Advanced Dementia: Brain-State Characteristics and Clinical Indicators of Early Mortality

INTRODUCTION

Increased life expectancy exposes elderly people to physical and mental vulnerabilities and diseases and increases the risk of developing dementia. Over five million of North America’s population is currently suffering from dementia, and by 2050, it is expected to reach 13 million. Dementia (e.g., Alzheimer’s and vascular dementia) is now considered the sixth leading cause of death in the United States [1]. Mortality rates in Alzheimer’s disease (AD) increased by 55% from 1999 to 2014. AD is age-dependent; 17% of AD patients are over the age of 75 and a third of all diagnosed patients are 85 and older [1].

The clinical course of dementia is initially characterized by impairment of higher cognitive functions (e.g., verbal memory, planning and initiating actions, selective attention mechanisms, and self-awareness). As the disease progresses, the increased deterioration of cognitive functions might ultimately result in the disappearance of motor and emotional-somatic responses associated with limbic-circuitry neurodegeneration and impairments in the autonomic nervous system [2]. Impairments in everyday functioning are noticeable and consistent with the patient’s decreased level of awareness, which in some cases, could lead to a permanent vegetative-state (VS) or a state of unresponsive wakefulness [3]. The severity of every-day dysfunction initially affects routine household tasks (shopping, cooking, and cleaning), and later interferes with basic personal care (bathing, clothing, walking, sphincter control), which are likely to lead to bed confinement and wheelchair-dependent mobility. The pervasive impairments in the advanced stages of dementia often include skeletal muscle dysfunctions (e.g., excessive muscle tone) leading to difficulties in locomotion and to gait instability, followed by falls and fractures; imposing disability and confinement to bed, and accelerating mortality. Similarly, impaired ability to activate swallowing smooth muscles will cause food and fluid to be aspirated into the lungs causing pathological inflammation and pneumonia. Regrettably, the final stage of advanced dementia (Ad-D) is mainly characterized by immobility, lack of smooth-muscle control (bladder and sphincters dysfunction), lack of communication with the environment, urinary and gait disturbance, spasticity, episodes of fever and infections, and the appearance of pressure ulcers (PU) [4, 5]. Signs of pathological versus non-pathological early cognitive decline is a main concern among many aging researchers developing preventive treatment strategies in aging people at risk for developing dementia; however, clinical detection of the final stages involving terminal accelerated cognitive decline is poor.

Technological advances and their availability in the medical setting extend life by applying compact and user-friendly respirators, dialysis service, enteral feeding (to patients with swallowing and malnutrition problems), and, by providing antibiotics for infectious events, all of which precede the final stage of advanced dementia. The time-course of Ad-D is limited due to increased comorbid medical conditions; however, although this phase represents the final progressive stage preceding mortality, its duration is not necessarily predictable. Advanced dementia is viewed as a progressive functional-cognitive decline stage, measured and defined by the Mini-Mental State Examination (MMSE), Clinical Dementia Rating scale (CDR), and everyday functioning/basic activities of daily living (ADL) scales; however, these measures are not sensitive in detecting early versus late mortality. For instance, Ad-D patients without comorbid complications survive across longer final-stage durations than Ad-D patients with comorbidities such as diabetes with target organs complication and grade IV heart failure. Ad-D patients with comorbid complications are likely to fit an early mortality prognosis. Therefore, systemic and cardiovascular conditions accelerate mortality in these patients as indicated by earlier mortality in vascular dementia versus AD patients [6]. For instance, AD patients’ survival can extend up to 20 years from disease onset or diagnosis [1]. Even at the more progressive stages of Ad-D, life expectancy is often illusive, possibly due to the fact that clinicians have not consistently identified what particular brain-states and quantitative clinical characteristics may indicate Ad-D stage-duration, which can facilitate predictions indicating accelerated mortality; prescribing the expected appropriate palliative care to treat Ad-D patients with accelerated functional decline and co-morbid complications.

