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Supervisors
Professor Kaisu Pitkälä, M.D., Ph.D.
University of Helsinki, Department of General Practice and Primary Health Care Helsinki, Finland
Docent Marja-Liisa Laakkonen, M.D., Ph.D.
University of Helsinki, Department of General Practice and Primary Health Care, Helsinki, Finland
Reviewers
Professor Anne Remes, M.D., Ph.D.
University of Oulu, Department of Neurology Oulu, Finland
Docent Pirkko Jäntti, M.D., Ph.D.
University of Tampere, Department of Medicine Tampere, Finland
Opponent
Docent Antero Leppävuori, M.D., Ph.D.
University of Helsinki, Department of Psychiatry Helsinki, Finland
Cover
Hugo Simberg: ”Towards the evening”, 1913 With permission of The Finnish National Gallery
ISBN 978-951-51-3847-7 (paperback) ISBN 978-951-51-3848-4 (PDF) http://ethesis.helsinki.fi
To my family
”Old age is a beautiful crown,
which is found only from the paths of wisdom, moderation, justice, and love”
modified from J. G. Von Herder
Contents
__________________________________________________________________________________________
List of abbreviations 7
List of original publications 9
Abstract 10
Tiivistelmä 12
1. Introduction 14 2. Review of the literature 16 2.1. Dementia 16 2.1.1. Epidemiology 17
2.1.2. Diagnostic criteria 17
2.1.2.1. Subtypes of dementia and their neuropsychiatric profiles 19 2.1.2.2. Diagnostic procedures of dementia 25 2.1.3. Neuropsychiatric symptoms (NPSs) of dementia 25 2.1.3.1. Evaluation of NPSs 27 2.1.3.2. Models for predisposing and precipitating factors of NPSs 29
2.1.3.3. Approaches for management of NPSs 30 2.1.3.4. Apathy 32 2.1.3.5. Psychotic symptoms 39
2.2. Delirium 45 2.2.1. Epidemiology of delirium 45
2.2.1.1. Delirium in general hospital settings 45 2.2.1.2. Delirium in nursing homes 46
2.2.2. Diagnostic criteria of delirium 46
2.2.2.1. Detection of delirium 48
2.2.2.2. Motor subtypes of delirium 49
2.2.3. NPSs in delirium 51 2.2.4. Predisposing and precipitating factors of delirium 52
2.2.5. Prevention of delirium 55
2.2.6. Treatment of delirium 55
2.2.7. Outcome of delirium 56
2.2.8. Experience and recall of delirium 57
2.3. Overlapping of NPSs in dementia and delirium 57
2.4. Stress responses in dementia, delirium, and NPSs 59
2.5. Summary of the literature 61
3. Aims of the study 62
4. Methods 63
4.1. Participants 63
4.2. Assessment methods 65
4.3. Ethical considerations 67
4.4. Statistical methods 68
5. Results 69
5.1. Acute delirium and NPSs among patients with dementia (Articles I and II) 69
5.2. Apathy in frail older patients (Article III) 74
5.3. Triggers of delirium (Article IV) 76
6. Discussion 78
6.1. Acute delirium and NPSs among patients with dementia 78
6.2. Psychotic symptoms in dementia 80
6.3. Apathy 82
6.4. Triggers of delirium among those with and without dementia 84 6.5. Differences and similarities in NPSs in dementia and delirium 85
6.6. Strengths and limitations of the study 88
7. Conclusions 90
8. Implications for clinical work and future studies 91
9. Acknowledgments 92
10. References 94
11. Appendices 119
12. Original publications 139
7 LIST OF ABBREVIATIONS
AD ADL ADNI AGS ANS APA ARD BPSD BvFTD CAM CDR CMAI CSF DIS DLB DMC DMS DMSS DPS DSD DSM III DSM IIIR DSM IV DSM-5 FTLD GAR GDB IADL ICD-10 LHPA-AXIS MBI
MCI MDAS MID MMSE NCD NPI NPI-C
Alzheimer`s disease Activities of daily living
Alzheimer’s Disease Neuroimaging Initiative American Geriatrics Society
Autonomic nervous system American Psychiatric Association Alcohol-related dementia
Behavioral and psychological symptoms of dementia Behavioral variant frontotemporal dementia
Confusion Assessment Method Clinical Dementia Rating
Cohen-Mansfield Agitation Inventory Cerebrospinal fluid
Delirium Intervention Study Dementia with Lewy bodies Delirium Motor Checklist
Delusional misidentification syndrome Delirium Motor Subtype Scale Delirium Phenomenology Study Delirium superimposed on dementia
Diagnostic and Statistical Manual of Mental Disorders, third edition Diagnostic and Statistical Manual of Mental Disorders, third edition revised Diagnostic and Statistical Manual of Mental Disorders, fourth edition Diagnostic and Statistical Manual of Mental Disorders, fifth edition Frontotemporal lobar degeneration
Global Attentiveness Rating Goal-directed behavior
Instrumental activities of daily living
International Classification of Diseases, tenth edition Limbic-hypothalamic-pituitary-adrenal axis
Mild behavioral impairment Mild cognitive impairment
Memorial Delirium Assessment Scale Multi-infarct dementia
Mini-Mental State Examination Neurocognitive disorder Neuropsychiatric Inventory
Neuropsychiatric Inventory, clinical/clinician version
8 NPI-NH
NPI-Q NPS PDD PET PFC RCT REM SSRI VAD WKS
Neuropsychiatric Inventory, nursing home version
Neuropsychiatric Inventory questionnaire, short clinical version Neuropsychiatric symptom/syndrome
Parkinson´s disease dementia Positron emission tomography Prefrontal cortex
Randomized controlled trial Rapid eye movement
Serotonin selective reuptake inhibitor Vascular dementia
Wernicke-Korsakoff syndrome
9 LIST OF ORIGINAL PUBLICATIONS
This thesis is based on the following original publications, referred to in the text by their Roman numerals:
I. Hölttä E, Laakkonen M-L, Laurila JV, Strandberg TS, Tilvis RS, Kautiainen H, Pitkälä KH. The overlap of delirium with neuropsychiatric symptoms among patients with dementia. Am J Geriatr Psychiatry 2011;19:1034-1041.
