quasilinear decline in cognitive function and the expression of BPSD suggesting possible independent pathophysiological mechanisms. Neuropathologic and neuroimaging data suggests that BPSD reflect regional involvement verses diffuse brain pathology. In AD, for example, increased plaque and tangle burden in frontal and limbic areas correlates with psychotic and affective symptoms, while involvement of the anterior cingulate is associated with apathy and depression. As pointed out by Cassanova et al. (Cassanova et al. 2011), the complex interplay of neuropathology with neurochemical, premorbid psychiatric history, environmental, social, and genetic factors will influence the expression of BPSD. Few studies have demonstrated a consistent relationship between the emergence of specific BPSD and the natural course of the disease. However, some trends have been noted. For example, in comparing the onset of BSPD before and after the diagnosis of AD was made, Jost and colleagues (1995) found a progression of symptoms, in which depression, social isolation, anxiety, and suicidal ideation were among the first to arise. Later in the disease, irritability, agitation and aggression, loss of social comportment (e.g., inappropriate sexual behavior), and psychotic phenomena, including hallucinations and delusions, were commonly observed. This trend is evident when comparing BPSD in patients who are treated in outpatient settings with those in patients requiring inpatient hospitalization for behavioral reasons.
Currently, there are no medications approved by the US Food and Drug Administration (FDA) for the treatment of BPSD. The judicious use of high-dose, high-potency neuroleptics and anticonvulsants remains popular among inpatient providers despite these risks, while outpatient providers are more likely to utilize SSRIs, cholinesterase inhibitors, and low-dose, low potency neuroleptics to manage symptoms. Further complicating BPSD management, few accepted standards for non-pharmacological treatments exist. Many practitioners consider the guidelines established by the ‘Expert Consensus Panel for Using Antipsychotic Drugs in Older Patients’ (Alexopoulos et al. 2004), the ‘American Geriatrics Society Guide to Management of Psychotic Disorders and Neuropsychiatric Symptoms of Dementia in Older Adults’ (2011), and the ‘IPA guidelines to BPSD’ (Draper et al. 2012) to be good starting points. Nevertheless, many treatments are initiated on an empirical basis; trial and error is often the rule rather than the exception.
Below, we outline the most common neuropsychiatric symptoms in neurodegenerative diseases that are captured by the Neuropsychiatric Inventory (NPI; (Cummings 1997); Table 13.2). Many symptoms are extremely difficult to target with the currently available psychotropic medications (Table 13.3). For simplicity, we divide the BPSD into symptom clusters that are widely recognized in general neuropsychiatry (e.g., affective, psychotic, vegetative, etc.). Particular emphasis is placed on the underlying neuroanatomy and neurochemistry that correlates with symptoms. More comprehensive reviews focusing on the neurobiology and functional anatomy of BPSD can be found elsewhere (e.g., (Geda et al. 2013)).
Table 13.2
Most common neuropsychiatric symptoms based on informant report using the NPI-Q
Delusions |
Hallucinations |
Agitation |
Depression |
Anxiety |
Euphoria |
Apathy |
Disinhibition |
Irritability |
Aberrant motor behavior |
Sleep disturbance |
Appetite disturbance |
Table 13.3
Behaviors with poor response to drugs
1. Wandering |
2. Pacing |
3. Attempting to leave |
4. Disruptive vocalizations |
5. Incontinence |
6. Failure to bathe |
13.4.1 Affective Symptoms
Loss of neurons in the dorsal raphe nuclei has been implicated in the development of depression in normal aging and AD. These neurons synthesize and release serotonin. They are segregated into multiple paramedian nuclei that project to a myriad of brain regions implicated in mood disorders such as limbic, peri-limbic, and frontal areas of the cerebral cortex. Emerging evidence suggests that there is a ‘normal’ age-related loss of dorsal raphe neurons. This predisposes the elderly to depression. This effect appears more robust in AD patients. PET imaging used to examine metabolic activity of dorsal raphe neurons in AD patients has shown a reliable decrease in activity beyond age-matched controls. Alterations in serotinergic tone have been implicated in several other BPSD that include apathy, agitation and aggression, and sleep changes. Some studies have also reported a decrease in NA in the locus coerulus in depressed patients with AD. Others have found increased NA activity in target areas, e.g., frontal and limbic cortex, perhaps to compensate for dysfunction elsewhere in the nervous system.