There is substantial growth in the absolute number of patients suffering from Ad-D in medical and non-medical settings. Most Ad-D patients are cared for at home and some are treated in nursing homes or skilled-nursing medical departments. Treatment for people suffering from Ad-D is usually provided by a primary care medical team, family physicians, community nurses, home-care nurses, or by hospice medical teams within the community [7]. Ad-D patients suffering from complex medical problems are hospitalized in Nursing and Skilled Nursing settings where treatment is provided by geriatric-medicine physicians and nurses [8].

Thus, the absence of reliable prognostic predictors of survival in dementia patients generates a multitude of ethical dilemmas. In accordance, there is an urgent clinical need for evidence-based decisions in advanced dementia that could directly and positively influence end of life treatment and preparation of family and health care providers toward predetermined mortality. Lacking objective brain-state parameters (e.g., event-related EEG/MEG or functional MRI), as well as their cross-validation with quantitative clinical indications (e.g., disability, level of awareness, malnutrition, PU, co-morbid systemic diseases, and unstable medical condition) currently provides partial prognosis in Ad-D patients, and limits clinicians’ ability to forecast early mortality. Accordingly, these final stages of dementia are characterized by poor quality of terminal-life spanning over months to years and resulting in an untimely/unexpected death.

Therefore, the authors suggest empirically-validated diagnostic and prognostic assessments in Ad-D patients. The current review outlines EEG parameters in conjunction with standard clinical assessments significantly associated with accelerated mortality in Ad-D patients [9]. Importantly, these parameters could aid in predicting early mortality that could lead to changes in treatment decisions and strategies, and ultimately affecting ethical considerations consistent with final-stage clinical-manifestations and levels of suffering in progressive final-stage dementia patients.

BRAIN-STATE PREDICTORS IN DEMENTIA PROGNOSIS

In response to the debilitating clinical conditions observed in Ad-D patients, it would be prudent to propose reliable brain-state parameters (i.e., EEG alpha activity during eyes open versus eyes closed) [10] that were validated in randomized clinical trials examining underlying pathological neural activity in Ad-D patients. In correspondence, the current research review suggests brain-state parameters that were investigated across different aging populations (e.g., vascular dementia versus AD versus healthy controls) and over time (i.e., predicting mortality versus survival). In earlier phases of dementia preceding Ad-D onset, monitoring these EEG parameters could signal the approaching onset of pathological age-related accelerated-deterioration in cognitive and everyday-functioning versus normal cognitive decline in matched healthy controls [11]. Importantly, these brain-state parameters need to be cross-validated with other neuroimaging techniques such as fMRI, PET, and MEG. For prognostic purposes, the authors adopt an empirically-based theoretical perspective that brain-state predictors should be sensitive to neurophysiological changes related to decrements in cognitive functioning (i.e., severe cognitive impairment according to MMSE scores) over time and to changes in levels of awareness [10]. In support of this theoretical premise, a recent EEG study indicated that functional impairment of cortical neural synchronization across AD patients, mild cognitive impairment (MCI) patients, and healthy controls was characterized by progressive impairment of EEG alpha reactivity in resting “open eyes” versus “closed eyes” conditions, which also represent different modes of awareness [10]. These findings suggested that alpha reactivity in “eyes-open” versus “eyes-closed” conditions might predict the deterioration of higher functions in subjects with progressive cognitive decline, as well as predicting accelerated decline from mild to severe dementia (i.e., severe cognitive and functional decline), and thus may be utilized later to predict accelerated disease-progression brain-states (e.g., paroxysmal occipital alpha reactivity) that may signal early mortality in Ad-D patients.