II. Hölttä EH, Laakkonen M-L, Laurila JV, Strandberg TS, Tilvis RS, Pitkälä KH.
Psychotic symptoms of dementia, their relationship with delirium and prognostic value. Eur Geriatr Med 2015;6:257-261.
III. Hölttä EH, Laakkonen M-L, Laurila JV, Strandberg TS, Tilvis RS, Pitkälä KH.
Apathy – prevalence, associated factors and prognostic value among frail older in-patients. J Am Med Dir Assoc 2012;13:541-545.
IV. Hölttä EH, Laurila JV, Laakkonen M-L, Strandberg TS, Tilvis RS, Pitkälä KH.
Precipitating factors of delirium: Stress response to multiple triggers among patients with and without dementia. Exp Gerontol 2014;59:42-46.
These articles have been reprinted with the permission of their copyright holders.
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Abstract
Background: Dementia with neuropsychiatric symptoms (NPSs) and delirium are the two most important and challenging neurocognitive disorders among frail, older, multimorbid patients. Both disorders manifest with cognitive decline and multiple NPSs. Psychotic symptoms co-occur with these syndromes. Apathy is common in dementia, whereas hypoactive form resembling apathy is the most common form in delirium.
Dementia patients are prone to delirium, and a large proportion of patients with delirium develops dementia in a few years. However, little is known about how these syndromes – dementia with NPSs and delirium – co-occur and overlap in their symptoms, and patients with and without dementia differ in delirium with respect to precipitating factors and symptom profile.
Objectives: The aim of the study in this thesis was to investigate NPSs in dementia and delirium, their overlap, co-occurrence, and prognostic value in these syndromes. The stress- related triggers of delirium were compared among patients with and without dementia.
Methods: Of all 425 participants in the Delirium Phenomenology Study (DPS), 60% (N=255) had dementia, and 25% (N=106) suffered from delirium. All 425 patients in the DPS were included in substudy three (Article III), whereas only those with dementia (N=255) were included in the first and second substudies (Articles I and II). The fourth substudy (Article IV) (N=193) included a combined data of all 106 patients suffering from delirium in the DPS and participants of an intervention arm of the Delirium Intervention Study (DIS) (N=87).
These studies consisted of thorough geriatric assessments, observations of behavior, interviews of patients and caregivers, and tests of cognitive functioning and attention. NPSs were evaluated with questionnaire items with yes/no answers in line with those of the Neuropsychiatric Inventory (NPI). Precipitating factors of delirium were analyzed thoroughly.
Data on hospital days, institutionalizations, and mortality were retrieved from central registers.
Results: Of patients with dementia (N=255), 66 suffered from delirium and 127 from multiple NPSs without delirium. There were 56 delirious patients with multiple NPSs. Thus, dementia patients with multiple NPSs and those with concurrent delirium were highly overlapping.
Delirium superimposed on dementia co-occurred with psychotic symptoms in half of the cases. Psychotic symptoms in dementia patients occurred among those both with and without delirium, delusional symptoms being the most common. Misidentifications occurred among patients with dementia also without other psychotic symptoms. Patients with delirium showed poor outcome relative to those with multiple NPSs without delirium or those with neither multiple NPSs nor delirium.
Of the whole sample of 425 patients, 23% suffered from apathy. Apathy was associated with male gender, severe dementia, delirium, and disability. Apathy was an independent predictor
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of mortality in a Cox proportional hazard model adjusted for age, gender, dementia, and delirium (HR 1.71, 95% CI 1.13-2.61).
Of the 193 patients suffering from delirium, most had multiple triggers behind the delirium.
However, patients with dementia needed less triggers to develop delirium. Infections, metabolic conditions, trauma, and surgery were more common among patients without dementia than among those with dementia, whereas patients with dementia suffered more often from substance abuse (medication or alcohol). The groups with and without dementia did not differ with respect to mortality. Hypoactive delirium was the most common motor type of delirium in patients with and without dementia.
Conclusions: When managing complex NPSs among patients with dementia, it is important to exclude possible delirium underlying the symptoms because delirium, by definition, has a causative agent, which may be amenable to intervention. The guidelines for interventions for NPSs and delirium differ, and management may have an impact on patient’s prognosis.
Psychotic symptoms are common in both hyperactive delirium and dementia, and thus, cannot be used to distinguish between these syndromes. Apathy is common among older inpatients and predicts poor prognosis. Because apathy may mask hypoactive delirium, silent delirium warrants special attention in clinical work. In old age, multiple stress triggers are associated with delirium and the NPSs in dementia. Predisposing and precipitating factors underlying these neurocognitive disorders should be evaluated thoroughly.
Tiivistelmä
Taustaa: Muistisairaus neuropsykiatrisin oirein ja iäkkään akuutti sekavuusoireyhtymä (delirium) ovat tärkeimmät ja haasteellisimmat neurokognitiiviset sairaustilat haurailla, monisairailla ikäihmisillä. Molempiin liittyy kognitiivisen tason lasku ja moninaisia neuropsykiatrisia oireita. Kummassakin oireyhtymässä esiintyy psykoosioireita. Apatia on yleinen muistisairauksissa kun taas akuutissa deliriumtilassa apatiaa muistuttava hypomotorinen alatyyppi on yleisin. Muistisairaat potilaat ovat alttiita akuutille deliriumtilalle ja suuri osa deliriumtilaan sairastuneista sairastuu dementiatasoiseen muistisairauteen muutamien vuosien kuluessa. Kuitenkin tiedetään kovin vähän siitä miten nämä sairaustilat – muistisairauden neuropsykiatriset oireet ja akuutti deliriumtila ilmenevät samanaikaisesti ja miten niiden oireet menevät päällekkäin, ja kuinka muistisairaat ja ei muistisairaat eroavat deliriumin laukaisevien tekijöiden ja oireprofiilin osalta.
