Activities of Daily Living and Depressive Symptoms in Patients with Subjective Cognitive Decline,Mild Cognitive Impairment,and Alzheimer’s Disease

Abstract

Background:

Subjective cognitive decline (SCD) may be an early indicator for an increased risk of dementia. The exact definition of SCD remains unclear and has recently become a major research interest.

Objectives:

To determine impairments in activities of daily living (ADL) and depressive symptoms in elderly individuals with SCD, mild cognitive impairment (MCI), and Alzheimer’s disease (AD).

Methods:

We included 752 consecutive patients suffering from SCD, non-amnestic (naMCI) or amnestic MCI (aMCI), AD, and 343 healthy controls into this prospective cohort study. A neuropsychological test battery, B-ADL and BDI-II was performed.

Results:

SCD patients showed a decreased performance in ADL compared to controls. Performance in ADL declined concurrently with cognitive abilities along the controls−SCD−naMCI−aMCI−AD continuum. Individuals with cognitive complains, no matter if SCD, MCI, or AD patients, reported more often depressive symptoms compared to healthy controls without complaints. Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. Adjusting for depressive symptoms, there was no significant group difference between the control versus the SCD group (OR 1.1, CI 0.6–1.7).

Conclusions:

SCD is a heterogeneous clinical condition. Specific features such as slightly impaired ADL and depressive symptoms are associated with SCD. Clinical markers may serve as an indicator for preclinical AD and in combination with biomarkers guide to an early diagnosis of a progressive neurodegenerative disease.

Keywords

Activities of daily living Alzheimer’s Disease depressive symptoms mild cognitive impairment subtypes subjective cognitive decline

INTRODUCTION

There is increasing evidence that subjective cognitive decline (SCD), even at the stage of normal performance on cognitive tests, is associated with increased risk for future cognitive decline and Alzheimer’s disease (AD) [1 –5]. SCD may be a very early symptom of cognitive decline, reflecting aspects of meta-memory of affected individuals. However, usual neuropsychological tests fail to show a difference between SCD and healthy uncomplaining controls [2, 6, 7 , 2, 6, 7]. Self-focused attention and depressive symptoms seem to play an important role in SCD [8]. However, it is not clear how this fact interacts with objective memory performance [8]. To date, there is neither a standardized SCD assessment in current mild cognitive impairment (MCI) or dementia criteria sets, or a consensus on the definition of SCD. Different terms such as subjective cognitive impairment, subjective memory decline, subjective memory impairment, and memory complaints, among other terminologies have been used in the past. In the need of a common terminology and a clear definition, SCD was recently proposed as most appropriate for further use [2].

Biomarkers as well as AD-type neuropathological changes occur years before distinct clinical symptoms, even in the stage of SCD. This may be an indicator for the already advanced neuronal damage at the time of overt clinical symptoms [9 –11]. Better characterization of prodromal stages with regards to clinical symptoms has therefore become an interesting research field and may be especially beneficial for the development of future preventive therapeutic strategies.

As impairments in activities of daily living (ADL) have been found to be a strong predictor of progression to dementia in patients in prodromal stages of AD [5 , 12–14], we assumed that this could even be apparent in the early stage of SCD.

Therefore, we investigated possible differences in impairments of ADL between healthy controls, SCD, MCI, and AD patients in this study. As depressive symptoms seem to be a major confounder in the diagnosis of SCD, we further assessed depressive symptoms in all subgroups. Moreover, we correlated impairments in ADL with presence of depressive symptoms in the respective subgroups.

METHODS

The current data are part of a larger research project, the Vienna Conversion to Dementia Study (VCD-Study). The VCD is a prospective cohort study encompassing consecutive, community-dwelling patients complaining of cognitive problems who come to the memory outpatient clinic for assessment of a possible cognitive disorder. The Ethical Committee of the Medical University of Vienna has approved the study protocol, and written informed patient consent to perform this study has been received.