The current review subsection will mainly focus on EEG measures of cognition, mainly because clinical EEG systems are widely available, are inexpensive and directly measure neurophysiological brain-activity (unlike fMRI or PET which provide an indirect measure of neural activity with low temporal resolution) and can be applied in almost any medical and non-medical setting. In parallel, examining auditory event-related potentials (ERPs) that directly record time-locked cortical electrophysiological-responses (via EEG acquisition) associated with excitatory neural mechanisms (such as N-methyl-D-aspartate (NMDA) receptor activity) can denote the severity of dementia and could be applied to monitor disease progression, particularly in AD patients [12]. In relevance to disease progression, it may be informative to monitor frontal theta and alpha spectral-EEG activity. It has been shown that excessive frontal theta power and slower EEG alpha frequencies reflect pathological age-related activity in dementia patients versus aging healthy controls [13, 14]. In regard to pathological cognitive decline detection preceding advanced dementia, verbal memory retrieval deficits are associated with abnormal EEG theta dynamics [15, 16]. Accordingly, detection of abnormal theta and alpha dynamics may be utilized later to predict disease progression in more advanced stages of dementia. One of the earliest studies examining the relationship between EEG parameters and dementia severity in mild-to-advanced dementia stages has indicated that incremental levels of EEG abnormality represent successive stages of increasing intellectual reduction as reflected in progressive organic dementia patients [17]. Although their study was not focused on predicting survival only in Ad-D patients, their findings (in patients with various types and stages of dementia) indicated that severely abnormal EEGs were dominated by delta and theta activity (i.e., paroxysmal relative theta and relative delta power across 16 channels), and these abnormal EEGs were more pronounced in Ad-D patients versus patients in earlier stages of the disease. This implied that paroxysmal theta and delta power may predict clinical outcome in patients across all stages of the disease. In support of this association between changes in EEG and prognosis, their findings revealed a significant relationship between the degree of intellectual defect and level of EEG abnormality. Thus, although EEG predictors of survival in advanced dementia are scarce, these early findings created a preliminary conceptual framework to investigate abnormally dominating -paroxysmal slow-wave EEG parameters during resting brain-state conditions (during eyes-closed versus eyes-open conditions) as predictors of clinical outcome, and particularly forecasting survival-duration in Ad-D patients with debilitating cognitive impairments.

Critically, a subset of prognostic brain-state parameters indicating disease-onset and disease progression in AD and other dementias can be implemented to predict accelerated functional disability and early mortality in Ad-D patients (entering the final-stages or approaching the terminal stage). For instance, particular quantitative EEG (QEEG) markers such as relative theta power during particular cognitive tasks are related to AD severity in patients defined as mild to moderate cognitive impairment in dementia patients displaying MMSE scores between 15 to 26 [18]. Importantly, cognitive-severity MMSE scores in the AD group were significantly associated with an overall QEEG factor explaining 39.3% of MMSE score variability where theta relative power (during eyes closed and during face-encoding tasks) showed the strongest association (versus relative delta, alpha, and beta power). In support of slow-wave EEG abnormalities indicating disease progression in AD patients and contributing to neurodegenerative processes associated with blood-brain barrier (BBB) dysfunction [19], paroxysmal increased-relative theta power was significantly more pronounced in AD patients versus MCI patients and versus healthy controls, and relative alpha power was reduced in AD patients versus MCI patients (open versus close eyes QEEG paradigm, averaged across 19 channels). More so, in the group that displayed higher paroxysmal slow-wave activity (PSWA), 90% were AD patients versus 41% AD patients in the lower-PSWA groups. Their results suggested PSWA level as an indicator of abnormal paroxysmal neural reactivity associated with microvascular pathology. BBB dysfunction has also been suggested as a precursor brain-state that underlies the increased occurrences of PSWA features (i.e., extreme high levels of relative theta 4–6 Hz) as a contributing to neurodegeneration and subclinical seizures in AD. This type of BBB-related abnormal EEG marker in AD patients could signal pathological transformation of activity within cortical networks that may also distinguish chronic AD patients displaying mild-to-severe cognitive impairments [19] from dementia patients with severe cognitive impairments entering the advanced stages of the disease, characterized by early mortality. Although abnormal BBB-related EEG markers were implicated as contributing to disease progression in AD patients with moderate-to-severe cognitive impairments, the authors note that further investigation is required to suggest that these BBB-related EEG parameters predict early mortality in Ad-D patients. In line with earlier finding on EEG abnormalities and their association with dementia progression [20], excessive frontal theta power is associated with progressive decline in higher cognitive functions in elderly dementia patients [14]. Therefore, if excessive frontal EEG theta activity is validated across time and between clinical subgroups (e.g., advanced versus pre-advanced dementia patients) as a reliable predictor of disease progression in Ad-D patients with severe cognitive impairments, it may replace insensitive clinical tests focusing only on the overt behavior and global cognitive deficits, which do not necessarily reflect a particular neurocognitive mechanism associated with “aging brain” pathologies [12, 22].