Tutkimuksen tavoitteet: Tämän tutkimuksen tavoitteena oli selvittää neuropsykiatrisia oireita sekä akuuttiin deliriumtilaan sairastuneilla että muistisairailla, tutkimuksessa tarkasteltiin niiden päällekkäisyyksiä, samanaikaisuutta sekä vaikutusta ennusteeseen. Stressiin liittyviä, deliriumia laukaisevia tekijöitä vertailtiin sekä muistisairailla että ei-muistisairailla.
Metodit: Kaikista Delirium Phenomenology Study (DPS)-tutkimukseen (N=425) osallistuneista 60%:lla (N=255) oli dementiatasoinen muistisairaus ja 25% (N=106) sairasti akuuttia deliriumtilaa. Kaikki 425 DPS-tutkimuksessa mukana ollutta osallistui kolmanteen osatutkimukseen (Artikkeli III). Kun taas vain ne, jotka sairastivat dementiatasoista muistisairautta (N=255) olivat mukana ensimmäisessä ja toisessa osatutkimuksessa (Artikkelit I ja II). Neljäs osatutkimus (Artikkeli IV) sisälsi yhdistetyn aineiston DPS- tutkimuksen akuuttia deliriumtilaa sairastaneista potilaista (N=106) sekä Delrium interventiotutkimuksen (DIS) interventioryhmän kaikista deliriumpotilaista (N=87).
Tutkimukset sisälsivät kokonaisvaltaisen geriatrisen arvioinnin, käytöksen havainnoinnin, potilaiden ja hoitavien henkilöiden haastattelun sekä kognitiivisen toimintakyvyn ja tarkkaavaisuuden testit. Neuropsykiatriset oireet seulottiin tutkimusta varten laaditulla kyselykaavakkeella kyllä/ei- vastauksin Neuropsychiatric inventory (NPI) mittarin mukaisesti.
Akuutin deliriumtilan laukaisevat tekijät selvitettiin perusteellisesti. Rekistereistä kerättiin toteutuneet sairaalahoitojaksot, laitoshoitoon sijoitukset ja kuolleisuustiedot.
Tulokset: Tutkimuksessa mukanaolleista muistisairaista (n=255), 66 sairasti deliriumtilaa, 127:llä muistisairaalla oli useita neuropsykiatrisia oireita ilman deliriumtilaa. Delirium- potilaista 56:lla oli useita neuropsykiatrisia oireita. Muistisairailla joilla oli paljon neuropsykiatrisia oireita ja niillä, jotka kärsivät deliriumtilasta oli siis paljon päällekkäisyyttä.
Muistisairailla akuutti deliriumtila esiintyi yhtäaikaa psykoottisten oireiden kanssa puolessa tapauksista. Psykoosioireita esiintyi sekä akuutissa deliriumtilassa että pelkästään
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muistisairailla ja deluusio-oireet olivat muistisairaiden yleisimpiä psykoosioireita.
Väärintulkintaoireita esiintyi muistisairailla myös ilman varsinaisia psykoosioireita.
Akuutissa deliriumtilassa ennuste oli huono verrattuna niihin, joilla oli pelkästään useita neuropsykiatrisia oireita tai niihin joilla ei ollut kumpiakaan.
Kaikista 425 potilaasta, 23% kärsi apatiasta. Apatia oli yhteydessä miessukupuoleen, vaikeaan muistisairauteen, akuuttiin deliriumtilaan ja toiminnanvajeisiin. Apatia oli itsenäinen kuolemanvaaraa ennustava tekijä Coxin mallissa, joka oli vakioitu iällä, sukupuolella, muistisairaudella ja akuutilla sekavuustilalla (HR 1.71, 95% CI 1.13-2.61).
Niistä 193 potilaasta, jotka kärsivät akuutista deliriumtilasta, useimmilla oli taustalla monta laukaisevaa tekijää. Kuitenkin muistisairailla oli vähemmän laukaisevia tekijöitä deliriumin taustalla. Tulehdukset, aineenvaihdunnalliset häiriöt, traumat ja postoperatiivinen tila olivat yleisempiä ei-muistisairailla, kun taas muistisairailla päihteiden (alkoholi tai rauhoittavat lääkkeet) käyttö nousi useammin esiin laukaisevina tekijöinä. Ryhmät eivät eronneet toisistaan kuolleisuuden suhteen. Hypomotorinen muoto oli kummassakin ryhmässä tavallisin deliriumin motorinen alatyyppi.
Johtopäätökset: Hoidettaessa monimuotoisia ja vaikeita neuropsykiatrisia oireita muistisairailla on tärkeää poissulkea mahdollinen akuutti deliriumtila näiden oireiden taustalta, koska yleensä akuuttiin deliriumtilaan liittyy laukaiseva tekijä, jolla voi olla suotuisa vaste hoitointerventiolle. Muistisairauksien neuropsykiatristen oireiden ja deliriumtilan hoito-ohjeet eroavat toisistaan ja hoidolla voi olla merkittävä vaikutus potilaan ennusteeseen.
Psykoosioireet ovat yleisiä hyperaktiivisessa deliriumtilassa ja muistisairauksissa, ne eivät kuitenkaan tue näiden oireyhtymien erotusdiagnostiikkaa. Apatia on yleinen iäkkäillä sairaalapotilailla ja se on huonon ennusteen merkki. Hypomotorinen eli hiljainen deliriumtila vaatii erityishuomiota, koska se voi kätkeytyä apatiaoireen taakse ja voi jäädä huomiotta.
Iäkkään muistisairaan akuutin deliriumtilan ja muistisairauteen liittyvien neuropsykiatristen ja käytösoireiden taustalta löytyy useita laukaisevia tekijöitä. Altistavat ja laukaisevat tekijät akuutin deliriumtilan ja muistisairauden neuropsykiatristen oireiden taustalta on tärkeää selvittää huolellisesti.
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1. Introduction
Acute symptomatic mental disorder was recognized by Hippocrates and his peers already 2500 years ago (Hogg 2013). This syndrome had such features as fever, cognitive and behavioral disturbances, and disruption of sleep, which improved when the fever diminished.