All patients received a complete neurological examination, standard laboratory blood tests, and psychometric testing. In most cases, a magnetic resonance imaging (MRI) scan of the brain was obtained. In determining significant cerebrovascular disease, both neuroimaging and clinical patient features were used. Inclusion and exclusion criteria were similar to other studies. Patients were excluded from the study if any of the following conditions applied: (a) evidence of stroke as determined by neuro-radiologic and clinical examination; (b) history of severe head injury; (c) current psychiatric diagnosis according to ICD-10 [15], however, patients with (sub-) depressive symptoms were included because (sub-) depressive symptoms often occur in elderly patients; (d) any medical condition that leads to severe cognitive deterioration including renal, respiratory, cardiac, and hepatic disease.

All participants were subjected to the Neuropsychological Test Battery Vienna (NTBV) that included attention, executive functioning, language, and memory domains with corresponding domain z scores [16, 17]. The Alters-Konzentrations-Test (AKT) [18], a geriatric cancellation test, the digit symbol subtest of the German WAIS-R [19], the symbol counting task from the cerebral insufficiency test (C.I.) [20], the Trail Making Test B [21], and the score difference of the Trail Making Test A and B [21] were applied to assess attention. Executive functions were investigated using the Trail Making Test A [21], the Five-Point Test [22], the Maze Test from the NAI Test Battery [23, 24], the Stroop Test from the NAI Test Battery [23, 24], and the interference test from the C.I. [20]. Naming as many words beginning with the letters b, f, and l that came to mind within one minute for each task was used to tap lexical verbal fluency. In order to test language functions, we used verbal fluency tasks and a confrontation naming task [25]. Naming as many animals, supermarket items, and tools that came to mind within one minute for each task was used to tap semantic verbal fluency. The modified Boston Naming Test (mBNT) [26] was used for assessing naming capabilities. Episodic memory was tested using the Verbal Selective Reminding Test (VSRT) with the subtests of immediate recall, total recall, delayed recall, and recognition [27].

After the completion of the evaluation, the cognitive status of MCI subtypes was determined according to the Peterson criteria [15], and the cut off score used was 1.5 standard deviations below age and education corrected norms using a normative sample of cognitively healthy controls. For this purpose, the flexible GAMLSS (Generalized Additive Models for Location, Scale and Shape) model class was used [16, 28]. The minimum mode of MCI classification was used and patients were divided into three groups of patients based on cognitive features as follows: SCD patients (z-scores of each single test were greater than –1.5 SD), aMCI patients (the z-score of at least one memory test was below –1.5 SD), naMCI patients (there is at least one domain other than the memory domain where the minimum of the z-scores within this domain was below –1.5 SD), respectively. AD was diagnosed according to the NINCDS-ADRDA [29] and DSM-IV criteria [30].

Patients

Seven hundred fifty-two consecutive patients complaining about memory problems, which came to the memory outpatient clinic for assessment of a possible cognitive disorder and fulfilled the inclusion criteria, were included in the study. Patients were either referred by physicians or were self-referrals.

Cognitively healthy control subjects

Three hundred forty-three cognitively healthy control subjects were included in the study. Great care was taken enrolling a sufficient number of cognitively healthy control subjects living independently at home. Control subjects were recruited by means of advertisements. They underwent a rigorous screening evaluation using a standardized clinical interview and cognitive screening. They were assessed as being in good health. Cognitive status was given special attention and cognitively healthy control subjects were screened for intact cognition. They were required to have an MMSE score [31] greater than or equal to 27 and a MOCA Score [32] greater than or equal to 26 adjusted foreducation.

Assessment of activities of daily living

For the assessment of activities of daily living, the Bayer Activities of Daily Living (B-ADL) scale was used. The B-ADL has been developed on an international basis to assess deficits in the performance of everyday activities. The scale’s main target group is community dwelling patients, who suffer from MCI or mild-to-moderate dementia. It comprises 25 items and takes the form of a questionnaire to be completed by the patient or a caregiver or some other informant sufficiently familiar with the patient. Ratings are made on a 10-point Likert-type scale. The total score takes values between 0 and 10 [33]. A higher score indicates an increase in impairments in ADL.