Dementia patients classified as being at their final progressive-stages are vulnerable to increased neurodegeneration in cortico-limbic structures; therefore, these patients may become unresponsive to external stimuli, leading to a VS or unresponsive-wakefulness diagnosis. This condition implies that they are less likely to process sensory signals effectively (person’s voice, spoken word, and familiar face) in order to communicate with their immediate surroundings and are partially aware or unaware of their current condition. Application of functional EEG assessments (such as extracting their mean global-theta activity following a verbal command, across 32 channels) [9] and auditory ERP testing in these patients can inform clinician and family if they can consciously recognize changes in auditory stimuli, and whether they are later able to comprehend spoken words (such as in motor-command EEG paradigms). On the other hand, if we detect paroxysmal high-amplitude theta activity following verbal command (e.g., “open your eyes”), it could indicate that the unresponsive Ad-D patients are actually at their final terminal-stage, unaware of their environment, and that they have a lower chance of survival in the next 10 months versus other Ad-D patients showing theta activity close to or within the normal range. A subgroup of these Ad-D patients may be in a minimal conscious state and are considered to have higher level of awareness and better prognoses versus Ad-D patients with a VS diagnosis [9].

In relevance to the limitations related to Ad-D diagnosis and prognosis, it is evident that observable changes in cognitive impairment severity dominate the detection of advanced dementia onset and its progression, particularly in the clinical setting. Although this limitation in Ad-D diagnosis obscures clinicians’ ability to predict early mortality in Ad-D patients, the authors suggest that utilizing EEG parameters that are directly related to these progressive cognitive impairments, particularly those that also denote abnormal neurophysiological functioning, may be applied to predict early mortality in Ad-D patients. This hypothesis would need to be examined in large samples of Ad-D patients, over time, and versus dementia patients in earlier phases of the disease.

CLINICAL PREDICTORS IN ADVANCED DEMENTIA PROGNOSIS

In the following section, we outline a medical literature review exploring reliable clinical tools that may be used to assess the severity of dementia and predict short-term survival [23].

Risberg [24] has developed the Functional Assessment Staging (FAST) clinical assessment in AD patients and proposed seven stages of functional and cognitive deterioration associated with the ability to perform basic tasks. Stage one is considered “normal” functioning and stage 7f is denoted as severe pathological functioning. Stage 7c appears in several studies as an “onset-marker” of the advanced-stages in dementia. This functional index was also classified by the American Hospice Association as a criterion for hospice entry including survival-prognosis of less than six months. The 7c stage indicates loss of basic locomotor abilities such as transferring from bed to chair, lack of control over both sphincters (bowl and bladder control), inability to perform basic daily tasks (hygiene, bathing, clothing), and loss of verbal communication skills to a one-word level of communication [24].

Morris [25] developed the CDR scale, which established six categories for clinical assessment of elderly people with or without dementia. Normal level is indicated by a final score of zero and the most severe level generates a score of three; indicating loss of memory and related cognitive deficits such as poor verbal memory retrieval, disorientation, and compromised ability to make judgements or solve problems. Also, this level of severity includes significant functional-capacity impairment, and poor awareness of personal hygiene, which are also highlighted in Risberg’s final functional stages. In accordance with Morris’s CDR assessments, accelerated deterioration in cognition and in functional capacity characterizes the final stages of dementia [25].