Hippocrates made a distinction between this acute syndrome (delirium) and mental illness of unknown cause (later called dementia) (Hogg 2013).
The term “dementia” was first used in the English language medical literature in the mid- 1800s. Dementia referred to a form of “incoherence” involving impairments in memory, reasoning, and other cognitive abilities (Whitehouse and George 2008, Thomas and Dening 2013). Alois Alzheimer described the first “Alzheimer´s disease” patient, Auguste Deter, in 1906. She was a 51-year-old woman with a 5-year history of progressive cognitive impairment and psychiatric symptoms such as hallucinations, delusions, severely impaired social functioning, sleep disturbances, and nightly screaming (Ferri et al. 2005, Whitehouse and George 2008, Cipriani et al. 2011). As the population ages in developed countries, the scientific interest in neurocognitive disorders, especially dementia, has grown substantially (Whitehouse and George 2008, Thomas and Dening 2013). Despite active research in the field, the understanding of the pathology, etiology, symptoms, and management of various forms of dementia remains limited (Whitehouse and George 2008, Alzheimer’s Association 2016).
The definition for behavioral symptoms of dementia was first presented in the 1980s when agitation was described (Cohen-Mansfield and Billig 1986). Shortly thereafter, the complex behavioral disturbances related to dementia were recognized, and the term “Behavioral and Psychological Symptoms of Dementia (BPSD)” was defined as “signs and symptoms of disturbed perception, thought content, mood, or behavior that frequently occur in patients with dementia” (Finkel et al. 1996). The Neuropsychiatric Inventory (NPI) was developed to assess these symptoms in 1994 (Cummings et al. 1994). The stigmatizing term “dementia”
was replaced in the diagnostic criteria of the DSM-5 (APA 2013) with “major or minor neurocognitive disorder” (APA 2013, Thomas and Dening 2013). As understanding of the structural and neurobiological disturbances of brain related to dementia advanced, the term BPSD was also replaced by (noncognitive) neuropsychiatric symptoms (NPSs) and a variety of behavioral symptoms (Jeste and Finkel 2000, Vilalta-Franch et al. 2010, Lyketsos et al.
2011, Kales et al. 2015).
NPSs in dementia implicate the need to assess them and develop new treatments. However, the multimodality of these symptoms, symptom clusters, and syndromes, such as apathy and psychosis, has hampered clinical studies (Jost and Grossberg 1996, Jeste and Finkel 2000, Cohen-Mansfield 2001a, Ishii et al. 2009, Nowrangi et al. 2015). Conflicting support has emerged for their pharmacological and nonpharmacological treatments (Nowrangi et al. 2015).
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The diagnostic criteria of delirium have changed several times over the years after its initial appearance in the DSM-III (APA 1980). However, the core features, i.e. disturbances of attention and cognition, have remained in the criteria. In addition, all DSM criteria have emphasized the underlying causative factor (medical condition, toxin, or medication).
Although NPSs have not been presented as core features in all diagnostic criteria, they are prevalent in delirium (Pitkälä and Laurila 2007, Blazer and von Nieuwenhuizen 2012, Inouye et al. 2014). These patients typically present with symptoms of hallucinations, agitation, and apathy (Pitkälä and Laurila 2007, Miyoshi and Morimura 2010, Inouye et al. 2014). Delirium is very prevalent among multimorbid, geriatric patients and associated with poor prognosis. A large proportion of frail, older, delirious patients may develop dementia within a few years, be admitted to institutional care, or become deceased (Laurila 2004). There is evidence for preventive strategies for delirium, but the efficacy of its management remains obscure (Young et al. 2010, O`Mahony et al. 2011). Guidelines suggest pharmacological treatment for such delirium symptoms as agitation, psychotic symptoms, or emotional disturbances/symptoms (Inouye 2006, Young et al. 2010, O`Mahony et al. 2011). However, trials exploring the efficacy of antipsychotics in management of delirium may lack external validity (Schrijver et al. 2016).
In summary, NPSs are prevalent in both dementia and delirium, and they also share common features. Patients with dementia are known to be prone to delirium during acute illnesses (AGS/NIA 2015). To date, the research lines of dementia and delirium have remained separate, and limited data of the overlap of these syndromes exist. This study investigates the common NPSs in dementia and delirium, their co-occurrence and overlap, and their prognostic value in these syndromes.
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2. Review of the literature
2.1. Dementia
Dementia is a chronic, progressive neurocognitive disorder (NCD) associated with neuro- pathological and neurochemical changes in the brain (APA 2013). It is a syndrome with various symptoms and signs involving higher cognitive functions (e.g. learning and memory, orientation, comprehension, language, executive function, judgment, and attention), activities of daily living, and emotional and social behaviors (Hughes 2011, APA 2013).
Dementia is an umbrella term used to describe various progressive etiological subtypes, the most common of which is Alzheimer’s disease (AD) (Figure 1) (Hughes 2011, APA 2013).
Figure 1. Neurocognitive disorders and dementia according to the DSM-5 classification by the American Psychiatric Association (APA 2013).
AD=Alzheimer’s disease, ARD=Alcohol-related dementia, BvFTD=Behavioral variant frontotemporal dementia, DLB=
Dementia with Lewy bodies, FTLD= Frontotemporal lobar degeneration, MCI= Mild cognitive impairment, PDD= Parkinson’s disease dementia, PPA= Primary progressive aphasia, VAD= Vascular dementia.
* e.g., Creutzfeld-Jakob disease, human immunodeficiency virus (HIV)-related dementia, traumatic brain injury, Huntington’s disease, and substance- (other than alcohol) or medication-induced neurocognitive disorder.
