Friedel M. Reischies

Study on COgnition and Prognosis in the Elderly (SCOPE)

The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains >160 mmHg, or has decreased by <10 mmHg since the randomization visit, or DBP is >85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged.

Attention and Executive Control Predict Alzheimer Disease in Late Life: Results From the Berlin Aging Study (BASE)

OBJECTIVE Longitudinal studies of neuropsychological changes in the preclinical phase of Alzheimer disease (AD) have yielded mixed results. Although some studies report tests of episodic memory, others report tests of attention and executive functions as reliable predictors of subsequent AD. Following theoretical models of neuropsychological processes before AD onset, the authors examined the predictive value of attention and executive function in the preclinical phase of AD in old age. METHODS Authors studied the cognitive performance of 187 initially normal participants of the Berlin Aging Study, a community-based representative sample of Berlin citizens age 70 to 103, over a period of 4 years. Tests of attention and executive function (Digit Letter Test, Trailmaking Part B Test, Digit Symbol Substitution Test, and Identical Pictures Test) and of learning and recall functions (Activity Recall, Memory for Text, and Paired-Associate Learning) were administered at baseline. Diagnosis of AD was made according to NINCDS-ADRDA criteria (probable AD). Receiver operating characteristics curve analyses and Cox regression analyses were used to assess the diagnostic accuracy and predictive value of the neuropsychological tests at baseline for incident AD after 4 years. RESULTS After 4 years, 15 participants had developed AD. Tests of attention and executive function discriminated best between nonconverters and incident AD cases. A similar pattern was found in survival analyses; attention and executive function tests, together with tests of learning and recall, significantly predicted incident AD over and above age, gender, and education. CONCLUSION These results support theoretical models of attention and executive function in the preclinical phase of AD in old age.

Comorbidity of mild cognitive disorder and depression--a neuropsychological analysis.

Abstract Mild cognitive impairment is found in many cases of depression, and it is mostly assumed to improve during the time course of depression remission.Recent data question the reversibility of low cognitive test performance in depression. The aim of this study is to determine the degree of reversibility and the proportion of patients who will not demonstrate reversibility of cognitive dysfunction.Consecutive inpatients suffering from depression (N=102) were investigated and N=82 matched control subjects. N=57 of the patients were diagnosed as major depression according to DSM-IV. A total of N=67 could be retested after remission of depression (N=32 of the patients with major depression) and a matched control group (N=62). Neuropsychological tests were applied in a test session which avoids the effects of fatigue in the patients by the short duration of strenuous tests.For most neuropsychological tests an impaired performance in the depressed patients was found. About one third of the depression subjects performed in an impaired level in tests of averbal memory and verbal fluency (below 5th percentile). In the follow-up investigation, a slight improvement in performance could be assessed for both the depression and the control group, which was, however, attributed to a general test training effect. No normalization of cognitive test performance was found in spite of complete recovery of the affective symptoms. No correlation between the duration of the disease before the index episode or number of episodes and cognitive deficits could be found.The data of the neuropsychological deficits of depressed patients, which are stable in the time course of the affective disorder, may indicate that these patients may suffer from comorbidity of both depression and mild cognitive disorder. The findings are discussed as 1) indicating only a minor impact of the depressed mood on the cognitive performance and 2) they are consistent with a role of brain lesions which have been reported in several studies in a subgroup of depression.

Complex Mental and Physical Activity in Older Women and Cognitive Performance: A 6-month Randomized Controlled Trial