Mitchell’s [26] Minimum Data Set Scale (MDS) identified 12 factors that can assign predictive-mortality estimates within six months in patients with advanced dementia in nursing homes. These clinical prognoses rely on factors such as: gender and age (e.g., men 83 years old or older), poor personal care and lack of control over bowel function, being restrained to bed, heart failure, cancer, unstable hemodynamic conditions, low levels of oxygen in blood and shortness of breath, low level of alertness across all daily hours, and malnutrition. Unlike previously mentioned scales (e.g., FAST, CDR, FIM), Mitchell’s MDS involves the evaluation of systemic physiological parameters such as hemodynamic activity and cardiovascular functioning allowing the utilization of objective quantitative clinical markers in predicting prognosis and mortality. These systemic biomarkers may signal the onset of final neurodegenerative stages that could lead to a VS or accelerated mortality.

March’s [27] Alzheimer’s-Hospice Placement Evaluation scale (AHOPE) evaluates 9 factors for indicating a six-month prognosis in patients with advanced dementia that are suitable for hospice care. These factors are scored on a scale of 9–36 from low to high severity of dementia symptomology within the following functional categories: level of awareness, establishing contact with gaze, ability to speak, increased muscle tone, swallowing problems, and weight loss. This clinical assessment is in accordance with other scales that emphasize levels of awareness (e.g., CDR) and basic everyday functions such as immobility, washing, getting dressed, personal hygiene, communication, and feeding (FAST, CDR, MDS). Importantly, it includes a non-verbal communication component (gaze control) related to establishing contact with other people.

Mitchell’s scale [28], also called the Advanced Dementia Prognostic Tool (ADEPT), characterizes 12 subscales for assessing survival in patients with advanced dementia in a nursing-home setting. Main classification associated with debilitating conditions include: demographic (age and gender), malnutrition with weight loss, low oral intake, a body mass index (BMI) below 18.5, bed restraint, ADL score equal 28, bowel incontinence, at least one PU, heart failure, and shortness of breath. Like other AD-d clinical assessment scales, ADEPT also emphasizes nutritional conditions (e.g., MDS, AHOPE), immobility (e.g., FAST, MDS), and cardiovascular and respiratory issues (MDS); however, it sheds light on additional important systemic-related inflammation and impairments in cellular-adhesive skin properties (e.g., PU) associated with AD etiology [2], which can be objectively quantified and are associated with accelerated mortality [28].

Aminoff [29] developed the Mini-Suffering State Examination (MSSE) and determined 10 signs of suffering and discomfort that predict mortality within 6 months in patients with Ad-D. Categories for assessing suffering include restlessness, screaming, pain, PU, malnutrition, eating and swallowing problems, invasive procedures, unstable medical conditions, and level of suffering according to the treating staff and family. Importantly, the MSSE takes into consideration the level of suffering as observed by the health-care teams and the patients’ families, as well as specific behaviors that are correlated with suffering such as restlessness, screaming, and expressed levels of pain [29]. These markers are important as they can contribute to solving ethical dilemmas related to end-of-life treatment decisions to significantly reduce the subjective suffering of demented patients in debilitating conditions. As in ADEPT, PU are also assessed to evaluate the severity of prognoses [28].

Jaul and Calderon-Margalit [3] followed and examined patients with advanced dementia who had reached a VS over a 17-month period. The clinical indices of the study were Rapoport’s Disability Rating Scale (DRS) and Teasdale’s Glasgow Coma Scale (GCS). 38.7% of these VS patients died during the course of the study and the median “final-period” of survival in these VS patients was 127 days. Over 58% of AD-d patients with VS comorbidity suffered from PU. In Jaul and Calderon-Margalit’s investigation [8], a significant correlation was found between the Rapoport and Glasgow assessment scales indicating that they may evaluate common clinical constructs. Most importantly these finding implied that the severity of PU in Ad-D was related to the risk of accelerated mortality.