Neurocogni ve Disorder (NCD)
Minor Neurocogni ve Disorder
Major Neurocogni ve Disorder
DEMENTIA
”Memory disease”
AD VAD
DLB MCI
FTLD PDD ARD
PPA BvFTD DELIRIUM
Other*
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2.1.1. Epidemiology
Dementia is a disease of the elderly. Age-standardized prevalence in those 60+ varies between 5% and 7% worldwide (Prince et al. 2013). Because the population is aging, the number of people living with dementia worldwide is expected to double every 20 years (Ferri et al. 2005). The estimated number of people with dementia in 2010 was 35.6 million. The figures for the years 2030 and 2050 are estimated to be 66 million, and 115 million, respectively (Prince et al. 2013).
Alzheimer Europe (2013) estimated the number of people with dementia in Finland in 2012 at about 92 000. This represents 1.71% of the total population. In Finland, the number of people with dementia as a percentage of the population is somewhat higher than the EU average of 1.55% (Alzheimer Europe 2013). Among people aged 65 years and over, 5-9% suffer from dementia (Viramo and Sulkava 2015). The prevalence depends on definition of dementia and whether mild cases are included. It is also dependent on the population studied and the screening instrument.
In Finland some twenty years ago, 200 000 people were estimated to suffer from mild cognitive impairment (MCI) (Lobo et al. 2000), in which the cognitive deficits do not yet interfere with capacity for independence in everyday life (APA 2013). Approximately 32- 42% of people with MCI will develop AD (Ward et al. 2013, Alzheimer’s Association 2016) and 15% other forms of dementia. Thus, MCI cases, including those who revert to normal cognition during follow-up, have a high risk of progressing to dementia, suggesting that a diagnosis of MCI at any time has prognostic value (Roberts et al. 2014).
In Finland, there were more than 50 000 older people in permanent institutional care (including health center wards, nursing homes, and assisted living facilities) in 2014 (National Institute of Health and Welfare 2014). Of these, 90-95% suffered from at least MCI and more than 70% from severe or very severe cognitive decline (Finne-Soveri et al. 2015).
2.1.2. Diagnostic criteria
The diagnositic criteria for dementia have changed over time. Table 1 describes how the criteria for major neurocognitive disorder (APA 2013) have varied in the DSM-IV (APA 1994), DSM-5 (APA 2013), ICD-10 (WHO 1993), and NINCDS-ARDRA criteria for AD (McKhann et al. 2011). The core features in all criteria include significant cognitive decline from previous level and its interference with daily functioning. In addition, all criteria note that cognitive decline does not occur exclusively in the context of delirium. All criteria include NPSs. However, only the NINCDS-ARDRA criteria describe them widely.
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Table 1. Diagnostic criteria of dementia, major neurocognitive disorder, and AD according to recent DSM and ICD classification systems and the NINCDS-ARDRA criteria (McKhann et al. 2011).
Core required criteria appear in dark gray and additional qualifying features in light gray.
DSM-IV DSM-5 ICD-10
Research criteria F00- F09
NINCDS- ARDRA criteria #
Significant cognitive decline from previous level 2) 5)
Decline in memory, learning new information 6)
Decline in judgment, thinking, planning, organizing /attention, executive function
1) 6)
Decline in perceptual – motor cognition
Decline in social cognition 6)
Cognitive deficits interfere with independence in everyday activities
Cognitive deficits do not occur exclusively in the context of delirium
3) Decline in emotional control or motivation/change in social
behavior manifesting as 1. emotional lability
4)
*
2. irritability 4) *
3. apathy 4) *
4. coarsening of social behavior 4) *
Other behavioral disturbances 5)
Psychotic symptoms 4)
Agitation 4)
Other specific behavioral symptoms 4)
Diagnosis is supported by evidence of damage of higher cortical functions such as aphasia, agnosia, apraxia
1) 4)
Cognitive decline should be present at least 6 months 5)
1) At least one of these symptoms/signs (disturbance in any dimensions of executive function) (aphasia, agnosia, apraxia). 2) Concern of an individual, a knowledgeable informant or clinician AND substantial impairment in cognitive performance, preferably documented by neuropsychological testing. 3) In addition, cognitive deficits are not explained by another mental disorder (e.g.
major depressive disorder, schizophrenia). 4) Diagnostic features specific to each of the subtypes of dementia are presented in each specific criteria of dementia subtypes. 5) Requires cognitive symptoms or NPSs that interfere with ability to function in usual activities. Cognitive impairment is diagnosed by a combination of history taking and objective cognitive assessment. 6) At least two areas of cognition. * at least one of these symptoms. # for AD.
In addition, all etiological diagnoses, including AD, have their own criteria (WHO 1993, APA 1994, APA 2013, McKhann et al. 2011). Furthermore, mild cognitive impairment (MCI) has its own criteria (APA 2013). The first NINCDS-ARDRA criteria (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) for clinical diagnosis of AD were developed in 1984 (McKhann 2011).
The criteria in Table 1 are for dementia in DSM-IV, major neurocognitive disorder in DSM-5, or Alzheimer’s dementia in NINCDS-ARDRA for AD.
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Dementia has received much attention in research over the past three decades. Drugs for AD were developed 20 years ago, but no major breakthroughs have been discovered since the 1990s, despite the more than 100 drugs and vaccines in the pipeline (Gauthier et al. 2016).
The etiology of dementias has remained largely unknown, although some specific genes have been found in the minority (Scheltens et al. 2016). Known risk factor genes are apolipoprotein E4 in AD (APA 2013) andC9ORF72 in behavioral variant frontotemporal dementia (BvFTD) (Solje et al. 2015).
Risk factor studies for AD and vascular dementia have recently received much attention (Ngandu et al. 2015, Scheltens et al. 2016).
Over the years, it has become clear that the pathology of AD may take years or even decades before dementia can be clinically recognized (Humpel and Hochstrasser 2011, Vega and Newhouse 2014, Jansen et al. 2015). Major neurocognitive disorders are often preceded by MCI/mild neurocognitive disorder (Humpel 2011a, APA 2013, Alzheimer’s Association 2016). MCI has been defined as the earliest form of dementia, progressing to AD in approximately 15-30% of cases per year (Humpel 2011b). Recognizing AD as early as possible (MCI and preclinical AD) is essential in order to develop curative treatments (McKhann 2011, Gauthier et al. 2016). Cerebrospinal fluid (CSF) biomarkers, such as amyloid beta peptide, total tau, and phosphorylated tau, were incorporated into the criteria of preclinical AD to identify AD as early as possible (McKhann 2011).