BACKGROUND Several reports suggest beneficial impacts of either physical or mental activity on cognitive function in old age. However, the differential effects of complex mental and physical activities on cognitive performance in humans remain to be clarified. METHODS This randomized controlled trial evaluates a cognitive and a physical standardized 6-month activity intervention (3 x 1.5 h/wk) conducted in Berlin (Germany). Two hundred fifty nine healthy women aged 70-93 years were randomized to a computer course (n = 92), an exercise course (n = 91), or a control group (n = 76), of whom 230 completed the 6-month assessment. Group differences in change over a period of 6 months in episodic memory (story recall, possible range, 0-21; word recall, possible range, 0-16), executive control (working memory, ie, time quotient of Trail Making Tests B/A), and verbal fluency were evaluated by analyses of covariance (intention to treat) adjusting for baseline, fluid intelligence, and educational level. RESULTS In contrast to the control group, both the exercise group, DeltaM (SD) = 2.09 (2.66), p < .001, and the computer group, DeltaM (SD) =1.89 (2.88), p < .001, showed improved delayed story recall. They maintained performance in delayed word recall and working memory (time measure) as opposed to the control group that showed a decline, DeltaM (SD) = -0.91 (2.15), p = .001, and DeltaM (SD) = 0.24 (0.68), p = .04, respectively. CONCLUSIONS In healthy older women, participation in new stimulating activities contributes to cognitive fitness and might delay cognitive decline. Exercise and computer classes seem to generate equivalent beneficial effects.

Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease

Objective: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). Methods: Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimers Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale–Revised. CSF was obtained from all patients. Results: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Aβ1-42/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD− patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. Conclusions: Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.

Effect of aging on stimulus-reward association learning

The flexible learning of stimulus-reward associations when required by situational context is essential for everyday behavior. Older adults experience a progressive decline in several cognitive functions and show deficiencies in neuropsychological tasks requiring flexible adaptation to external feedback, which could be related to impairments in reward association learning. To study the effect of aging on stimulus-reward association learning 20 young and 20 older adults performed a probabilistic object reversal task (pORT) along with a battery of tests assessing executive functions and general intellectual abilities. The pORT requires learning and reversing associations between actions and their outcomes. Older participants collected fewer points, needed more trials to reach the learning criterion, and completed less blocks successfully compared to young adults. This difference remained statistically significant after correcting for the age effect of other tests assessing executive functions. This suggests that there is an age-related difference in reward association learning as measured using the pORT, which is not closely related to other executive functions with respect to the age effect. In human aging, structural alterations of reward detecting structures and functional changes of the dopaminergic as well as the serotonergic system might contribute to the deficit in reward association learning observed in this study.

Depression bei Hochbetagten Ergebnisse der Berliner Altersstudie

ZusammenfassungIn der Berliner Altersstudie (BASE) wurde eine nach Alter und Geschlecht geschichtete Stichprobe von 516 Studienteilnehmern im Alter von 70 bis über 100 Jahren untersucht. Zur Diagnostik von depressiven Erkrankungen wurde neben den Fremd- und Selbstratingskalen (HAMD und CES-D) das halbstrukturierte GMS-A-Interview eingesetzt, auf dessen Basis Diagnosen nach DSM III-R erstellt wurden. Es fand sich eine Prävalenz von 9,1% für alle nach DSM III-R spezifizierten depressiven Störungen, wovon 4,8% Major Depression waren. Bei Hinzunahme von nach klinischer Einschätzung krankheitswertigen Depressionen, welche die Kriterien für eine spezifizierte DSM III-R-Diagnose jedoch nicht erfüllten, steigt die Depressionsprävalenz auf 26,9% an. Die Häufigkeiten in den verschiedenen Altersgruppen unterscheiden sich mit Ausnahme bei der CES-D nicht signifikant. Die Depressionsprävalenz für spezifizierte DSM III-R-Diagnosen ist bei Frauen mit 10,3% etwa doppelt so hoch wie bei Männern (5,6%). Depressive Patienten zeigen im Vergleich zu Kontrollpersonen keine signifikant schlechteren Werte im MMSE. Eine signifikant erhöhte Depressionsprävalenz findet sich im Vergleich zur Gesamtstichprobe bei Personen mit Multimorbidität (36,8%). Verheiratete Studienteilnehmer zeigen seltener eine depressive Erkrankung (14,9%). 13,2% der alten Menschen sprechen von Lebensüberdruß, 7,9% äußern einen Todeswunsch und 1,2% Suizidgedanken. Es besteht eine enge Beziehung zwischen Suizidalität und depressiven Erkrankungen. Im Bezug auf die Behandlung depressiver Störungen fand sich in 44% eine unzureichende Therapie. 6% der depressiven Studienteilnehmer wurden mit Antidepressiva behandelt, während 40% nur Benzodiazepine bekamen.SummaryIn the Berlin Aging Study (BASE) an age and gender stratified sample of 516 persons aged 70 to over 100 was assessed by means of the semi-structured GMS-A interview, the CES-D-self-rating scale and the Hamiltion-Depression-observer-rating scale. Prevalence rates were 4,8% for Major Depression, 9,1% for all DSM III-R specified depressive disorders and 26,9% of subthreshold depression was included. There was no increase in prevalence rates with age but an increase in scores on the self rating CES-D. The prevalence rates for DSM III-R specified depression in females was 10,3% and almost double that of men (5,6%). Depressed persons do not show significant cognitive impairment as measured with the MMSE in comparison to controls. As compared to the total sample higher prevalence rates of overall depression were seen in persons with multimorbidity (36,8%) and lower rates in married persons. 13,2% of the elderly talked about feeling tired with life, 7,9% had thoughts about death and 1,2% reported suicidal ideation, which was closely linked to depressive disorders. In 44% of depressed cases undertreatment was observed. Only 6% got Antidepressants but 40% benzodiazepines.