Findings such as these are difficult to interpret for a number of reasons. Neuromodulatory projection neurons from the brainstem project diffusely throughout the brain. In all instances, noradrenergic and serotonergic projections ascending to limbic and cortical structures are regionally unique. They employ various postsynaptic mechanisms and target different types of neurons, as well as different ‘compartments’ of those target neurons. The result is a complex, region-specific-effect of serotonin and noradrenalin. For example, noradrenergic transmission in the prefrontal cortex stimulates the release of dopamine, but has no effect on dopamine release in parietal and occipital corticies. Similarly, the effect of serotonin on cortical activity is highly variable, owing to the tremendous diversity of pre- and post-synaptic serotonin receptors. Exactly how this contributes to the BPSD is not known, but certainly impacts the pharmacologic approach used to target specific symptoms.
The superior frontal regions have been anatomically implicated in depression in normal controls and patients with AD and VaD. Several other areas that include the anterior cingulate, parahippocampal gyrus, amygdala, hypothalamus and limbic striatum are likely to be involved as well. The role of interoceptive, humoral, and sensory inputs to limbic circuitry remains unexplored in neurodegenerative diseases.
Depressed mood of varying intensity occurs in 30–40 % of patients with dementia. It is one of the most common BPSD and may develop at any stage of the disease. Depression is co-morbid with AD, DLB, VaD, PDD, and corticobasal syndromes (CBS). Recently, these symptoms have become of greater interest to clinicians and researchers. Depression was found to alter function, often preceding mild cognitive impairment (MCI) and heralding the transition to dementia. Some studies have even supported the association of biomarkers, such as Troponin and S100β (beta), with depression, while others reported that up to 1/3 patients with dementia and BPSD had prominent depressive symptomatology. A high association has been found between depression in dementia and symptoms of irritability, disinhibition, agitation, and anxiety.
Euphoria is medically recognized as a state of exaggerated sense of elation and well-being, most frequently associated with bipolar-spectrum disorders as well as damage to the anterior portions of the right hemisphere. An overexcited and elated mood could be a marker of frontal dysfunction and is often a sign of FTD. The affective disorders of BPSD are generally non-specific and can mimic hypomanic and manic states. Euphoria often precedes memory deterioration in FTD, for example. Once dementia has progressed, the identification of a hypomanic component becomes more difficult, as mental deterioration predominates.
13.4.2 Apathy/Behavioral Inertia
Symptoms of apathy in AD correlate with higher neuronal loss and an increased density of tangles in frontal areas. Similar patterns are seen with the accumulation of Lewy bodies in the same cortical regions. Neurochemically, multiple transmitters have been implicated, including a reduction in cortical NA and decreased dopaminergic and cholinergic signaling. Neuroimaging studies of apathy in Alzheimer’s disease have demonstrated atrophy and hypoperfusion of the anterior cingulate and orbitofrontal cortex.
Apathy is commonly seen in AD, VaD, progressive supranuclear palsy (PSP) and FTD. The term apathy is being used with increasing frequency in both neurology and psychiatry. However, its definition varies. Some consider it a symptom of other major psychiatric disorders, whereas others view it as a syndrome of its own. Apathy is a disorder involving motivation rather than mood, and exists on a continuum between abulia and akinetic mutism. Apathy has been characterized by reduced goal-directed behavior (in domains of cognition, emotional expression, and self-generated, voluntary purposeful behavior). Behaviorally, apathy can be seen as an increase in behavioral inertia. In other words, the neural resources required to engage in a given act are greater than what the individual is volitionally willing to expend.
There is strong evidence that apathy is a common finding in AD. The MMSE and other brief cognitive screens do not measure apathy. Clinically, there can be a co-occurrence of apathy and agitation, or apathy and depression. Several apathy scales (see below) can be administered to either patients or caregivers to ascertain a quantitative measure of apathy. In some studies, apathy is cited as the most common BPSD in AD. For example, a study by Craig and colleagues (2005) enrolled 435 patients with AD and concluded that apathy and indifference were the most frequent symptoms at 76 %, followed by aberrant motor behavior (65 %), appetite changes (64 %), irritability (63 %), and agitation/aggression (58 %). Apathy has been shown to be associated with a decline in ADLs and a predictor of conversion to dementia in MCI patients. Although the current data were obtained from randomized controlled trials (RCTs) that did not investigate apathy, per se, it has been readily noted that apathy/indifference are moderately distressing to caregivers. Treatment with cholinesterase inhibitors and/or psychosocial interventions are the only available modalities for treating apathy in AD that have been shown to have some efficacy. The use of stimulants or ‘stimulating’ SSRIs (e.g., fluoxetine) has become a common practice, but supporting data are limited. Medications will be discussed in more detail in subsequent sections.