2.1.2.1.Subtypes of dementia and their neuropsychiatric profiles
Major (dementia) and minor (MCI) NCDs are subtyped according to the known etiopathological entity underlying the cognitive decline. The subtypes are distinguished on the basis of time course, characteristic cognitive domains affected, and associated behavioral and functional symptoms. Evidence for distinct neuropsychiatric features has emerged (Cummings 1997, APA 2013). Table 2 describes cognitive and neuropsychiatric features, motor and other symptoms, and pathology of various subtypes of dementia.
The most common type of dementia syndrome is AD, comprising 60-80% of all dementias (Wilson et al. 2012, Alzheimer’s Association 2016). It is associated with core symptoms of cognitive decline from previous level and impairments in memory and learning (McKhann et al. 2011). Approximately 80% of patients have early NPSs such as anxiety and depression or apathy. With severe AD, psychotic features, irritability, agitation, and wandering are common (APA 2013, Alzheimer’s Association 2016).
Vascular dementia (VAD) is less prevalent as a pure cause of dementia, accounting for about 10-20% of dementia cases (Alzheimer’s Association 2016, Current Care Guidelines, Memory Disorders 2017). However, VAD is very common in older individuals with dementia, with
20
about 50% having pathologic evidence of vascular disorder. Of VAD cases, small vessel disease constitutes about 70% (Current Care Guidelines, Memory Disorders 2017).
Depression is common in VAD. Clinical factors distinguish vascular depression (VaDep) from non-vascular depression; these include older age, a medical history of hypertension and cardiac illness, psychomotor slowing, depressive symptoms with greater deficits in executive function, lack of initiative, and apathy (Strandberg et al. 2013, Aizenstein et al. 2016).
Dementia with Lewy bodies (DLB) is the third most common cause of dementia after AD, accounting for 10-15% of cases (Current Care Guidelines, Memory Disorders 2017) or up to 10-25% of cases (Alzheimer’s Association 2016). About 3-4% of dementia in the population is estimated to be due to Parkinson´s disease dementia (PDD) (Aarsland et al. 2005). Both DLB and PDD are important dementia syndromes that overlap in their clinical features, neuropathology, and management. Fluctuations of attention and wakefulness, visual hallucinations, depression, and neuroleptic sensitivity are common features of both. In clinical work, distinguishing features are in DLB spontaneous parkinsonism, which begins after the onset of cognitive decline, and in PDD cognitive decline, which develops in the context of established Parkinson´s disease (APA 2013, Gomperts 2016).
Frontotemporal lobar degeneration (FTLD) with behavioral or language variant is a disorder of middle age. In those younger than 65 years, FTLD is the second most common cause of dementia after AD (Ratnavalli et al. 2002). The prevalence of FTLD in the older population is low, about 4%. In this population, progressive nonfluent aphasia (PNFA) predominates (Johnson et al. 2005). Behavioral variant frontotemporal dementia (BvFTD) is characterized by behavioral changes, social dysfunction, and executive deficits (Rascovsky et al. 2011).
There is remarkable overlap between the clinical symptoms of BvFTDs and many psychiatric disorders, especially affective disorders and psychosis (Rascovsky et al. 2011).
Alcohol consumption and alcohol-related memory problems in the elderly are under-reported and often missed. The incidence and prevalence of alcohol-related dementia (ARD) vary across the studies. Variations may be due to differences in either the socio-demographic factors of study samples or the diagnostic criteria applied (Sachdeva et al. 2016). Older studies have suggested that of all cases of dementia, ARD accounts for approximately 10% (Smith and Kiloh 1981), and heavy use of alcohol is a contributory factor in 24% of dementia cases (Smith and Atkinson 1995). Sachdeva et al. (2016) reported in their recent review that the prevalence of alcohol abuse in dementia patients is 9-22% and the prevalence of dementia in alcohol abusers is 10-24%. Core NPSs in ARD are frontal (disinhibition and loss of emotional control, including aggressive or inappropriate affect, loss of planning and executive functions, and apathy) (APA 2013, Ridley et al. 2013, Rao and Draper 2015).
21 Table 2. Examples of cognitive and neuropsychiatric symptoms, motor and other features as well as neuropathological features in subtypes of dementia according to various criteria. Modified from WHO 1993, APA 1994, Cummings 1997, Jack et al. 2011, Lyketsos et al. 2011, McKhann et al. 2011, Rascovsky et al.2011, APA 2013, Ridley et al. 2013, Warren et al. 2013, Rao and Draper 2015, Alzheimer’s Association 2016. Cognitive symptomsNeuropsychiatric featuresMotor featuresOther featuresNeuropathological features Alzheimer´s disease (AD) Decline in memory. Impaired ability to acquire and remember new information. Impaired reasoning and handling of complex tasks and poor judgment. Impaired visuospatial abilities. Impaired language functions (speaking, reading, writing).
Changes in personality and behavior.The first sign of cognitive decline may be anxiety or depression. Mood fluctuations such as agitation, loss of drive, decreased interest in previous activities, impaired motivation and/or initiative (apathy) may be present. Social withdrawal, loss of empathy, compulsive or obsessive behaviors, socially unacceptable behaviors. Depression and apathy are the most frequently observed symptoms in people with early AD, although verbal and physical agitation is also common across all stages of AD. As the disease progresses, delusions, hallucinations, and aggression become more common, whereas apathy is the most persistent and frequent NPS throughout all stages of AD.
Physical agitation is common across all stages of AD.
Advanced cases may present stiffness, epileptic fits,
and proneness to fa
lls.
Social cognition, ability to listen to and enjoy music, emotional interpretation, and emotional communication tends to be preserved until late in the course of the disease.