Cintra et al. [30, 31] found that route-feeding, along with increased manifestation of PU, stroke, sarcopenia and demographic variance were significantly associated with an increased risk of death in less than six months in elderly patients with advanced dementia.

PRESSURE ULCERS AS INDICATORS OF EARLY MORTALITY

PU have been found to significantly predict accelerated mortality in less than six months, particularly in Ad-D patients versus patients with other advanced chronic diseases [32]. In a retrospective study [33] in elderly bedridden immobile patients with PU and other chronic diseases, Ad-D patients (classified at final Ad-D stages, FAST > 6) with severe PU were at higher risk for accelerated mortality compared to Ad-D patients without PU. The difference in PU prevalence between the two groups with dementia and without dementia was statistically significant (76.6% versus 55.3% p = 0.002, OR = 2.65, CI: 1.4278–4.9255). In addition, median survival rate for PU elderly patients with dementia was significantly lower than in PU elderly patients without dementia (63 versus 117 days). Overall, elderly frail dementia patients displayed higher prevalence of PU and lower survival rates. Therefore, PU versus other comorbidities in Ad-D had a significant impact on mortality, implying that severe PU represents the final pathological stage and increased inflammatory burden. In relevance to ongoing pathological clinical conditions, the PU group was at higher risk of displaying more incidences of malnutrition, low BMI, low levels of albumin, and low levels of hemoglobin compared to the group without PU. Importantly, these research findings indicated an association between Ad-D and a higher prevalence of severe PU, and, that the average survival-duration of the PU group was significantly lower compared to those without PU [33]. In another study [34], 99 patients with Ad-D were classified as two subgroups: a PU group versus a group without PU. The notable replication of previous findings [34] was that the median survival-duration of patients in the PU group was significantly lower compared to the group without PU (96 days versus 863 days). The relative risk of mortality (Adjusting Hazard Ratio) in patients with advanced dementia and PU was 3.86. The conclusion following these replicated findings in Ad-D patients with PU [33, 34] was that patients suffering from advanced dementia and PU have significantly lower survival than non-PU patients with Ad-D, and fit the definition of terminal condition (e.g., mean survival of 96 days), which may require hospice-treatment support. In comparison, patients suffering from advanced dementia without PU that display normal levels of protein and hemoglobin should continue to be treated as chronic non-terminal Ad-D patients.

In search of common pathophysiological mechanisms underlying advanced dementia progression (such as AD) and the appearance of PU, a number of common mechanisms have been raised in several biological systems in humans. Based on recent findings indicating a common physiological mechanism that participates in the generation of PU and is associated with neurodegenerative mechanisms in the brain, it was suggested that specific peripheral AD-related biomarkers and the appearance of PU were interrelated [2]. Accordingly, excessive skin-fibroblast aggregation in people suffering from AD facilitates increased skin vulnerability, inducing high frequency of PU incidence [35].

In Ad-D terminal stages, abnormal motor cortex activity, various damaged areas in the brainstem, and overexcited motor neurons (that increase the tone and stiffness of the striated/skeletal muscles) that increase pressure on areas of the body prone to develop PU (elbows, knees, ankles, and feet) can cause significant impairments in basic motor functions. These impairments include abnormal smooth/striated muscle activity (e.g., difficulty in swallowing, which complicates the patients’ breathing causing aspirations and severe pneumonia), aspirations and inflammation, leading to a decrease in the consumption of calories and proteins, and resulting in an increase in the metabolic demand followed by a state of malnutrition.