Reward-based decision-making and aging

Healthy aging is associated with a number of neuroanatomical and neurobiological alterations that result in various cognitive changes. Both, the dopaminergic as well as the serotonergic system are subject to change during aging. Receptor loss and severe structural changes in PFC and striatum have been reported. Aging is associated with a progressive decline in several cognitive functions, such as episodic memory, working memory, and processing speed. Furthermore, it is associated with deficits in tasks requiring adaptation to external feedback of right or wrong, or task-switching. Here, we develop the hypothesis that this loss of behavioral flexibility is caused by structural and functional alterations of the reward system leading to impairments in reward processing, learning stimulus reinforcement associations, and reward-based decision-making. We review (a) data on neural correlates and substrates of reward processing in young healthy animals and humans, (b) evidence for age related functional and structural alterations of the reward system, and (c) behavioral and neuroimaging data of age effects on reward-based decision-making processes. Implications for neuroeconomics and neurodegenerative diseases are discussed.

Altered function of ventral striatum during reward-based decision making in old age.

Normal aging is associated with a decline in different cognitive domains and local structural atrophy as well as decreases in dopamine concentration and receptor density. To date, it is largely unknown how these reductions in dopaminergic neurotransmission affect human brain regions responsible for reward-based decision making in older adults. Using a learning criterion in a probabilistic object reversal task, we found a learning stage by age interaction in the dorsolateral prefrontal cortex (dlPFC) during decision making. While young adults recruited the dlPFC in an early stage of learning reward associations, older adults recruited the dlPFC when reward associations had already been learned. Furthermore, we found a reduced change in ventral striatal BOLD signal in older as compared to younger adults in response to high probability rewards. Our data are in line with behavioral evidence that older adults show altered stimulus–reward learning and support the view of an altered fronto-striatal interaction during reward-based decision making in old age, which contributes to prolonged learning of reward associations.

Prevalence of dementia in old age: clinical diagnoses in subjects aged 95 years and older.

Epidemiologic studies have consistently shown an exponential increase in the prevalence of dementia in the very old, but different standards of the investigators and the instruments, as well as the selection of the samples, limit the comparison of these studies. They usually include only a small number of participants aged 90 years and older. This investigation focuses on whether there is an exponential increase in the prevalence of dementia in people aged 90 years and older. The Berlin Aging Study (BASE) consists of a representative sample of elderly aged 70 to 105 years stratified by age and gender. Analyses of a BASE first sample (N = 156) with 52 participants aged 90 years and older showed an exponential increase in dementia from age 70 up to age 94 years, but the group aged 95 years and older (N = 26) showed a plateau near 45%, with no further increase in dementia prevalence.