For the purpose of this study the raw scores of the B-ADL were also transformed into z-scores using a normative sample and the flexible GAMLSS model class [34]. A B-ADL score below at least 1.5 SDs (B-ADL z-score < –1.5) of the age, gender, and education matched mean of the normative sample was chosen as a cut-off level. We defined participants below that cut-off as having a considerable degree of functional impairment.

Assessment of depressive symptoms

The Beck Depression Inventory (BDI-II), a 21-item instrument to detect depressive symptoms in adults, was used. It asks about how often one felt certain ways within the past two weeks, rated on a four-point scale. The total score takes values between 0–63. By clinical experience a score above 10 was here defined to be indicative of clinically relevant depressive symptoms [35].

Statistical methods

Demographic variables, BDI-II and B-ADL scores are described as median and quartiles due to the skewed distribution of most of these variables. Z-scores of the neuropsychological test variables are described by means and standard deviations.

In order to compare dependent variables between groups, Kruskal-Wallis tests have been computed. Post hoc tests were performed using the Dwass-Steel-Critchlow-Fligner method to correct for multiple comparisons.

B-ADL score below at least 1.5 SDs (B-ADL z-score < –1.5) of the age, gender, and education matched mean of the normative sample—chosen as a cut-off level for definition of a considerable degree of functional impairment—was investigated using logistic regression models with adjustment for depressive symptoms. We performed the logistic regression model with the factor cognitive group status (controls, SCD group, naMCI group, aMCI group, AD group) with depressive symptoms as a co-variable and activities of daily living as a dependent variable (B-ADL z-score < –1.5).

Associations between B-ADL and other variables are quantified using Spearman’s correlation coefficients. The reported p-values are the result of two-sided tests. p-values ≤0.05 were considered to be statistically significant. All computations were performed using SAS software Version 9.4 (SAS Institute Inc., Cary, NC, USA, 2002-2012), except GAMLSS estimation, which was done using R 3.0.3.

RESULTS

We included 1,095 individuals into this prospective cohort study. Demographic variables of study participants were similar in all groups, except the higher age in the AD group (Table 1). The neuropsychological performance of controls and patient groups are reported in Supplementary Table 1.

The B-ADL scores increased with decreasing cognitive status (Fig. 1). Post hoc testing revealed no significant group differences for pairwise group comparisons between SCD versus naMCI, naMCI versus aMCI, and aMCI versus AD, but significant results for all other pairwise group comparisons, in particular between controls and SCD (corrected p < 0.05). The frequency of considerable functional impairment likewise increased from 22.3% in controls to 34.6% in the SCD group, 45.3% in the naMCI group, 47.3% in the aMCI group, and 63.3% in the AD group. The BDI scores were lower in the controls and similar in all other groups (Fig. 2). 17.7% of controls, 45.5% of the SCD group, 50.0% of the naMCI group, 42.3% of the aMCI group, and 46.7% of the AD group reported depressive symptoms.

Finally, we investigated the impact of cognitive status on the risk of having a considerable degree of functional impairment (B-ADL z-score < –1.5) while adjusting for depressive symptoms. The influence of the continuous BDI scores on the dichotomous B-ADL scores was similar through all cognitive subgroups, therefore meaning that the difference of the B-ADL scores between all subgroups is independent from the BDI scores. Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. There was no significant group difference between the control versus the SCD group (OR 1.1, CI 0.6–1.7), a strong tendency for statistically significance between the SCD versus the naMCI group (OR 1.5, CI 0.9–2.4) and the naMCI versus the aMCI group (OR 1.3, CI 0.9–1.8), and a statistical significance for the control versus the naMCI (OR 1.5, CI 1.1–2.3), the aMCI (OR 2.0, CI 1.3–2.9), and the AD group (OR 4, CI 2.1–7.5), the SCD group versus the aMCI (OR 1.9, CI 1.1–3.1) and the AD group (OR 3.8, CI 1.9–7.7), the naMCI group versus the AD group (OR 2.6, CI 1.4–4.8), and the aMCI group versus the AD group (OR 2.0, CI 1.1–3.8) (Table 2).