Neuropathological changes of AD start several decades before the first clinical symptoms become apparent. The hallmark pathologies: progressive accumulation of the protein fragment beta-amyloid (plaques) outside neurons in the brain and twisted strands of the protein tau (tangles) inside neurons. These changes are eventually accompanied by damage and death of neurons, especially in entorhinal and hippocampal areas. Several neurotransmitter systems are affected in AD, while cholinergic mechanisms are implicated in attention and arousal, glutamate systems likely underlie deficits in memory. Vascular dementia (VAD) Decline may be prominent in complex attention (including processing speed) and frontal- executive function. Impaired judgment or impaired ability to make decisions, plan, or organize are often the initial symptoms. Symptoms depend on the location of the vascular lesions and neuronal network in the brain.
Mood changes, abulia, “vascular depression”,and emotional lability.Impairedmotor function, especially slow gait and poor balance. Patients may present neurological deficits.
Neurocognitive outcomes are often influenced by neuroplasticity factors such as education, physical exercise, and mental activity.
Cerebrovascular disease accountsfor the neurocognitive deficits. Major or mild vascular cognitive disorder with gradual onset and slow progression is generally due to small vessel disease, leading to lesions in white matter, subcortical ischemic vascular disease, or strategic infarct subtypes of poststroke in basal ganglia and/or thalamus areas. Cognitive deficits in these cases can be atributed to disruption of cortical-subcortical circuits.
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Table 2. Continued… Dementia with Lewy bodies(DLB) Fluctuating cognition with variations in attention and alertness.
Visual hallucinations that are well-formed and detailed hallucinations in sensory modalities. Depressive symptoms and delusions. Auditory and other nonvisual hallucinations are common, as are systematized delusions, delusional misidentifications, and depression.
Slowness, gait imbalance with other parkinsonian movement features Repeated falls. Antipsychotics may cause rigidity.
Rapid eye movement (REM) sleep behavior disorder. Neuroleptic sensitivity common, episodes of loss of consciousness, autonomic dysfunction (orthostatism)
The underlying neurodegenerative disease is synucleinopathy due to alphasynuclein misfolding and aggregation. Lewy bodies are abnormal aggregations of the protein alpha-synuclein in neurons. When they develop in a part of the brain cortex, dementia results. Several risk genes have been identified, but in most cases of DLB, there is no family history. Parkinson’sdiseasedementia(PDD) Cognitive declinefollowingthe onset of Parkinson´s diseaseApathy, personality changes, depressed mood, anxious mood, excessive daytime sleepiness, hallucinations, delusions.
Problems with movement, slowness, rigidity, tremor, and changes in gait.
Thisneurocognitive disorder shows marked motor impairment. REM sleep behavior disorder.
In PD alpha-synuclein aggregates in substantia nigra accompanied by severe neuronal loss. The aggregates cause degeneration of the nerve cells that produce dopamine. When PD progresses, it often results in dementia secondary to the accumulation of Lewy bodies also in the cortex similar to LBD or the accumulation of beta-amyloid clumps and tau tangles similar to AD. Frontotemporallobardegeneration(FTLD); behavioral variantfrontotemporal dementia(BvFTD) Prominent decline in social cognition and/or executive abilities. Memory remains.
Progressive development of behavioral and personality changes. Behavioral disinhibition, apathy or inertia, loss of sympathy or empathy, perseverative, stereotyped, or compulsive/ritualistic behavior, hyperorality, and dietary changes.
Variable overlap with atypical parkinsonism and motor neuron disease.
Insight is often impaired. There is often a paucity of associated neurological signs, though primitive reflexes (forced grasping or rooting) may emerge later in the course, and behavioral variant FTD may be associated with extrapyramidal or motor neuron signs.
About 50% of patients with frontotemporallobar degeneration (FTLD) report a positive family history. FTLD and corticobasal syndrome are genetically and pathologically heterogeneous. The common pathological theme underpinning FTLD is tissue deposition of abnormally aggregated proteins. MRI often shows frontal and anterior temporal lobe atrophy, which tends to be asymmetric between hemispheres and to spare more posterior cortical areas. Degree and extent of atrophy vary widely among individuals. Altered white matter signal may be prominent usually in close proximity to areas of cortical atrophy, where it may reflect gliosis. SPECT or FDG-PET may be diagnostically useful in detecting regional dysfunction.
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Table 2. Continued… Frontotemporallobardegeneration(FTLD); language variant Decline in language ability, in the form of speech production, word finding, object naming, grammar, or word comprehension.
Relative sparing in learning and memory and perceptual-motor function. Hyperorality. Disinhibited behavior.
Impulsive wandering.Insight is often impaired There are three language variants (semantic, agrammatic/ nonfluent; logopenic).
Heritability of particular FTLD syndromes varies substantially, semantic dementia is generally sporadic. The common pathological theme underpinning FTLD is tissue deposition of abnormally aggregated proteins. Non-fluent speech breakdown and development of parkinsonism are more commonly associated with tau than non-tau pathologies. A highly consistent and characteristic neuroanatomical (MRI) profile with selective, asymmetric anteroinferior temporal lobe cortical atrophy and hypometabolism, the gyral glia at the temporal poles often persisting only as a residual “knife blade” skeleton. Atrophy is predominantly left-sided with spread between the cerebral hemispheres and into more posterior temporal and inferior frontal cortices over time. Alcohol-related dementia (ARD) and Alcohol-induced persisting amnestic syndrome (Wernicke-Korsakoff syndrome (WKS) Often both cortical and subcortical pathology. Deficits most frequently in visuospatial function, memory, executive tasks. The WKS appears more heterogeneous in nature than originally documented, and deficits in executive tasks are commonly reported in conjunction with characteristic memory deficits.
Often frontal symptoms (disinhibition, loss of planning and executive functions, and disregard for the consequences of behavior).
Neurological symptoms such as ataxia.
Individuals with alcohol- related disorders have potential to at least partially recover in abstinence – both structurally and functionally. The effectss of thiamine deficiency (spatial memory impairment and increased perseverative behavior) are more persistent.