13.4.3 Anxiety
The pathophysiologic origins of anxiety are unclear. The disorder frequently co-occurs with depression. In individuals without dementia, a distributed network including the amygdala, medial prefrontal cortex, bed nucleus of the stria terminalis, and more ventral regions of the hippocampus have been implicated in the induction and maintenance of anxious states. There is evidence that modulating serotonergic transmission can affect anxiety. In addition, agents that increase GABAergic tone (e.g., benzodiazepines) can shift the delicate balance of cerebral excitation and inhibition towards the latter, leading to less anxious states. More studies are needed to pinpoint the neurobiology of this common symptom in BPSD and to determine if the underlying neurobiology differs significantly from what is observed in cognitively intact individuals.
Anxiety often occurs in AD, PD, and VaD. However, anxiety is rarely studied alone in medication trials for neurodegenerative diseases. It is usually coupled with depression and together form the ‘affective dyad’ in BPSD. Anxiety is often associated with irritability, aggression, agitation, and pathological crying. Some experts conceptualize anxiety as being on one end of a behavioral spectrum, with aggression at the other, while agitation lies in between the two, representing a transitional state between internal tension and outwardly-directed action. It has been challenging to quantify anxiety as a single variable. Refusal to bathe and attend to self-care have been attributed to anxiety. Repetitive sentences with senseless content also may be a sign of anxiety. However, these symptoms may result from any number of BPSD.
13.4.4 Agitation and Aggressive Behavior
As suggested above, agitation and aggression represent a continuum of behaviors that, in general, are out of proportion to the inciting stimulus (internal or external). Greater agitation in AD correlates with more neurofibrillary tangles in the bilateral orbitofrontal and left anterior cingulate cortices. Chemically, the disruption of serotonin systems appears to be relevant, as symptoms partially respond to SSRIs that are used as a first-line treatment to target aggression, followed by neuroleptics to counter disruption in the dopaminergic system. In studies of non-demented psychiatric patients, lower levels of the serotonin metabolite 5-HIAA in the CSF are the most strongly correlated neurochemical changes seen in aggressive patients.
Agitation is commonly observed in AD and bvFTD. In these diseases, it manifests as restlessness, pacing, fidgeting, increases in directed and non-purposeful motor activities, and abnormal vocalizations such as verbigeration or yelling. It is the most common symptom in AD accompanied by aggression. Aggression is expressed as verbal insults, shouting, hitting, and throwing things. Needless to say, both agitation and aggression necessitate an increase in personal care assistance, and at least at their onset, should prompt a complete metabolic and structural work-up to rule out any acute reversible causes (Table 13.4).
Table 13.4
Behavior as a form of communication about underlying processes: BPSD and common mimickers
1. Review possible physical contributions (i.e., pain and infections) |
2. Rule out delirium |
3. Check for dehydration |
4. Look at the patient’s medication list (for drug-drug interactions and anticholinergic side effects) |
5. Look for contributing environmental factors (noise, change of caregivers etc.) |
6. Consider psychiatric diseases such as depression and anxiety |
7. Sleep difficulties |
8. Consider unwitnessed falls and resulting fracture or hematoma |
Aggression/rage reactions and irritability are complex behaviors that frequently lead to assessment by physicians. Aggressive symptoms can be divided into physically aggressive symptoms, such as hitting, biting, punching, grabbing, and kicking; and verbally aggressive symptoms, such as yelling, cursing, and anger outbursts. Aggression is associated with FTD and the later stages of AD, VaD, and DLB. It can be influenced by environmental and physical factors, such as pain or changes in the environment, to name a few. It was recently demonstrated by a research team in England that systematically treating pain significantly reduced the frequency and intensity of aggressive acts in nursing home patients with moderate to severe dementia. Interestingly, empirical prescribing of analgesics reduced the overall severity of BPSD, suggesting that carefully screening for pain in patients with impaired communication can lead to an improvement in overall behavioral symptomatology.
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