We performed correlation analyses for the total group (n = 1,095) between B-ADL z-scores and MMSE, BDI-II scores, and neuropsychological subtest scores, which revealed low correlation coefficients (all correlation coefficients within±0.10, spatialized for diagnostic groups) except for BDI-II, which showed a moderate negative association (r = –0.46). Correlation analyses for single groups revealed very similar results. See Supplementary Table 2 for details. We also performed a stepwise logistic regression analysis in order to predict whether a patient has a considerable degree of functional impairment (B-ADL z-score < –1.5) based on observed characteristics of the patient (log BDI score, MMSE score, and all neuropsychological z-scores). Results revealed (expressed as Odds-ratio estimate with 95% confidence limits) that depressive symptoms (BDI score; odds- ratio = 2.5, CI = 2.2–2.9), attention (AKT total/time score; odds- ratio = 0.8, CI = 0.7–0.9); verbal memory (VSRT delayed recall score; odds- ratio = 0.8, CI = 0.7–0.8) and executive functioning (Nonverbal Fluency Five Point Test – perseverations score, odds- ratio = 1.3, CI = 1.1–1.5) were significant predictors of a considerable degree of functional impairment. None of the independent variables showed a significantly group-dependent effect.

DISCUSSION

The main goal of the present study was to investigate impairments in ADL in patients with SCD, MCI, and AD and compare it to healthy controls. We further examined whether there is an association between impaired ADL and factors such as depressive symptoms and neurocognitive functioning across different subgroups.

As expected, performance in ADL declined concurrently with cognitive abilities along the controls–SCD–naMCI–aMCI–AD continuum. Regarding a considerable degree of functional impairment in ADL, SCD patients showed a significant group difference compared to controls (corrected p < 0.05) (Fig. 1). We found that individuals with cognitive complains, no matter if SCD, MCI, or AD patients, reported more often depressive symptoms compared to uncomplaining healthy controls (Fig. 2). Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. While adjusting for depressive symptoms, no significant group difference was shown between SCD versus the control and the naMCI group respectively, whereas a significant group difference was still shown between SCD versus the aMCI and the AD group (Table 2). When investigating an association between ADL, neurocognitive functioning (measured by means of MMSE and several neuropsychological tests), and depressive symptoms in the total group as well as in the single groups, we found depressive symptoms to be a strong predictor of functional status. However, using logistic regression analysis in order to predict whether a patient has a considerable degree of functional impairment, we found that, besides depressive symptoms, attention, verbal memory, and executive functioning were also significantpredictors.

Better characterization of the clinical phenotype of SCD is important in terms of recognition of very early cognitive symptoms. Definition of pre-prodromal or pre-MCI stages of AD will be useful in the future to define target populations for prevention trials at a stage of only mild neuronal damage and with still sufficient functional compensation [1]. Mild impairment in ADL has been found to be a strong predictor of progression to dementia in patients with prodromal stages of AD [5, 36]. Findings suggest that SCD and difficulties in ADL could be early manifestations of the disease, which on the one hand could be easily captured, but on the other hand are often assumed as physiologic, age-related phenomena [13]. We see that SCD patients already report problems in ADL, however, this is closely related to depressive symptoms. Roughly half of the here reported SCD group showed significant depressive symptoms. The association of SCD with self-focused attention and depressive symptomatology has been described previously [7, 8]. In a recent study we found a strong association between subjective memory complaints, depressive symptoms, and cognition in patients attending a memory outpatient clinic [37]. This so called functional memory disorder was found to be more common in an above-average educational attainment, which was not present in the studied population of SCD patients here [7, 38]. On the other hand, depressive symptoms and thoughtfulness might also signalize the onset of disease. The relation between depression and cognitive decline has been often debated, with some supporting depression as a risk or prodromal factor of cognitive decline, and others supporting depression as a consequence of realization of cognitive decline [5]. The setting in which SCD patients were recruited in this study was a medical-help-seeking rather than a population-based sample, which might have biased selection of patients in the direction of over reporting of cognitive impairment [39]. This assumption might be underlined by the observation that SCD patients seemed to perform, on average, even better than healthy controls in neuropsychological subtests. See Supplementary Table 1. One might suggest that the examined SCD population is, at least in part, a cognitively well, self-focused-attention group. Patients’ ages when describing memory deficits are of interest in the assessment of SCD [2]. Median age in patients with SCD, naMCI, aMCI, and controls was similar, those suggested to be the main differential diagnostic groups in regard to SCD. Only the AD group showed a higher median age, therefore age corrected norms for neurocognitive testing and ADL assessments were used.