Alcohol may lead to structural and functional damage that is permanent in nature; however, there is debate about the relative contributions to lasting damage of the direct toxic effect of alcohol (neurotoxicity hypothesis) and the impact of thiamine deficiency. Prominent white matter loss (most notable in the prefrontal cortex, corpus callosum, and cerebellum) and neuronal loss in the superior frontal association cortex, hypothalamus, and cerebellum. The frontal lobes of individuals with diagnosed alcoholism appear particularly susceptible to damage, with evidence of markedly decreased neuron density, volume shrinkage, and altered glucose metabolism and perfusion. Thiamine deficiency and direct alcohol neurotoxicity produce similar brain effects: loss of cells in the basal forebrain, hippocampal acetylcholine hypofunction, and shrinkage of frontal gray and white matter, with thiamine deficiency characterized by additional lesions in the diencephalon. WHO= World Health Organization, APA= American Psychiatric Association, REM= Rapid eye movement, SPECT=Single-photon emission computed tomography, MRI= Magnetic resonance imaging, FDG-PET= Fluorodeoxyglucose - positron emission tomography
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In addition to those described in Table 2, there are other subtypes of dementia, e.g. major or mild neurocognitive disorder due to another medical condition, Creutzfeld-Jakob disease, HIV-related dementia, Huntington’s disease, substance (other than alcohol) or medication- induced neurocognitive disorder and traumatic brain injury (APA 2013).
When evidence of more than one type of dementia is present, an individual is said to have mixed dementia characterized by the hallmark abnormalities of more than one cause of dementia. Mixed dementias, due to more than one etiology, are present in approximately 15%
of individuals with dementia (Phelan et al. 2012). They increase with age and prevalence is highest in those aged 85 years or over (Alzheimer’s Association 2016). The most common types are AD combined with VAD, constituting about 60% of cases, followed by AD with DLB, or AD with VAD and DLB (Román et al. 2002).
Old-age neurocognitive disorders can be considered geriatric syndromes, conditions in which the underlying causes of typical symptoms (difficulties in memory and executive function) are multiple. According to Strandberg et al., most of the old-age memory diseases can be seen as a continuum; at one end, there is a clean AD-type disorder, whereas at the other end pure vascular cognitive impairment (VCI), as arterial changes become more common with age and are involved in most forms of memory disorders (Strandberg et al. 2013, Strandberg 2017).
In Cummings’ report, significant differences on neuropsychiatric profiles emerged (Cummings 1997, Cummings and McPherson 2001, Lai 2014). Different neurologic disorders have characteristic neuropsychiatric manifestations and distinctive NPI profiles. For example, patients with frontotemporal dementia exhibited significantly more apathy, disinhibition, euphoria, and aberrant motor behavior than patients with AD. Patients with progressive supranuclear palsy had significantly more apathy and less agitation and anxiety than patients with AD. Patients with vascular dementia were more likely to have depression and less likely to have delusions, and patients with DLB more often exhibited delusions and hallucinations than patients with AD (Cummings 1997).
In addition, many other conditions may cause symptoms like dementia, including some that are reversible and treatable. One meta-analysis reported that 9% of people with dementia-like symptoms did not in fact have dementia, but had other conditions that were potentially reversible (Clarfield 2003). Common causes of dementia-like symptoms are depression, delirium, side-effects from medications, thyroid problems, certain vitamin deficiencies, and excessive use of alcohol (Clarfield 2003).
25 2.1.2.2. Diagnostic procedures of dementia
The level of cognitive impairment is detected and dementia diagnosed with the aid of a combination of (1) history-taking from the patient and a knowledgeable informant and (2) an objective geriatric and/or neurologic assessment, including cognitive tests (in clinics, usually the Mini-Mental State Examination, MMSE) (Folstein et al. 1975), and/or neuropsychological battery of Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) (Morris et al.
1989). The patient is often assessed with Geriatric Depression Scale (GDS) (Yesavage et al.
1982-3), Cornell Scale for Depression in Dementia (CSDD) (Alexopoulos et al. 1988), Neuropsychiatric Inventory (NPI) (Cummings 1997), physical functioning (e.g. Alzheimer patients’ activities of daily living (ADCS-ADL) (Galasko et al. 1997), Clinical Dementia Rating Scale (CDR) (Hughes et al. 1982), and somatic status (McKhann et al. 2011, Current Care Guidelines, Memory Disorders 2017). Neuropsychological testing should be performed when the routine history and bedside MMSE cannot provide a confident diagnosis.
Neuroimaging (MRI, CT, PET, Beta-CIT-SPECT), laboratory tests (McKhann et al. 2011), and in distinct cases also CSF biomarkers (McKhann et al. 2011, Current Care Guidelines, Memory Disorders 2017, are used in diagnostics. Laboratory tests are used to exclude certain treatable causes for cognitive decline. Patient´s drug list is reviewed to deprescribe anticholinergic or other inappropriate drugs.
The course and typical characteristics vary across etiological subtypes of neurocognitive disorders. This variation can be useful in differential diagnosis and management of neuropsychiatric and behavioral symptoms (Cummings 1997).
2.1.3. Neuropsychiatric symptoms (NPSs) of dementia
While cognitive impairment is the defining diagnostic feature of all types of dementias, the clinical presentation frequently includes NPSs – disturbances in mood and affect, perceptions, and behavior. For example 80-90% of individuals with major neurocognitive disorder/dementia suffer from behavioral and psychological manifestations at some point in the course of their illness, and these features are also frequent at the mild stage of impairment (Jost and Grosberg 1996, Pitkälä et al. 2004, Nowrangi et al. 2015, Ismail et al. 2016).
Patients’ underlying resources and vulnerabilities vary individually, thus modifying phenomenology of the disorder (Cohen-Mansfield 2001a, Cohen-Mansfield 2001b). For example, the neuropathological changes of AD start several decades before the first clinical symptoms become apparent (Jansen et al. 2015). The first early sign of a neurocognitive disorder may be anxiety or depression (Lyketsos et al. 2011). In a population-based study by Lyketsos et al. (2002), about 40% of MCI participants exhibited NPSs and 30% of these were