In conjunction to motor function impairments, compromised or damaged somatosensory neural networks that impair the reception of pain signals from the periphery and the skin layers, may exacerbate PU development. Injury to the autonomic nervous system disrupting heart rate and pulse rhythms also may cause fainting, gait instability and falls (resulting in fractures), immobility, development of PU, and accelerated mortality [36]. The advanced stages of dementia are associated with excessive excitability of the sympathetic system that causes narrowing of blood vessels in the periphery and lack of blood supply in the skin level, a condition that leads to ischemia in the skin layer and the development of wounds. The sympathetic response creates a chain-reaction of increased renin, angiotensin, increased reactive oxidative stress (ROS), and increased levels of endothelin that increase the probability for vascular injury and stenosis. Cognitive impairment due to abnormal synaptic activity in different brain networks (i.e., excessive glutamatergic activity) can lead to unstable mood and psychomotor restlessness (many times resulting in friction and damage to the skin specifically within epithelium). Medication use and the side effects of antipsychotic drugs may cause drowsiness and an increase in muscle tone that further increases pressure on the skin layer and the appearance of PU.

ADVANCED DEMENTIA AND MORTALITY

The increased prevalence of Ad-D raises the clinical unmet healthcare need to find objective and quantitative, portable (e.g., patients’ bedside) and non-invasive measures that predict increased risk for early mortality. Ad-D patients are characterized by severe disability, eating problems, febrile episodes, pneumonia, PU, low mental and physical functioning, all representing risk factors for early mortality in Ad-D patients [3, 37]. Previous co-morbid systemic diseases in addition to dementia lead to accelerated mortality (cancer, congestive heart disease, diabetes, and stroke) [27, 30]. Concomitant geriatric conditions resulting from dementia clinical complications such as deep and diffuse PU, low levels of albumin, low hemoglobin, and low BMI increase the incidence of infections and inflammatory burden leading to cardiovascular and respiratory complications resulting in accelerated mortality [33, 38]. In contrast, the course of “wound-free” dementia (and normal level of albumin, hemoglobin, and body index level), is associated with better clinical outcome and longer survival.

There is a need to understand the physiology of the central and peripheral nervous systems in aging elderly people versus demented elderly people in different stages of disease-progression and to assess the relationship between the activity of these systems and age-related phenotypical pathologies, ultimately assisting to clinically decipher what type of activity predicts abnormal terminal conditions in Ad-D. The burden of complications resulting from dementia, comorbidities, and functional decline ultimately causes earlier mortality. Overall, accelerated mortality in Ad-D conditions is predictable if the medical staff takes into account clinical, behavioral, biological, and neurophysiological risk factors related to the progression of dementia, as highlighted in the current paper.

CONCLUSION

In sum, we suggest cross-validating these clinical indicators with objective brain-state or systemic-physiological parameters (e.g., changes frontal theta power or occipital alpha power, changes in albumin levels, PU onset and severity) to evaluate the risk for accelerated mortality in Ad-D patients. Importantly we propose that dementia care takers utilize specific objectively-derived classifications to assess the risk for entering the terminal Ad-D stages, which include: accelerated deterioration in cognition and functional capacity (related to alpha and theta activity), abnormal systemic physiological parameters (O₂ saturation-levels, inflammation burden, and protein levels), cardiovascular and respiratory issues (ECG and respiratory monitoring), nutritional conditions, decreased levels of awareness (EEG reactivity after verbal command), increased levels of suffering (phenotypical exemplars of screaming or restlessness behaviors), immobility, and the onset of PU along with their level of severity (directly observed and qualified).

Although there are several reliable clinical and behavioral parameters that can predict accelerated mortality in Ad-D individuals, the authors propose focusing mainly on two risk-factors for predicting accelerated mortality in terminal-stage patients with advanced dementia: PU and EEG brain-state parameters of awareness [9, 33]. These objective quantitative parameters are not dependent on the patient’s voluntary attention, or on clinicians’ interpretation or availability, and can be assessed routinely by the bedside. There are additional reliable factors that are likely to accelerate functional decline and mortality in Ad-D patients: demographic and clinical factors, decreased personal care, bed restraint, lack of control over the sphincters, low nutritional levels, swallowing problems, and unstable medical conditions, all of which can be quantified objectively to predict accelerated mortality in aging people with dementia.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/20-1563r2)