However, evidence from longitudinal data support SCD as a risk factor for future cognitive decline as well as cross sectional biomarker studies show an increased prevalence of preclinical AD in patients with SCD [1 , 4]. Due to the inconsistency of this clinical entity, one has to differentiate SCD patients in the pathway of a neurodegenerative disease versus SCD patients with specific associated personality traits respectively depressive symptoms. The latter is not associated with a progressive course of a neurodegenerative disorder [7, 38], whereas the former is.

There are limitations in the present study. We lack imaging data as MRI volumetry of temporal lobe, FDG, and PIB PET scans and examination of amyloid, tau, and phospho-tau in cerebrospinal fluid, which definitely could precise a possible neurodegenerative process. Furthermore this is not a longitudinal study and we do not have reports of development of SCD patients at this time.

Characteristics of SCD are heterogeneous and a set of features that will increase the likelihood of the presence of preclinical AD in individuals with SCD would be useful in the future. The clinical stage SCD by itself (alone or as defined today) will never be sufficient to diagnose preclinical AD [1, 2], but in combination with other clinical markers it may be used to assess an individual patients’ risk. As biomarkers now do not seem to be of high significance either [11], we sought to find additional easy-to-asses clinical markers highlighting a population at risk. Our results support the notion that impairment in ADL might be a useful predictor of future development of dementia in SCD; however, this has to be evaluated empirically. A longitudinal study from our research group is under way to investigate this question.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/15-0785r1).

Footnotes

Appendix

References

Jessen

(2014) Subjective and objective cognitive decline at the pre-dementia stage of Alzheimer’s disease Eur Arch Psychiatry Clin Neurosci 264(Suppl 1), S3–S7.

Jessen

, Amariglio

, van Boxtel

, Breteler

, Ceccaldi

, Chetelat

, Dubois

, Dufouil

, Ellis

, van der Flier

, Glodzik

, van Harten

, de Leon

, McHugh

, Mielke

, Molinuevo

, Mosconi

, Osorio

, Perrotin

, Petersen

, Rabin

, Rami

, Reisberg

, Rentz

, Sachdev

, de la Sayette

, Saykin

, Scheltens

, Shulman

, Slavin

, Sperling

, Stewart

, Uspenskaya

, Vellas

, Visser

, Wagner

(2014) A conceptualframework for research on subjective cognitive decline in preclinical Alzheimer’s disease AlzheimersDement 10, 844–852.

Luck

, Luppa

, Matschinger

, Jessen

, Angermeyer

, Riedel-Heller

(2015) Incident subjective memory complaints and the risk of subsequent dementia Acta Psychiatr Scand 131, 290–296.

Mitchell

, Beaumont

, Ferguson

, Yadegarfar

, Stubbs

(2014) Risk of dementia and mild cognitive impairment in older people with subjective memory complaints: Meta-analysis Acta Psychiatr Scand 130, 439–451.

Amieva

, Le Goff

, Millet

, Orgogozo

, Peres

, Barberger-Gateau

, Jacqmin-Gadda

, Dartigues

(2008) Prodromal Alzheimer’s disease: Successive emergence of the clinical symptoms Ann Neurol 64, 492–498.

Canevelli

, Blasimme

, Vanacore

, Bruno

, Cesari

(2014) Issues about the use of subjective cognitive decline in Alzheimer’s disease research Alzheimers Dement 10, 881–882.

Blackburn

, Wakefield

, Shanks

, Harkness

, Reuber

, Venneri

(2014) Memory difficulties are not always a sign of incipient dementia: A review of the possible causes of loss of memory efficiency Br Med Bull 112, 71–81.

Chin

, Oh

, Seo

, Na

(2014) Are depressive symptomatology and self-focused attention associated with subjective memory impairment in older adults? Int Psychogeriatr 26, 573–580.

Kryscio

, Abner

, Cooper

, Fardo

, Jicha

, Nelson

, Smith

, Van Eldik

, Wan

, Schmitt

(2014) Self-reportedmemory complaints: Implications from a longitudinal cohort withautopsies Neurology 83, 1359–1365.

10.

Jack

Jr , Knopman

, Weigand

, Wiste

, Vemuri

, Lowe

, Kantarci

, Gunter

, Senjem

, Ivnik

, Roberts

, Rocca

, Boeve

, Petersen

(2012) An operational approach to National Institute on Aging-Alzheimer’s Association criteria for preclinical Alzheimer disease Ann Neurol 71, 765–775.

11.

Jack

Jr , Wiste

, Weigand

, Rocca

, Knopman

, Mielke

, Lowe

, Senjem

, Gunter

, Preboske

, Pankratz

, Vemuri

, Petersen

(2014) Age-specific population frequencies of cerebral beta-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: A cross-sectional study Lancet Neurol 13, 997–1005.

12.

Peres

, Helmer

, Amieva

, Orgogozo

, Rouch

, Dartigues

, Barberger-Gateau

(2008) Natural history of decline in instrumental activities of daily living performance over the 10 years preceding the clinical diagnosis of dementia: A prospective population-based study J Am Geriatr Soc 56, 37–44.

13.

Reppermund

, Sachdev

, Crawford

, Kochan

, Slavin

, Kang

, Trollor

, Draper

, Brodaty

(2011) The relationship of neuropsychological function to instrumental activities of daily living in mild cognitive impairment Int J Geriatr Psychiatry 26, 843–852.

14.

Peres

, Helmer

, Amieva

, Matharan

, Carcaillon

, Jacqmin-Gadda

, Auriacombe

, Orgogozo

, Barberger-Gateau

, Dartigues

(2011) Gender differences in the prodromal signs of dementia: Memory complaintand IADL-restriction. a prospective population-based cohort J Alzheimers Dis 27, 39–47.

15.

Petersen

, Morris

(2005) Mild cognitive impairment as aclinical entity and treatment target Arch Neurol 62, 1160–1163 discussion, 1167.

16.

Lehrner

, Moser

, Klug

, Gleiss

, Auff

, Dal-Bianco

, Pusswald

(2014) Subjective memory complaints, depressive symptoms and cognition in patients attending a memory outpatient clinic Int Psychogeriatr 26, 463–473.

17.

Lehrner

, Maly

, Gleiß

, Auff

, Dal-Bianco

(2007) The Vienna Neuropsychological Test Battery (VNTB) for detectingdementia – standardization, norms, and validation Psychologie in Österreich 5, 358–365.

18.

Gatterer

(2008) Alters-Konzentrations-Test (AKT), Hogrefe, Göttingen.

19.

Tewes

(1994) Hamburg-Wechsler-Intelligenztest für Erwachsene - Revision 1991 (HAWIE-R), Verlag Hans Huber, Bern.

20.

Lehrl

(1978) Mehrfachwahl-Wortschatz-Intelligenztest MWT-B, Straube, Erlangen.

21.

Reitan

(1979) Trail Making Test (TMT), Reitan Neuropsychology Laboratory, Tucson.

22.

Regard

, Strauss

, Knapp

(1982) Children’s production on verbal and non-verbal fluency tasks Percept Mot Skills 55, 839–844.

23.

Johannsen

, Nitsch

, Oswald

, Reischies

, Rieder

(1997) [Aging as a chance–aging as a risk] Z Gerontol Geriatr 30, 480–485.

24.

Oswald

, Fleischmann

(1997) Das Nünberger-Alters-Inventar

Göttingen

Hogrefe Verlag

25.

Goodglass

, Kaplan

(1983 The assessment of aphasia and related disorders Philadelphia

Lea & Fabinger

26.

Morris

, Heyman

, Mohs

, Hughes

, van Belle

, Fillenbaum

, Mellits

, Clark

(1989) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease Neurology 39, 1159–1165.

27.

Lehrner

, Gleiß

, Maly

, Auff

, Dal-Bianco

(2006) Der verbale Selektive Reminding Test (VSRT). EinVerfahren zur Überprüfung verbaler Gedächtnisfunktionen Neuropsychiatrie 20, 204–214.

28.

Pusswald

, Moser

, Gleiss

, Janzek-Hawlat

, Auff

, Dal-Bianco

, Lehrner

(2013) Prevalence of mild cognitive impairment subtypes in patients attending a memory outpatient clinic–comparison of two modes of mild cognitive impairment classification. Results of the Vienna Conversion to Dementia Study Alzheimers Dement 9, 366–376.

29.

McKhann

, Drachman

, Folstein

, Katzman

, Price

, Stadlan

(1984) Clinical diagnosis of Alzheimer’s disease: Report of theNINCDS-ADRDA Work Group under the auspices of department of healthand human services task force on Alzheimer’s disease Neurology 34, 939–944.

30.

Saß

, Wittchen

H-U

, Zaudig

, Houben

(2003 Diagnostisches und statistisches Manual psychischer Störungen - Textrevision Göttingen

DSM-IV-TR. Hogrefe Verlag für Psychologie

31.

Folstein

, Folstein

, McHugh

(1975) “Mini-mentalstate”. A practical method for grading the cognitive state ofpatients for the clinician J Psychiatr Res 12, 189–198.

32.

Nasreddine

, Phillips

, Bedirian

, Charbonneau

, Whitehead

, Collin

, Cummings

, Chertkow

(2005) The Montreal Cognitive Assessment, MoCA: A brief screening tool for mild cognitive impairment J Am Geriatr Soc 53, 695–699.

33.

Hindmarch

, Lehfeld

, de Jongh

, Erzigkeit

(1998) The Bayer Activities of Daily Living Scale (B-ADL) Dement Geriatr Cogn Disord 9(Suppl 2), 20–26.

34.

Stasinopoulus

, Rigby

(2007) Generalized additive models for location scale and shape (GAMLSS) J Stat Softw 23, 1–46.

35.

Hautzinger

, Keller

, Kühner

(2006 Beck Depressions-Inventar Frankfurt

(BDI-II), Hurt

36.

Njegovan

, Hing

, Mitchell

, Molnar

(2001) The hierarchy of functional loss associated with cognitive decline in older persons J Gerontol A Biol Sci Med Sci 56, M638–M643.

37.

Lehrner

, Kogler

, Lamm

, Moser

, Klug

, Pusswald

, Dal-Bianco

, Pirker

, Auff

(2015) Awareness of memory deficitsin subjective cognitive decline, mild cognitive impairment,Alzheimer’s disease and Parkinson’s disease IntPsychogeriatr 27, 357–366.

38.

Schmidtke

, Pohlmann

, Metternich

(2008) The syndrome of functional memory disorder: Definition, etiology, and natural course Am J Geriatr Psychiatry 16, 981–988.

39.

Lehrner

, Kirchebner

, Auff

, Pusswald

(2015) Higher level of neuroticism in patients with problems with the sense of smell Wien Klin Wochenschr 127, 303–307.