Susanne Gräber

Diagnostic Value of Subjective Memory Complaints Assessed with a Single Item in Dominantly Inherited Alzheimer’s Disease: Results of the DIAN Study

Objective. We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimers disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN). Methods. The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: n = 107; NCs: n = 109), early symptomatic (CDR 0.5; MCs: n = 48; NCs: n = 8), and dementia stage (CDR ≥ 1; MCs: n = 28; NCs: n = 0). These groups were subdivided by the presence or absence of SMCs. Results. At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs (P = 0.6). At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs (P = 1.0). At CDR ≥ 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset. Conclusions. The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials.

Memory dysfunction of the frontal type in normal ageing.

In this study healthy subjects divided into five consecutive age groups (20-60 years of age) completed a series of memory tasks which had previously been shown to reveal impairments in patients with frontal lobe lesions. Significant age differences were found for free recall, retention rates for material which required effortful encoding, memory for temporal order and prospective memory. In the tests addressing these memory functions, subjects of more than 60 years of age performed more poorly than the youngest group, and they also showed evidence of false recognition (increased false alarm rates and confabulatory responses). The general pattern suggests that inefficient frontal functioning might contribute to age-related memory problems.

Subtypes of mild cognitive impairment in patients with Parkinson's disease: evidence from the LANDSCAPE study

Objective Inconsistent results exist regarding the cognitive profile in patients with Parkinsons disease with mild cognitive impairment (PD-MCI). We aimed at providing data on this topic from a large cohort of patients with PD-MCI. Methods Sociodemographic, clinical and neuropsychological baseline data from patients with PD-MCI recruited in the multicentre, prospective, observational DEMPARK/LANDSCAPE study were analysed. Results 269 patients with PD-MCI (age 67.8±7.4, Unified Parkinsons Disease Rating Scale (UPDRS-III) scores 23.2±11.6) were included. PD-MCI subtypes were 39.4% non-amnestic single domain, 30.5% amnestic multiple domain, 23.4% non-amnestic multiple domain and 6.7% amnestic single domain. Executive functions were most frequently impaired. The most sensitive tests to detect cognitive dysfunctions were the Modified Card Sorting Test, digit span backwards and word list learning direct recall. Multiple stepwise regression analyses showed that global cognition, gender and age, but not education or disease-related parameters predicted PD-MCI subtypes. Conclusions This study with the so far largest number of prospectively recruited patients with PD-MCI indicates that non-amnestic PD-MCI is more frequent than amnestic PD-MCI; executive dysfunctions are the most typical cognitive symptom in PD-MCI; and age, gender and global cognition predict the PD-MCI subtype. Longitudinal data are needed to test the hypothesis that patients with PD-MCI with specific cognitive profiles have different risks to develop dementia.

Cognitive Profiles in Parkinson’s Disease and Their Relation to Dementia: A Data-Driven Approach

Parkinsons disease is characterized by a substantial cognitive heterogeneity, which is apparent in different profiles and levels of severity. To date, a distinct clinical profile for patients with a potential risk of developing dementia still has to be identified. We introduce a data-driven approach to detect different cognitive profiles and stages. Comprehensive neuropsychological data sets from a cohort of 121 Parkinsons disease patients with and without dementia were explored by a factor analysis to characterize different cognitive domains. Based on the factor scores that represent individual performance in each domain, hierarchical cluster analyses determined whether subgroups of Parkinsons disease patients show varying cognitive profiles. A six-factor solution accounting for 65.2% of total variance fitted best to our data and revealed high internal consistencies (Cronbachs alpha coefficients >0.6). The cluster analyses suggested two independent patient clusters with different cognitive profiles. They differed only in severity of cognitive impairment and self-reported limitation of activities of daily living function but not in motor performance, disease duration, or dopaminergic medication. Based on a data-driven approach, divers cognitive profiles were identified, which separated early and more advanced stages of cognitive impairment in Parkinsons disease without dementia. Importantly, these profiles were independent of motor progression.

Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.

BACKGROUND Data on gender-specific profiles of cognitive functions in patients with Parkinsons disease (PD) are rare and inconsistent, and possible disease-confounding factors have been insufficiently considered. METHOD The LANDSCAPE study on cognition in PD enrolled 656 PD patients (267 without cognitive impairment, 66% male; 292 with mild cognitive impairment, 69% male; 97 with PD dementia, 69% male). Raw values and age-, education-, and gender-corrected Z scores of a neuropsychological test battery (CERAD-Plus) were compared between genders. Motor symptoms, disease duration, l-dopa equivalent daily dose, depression - and additionally age and education for the raw value analysis - were taken as covariates. RESULTS Raw-score analysis replicated results of previous studies in that female PD patients were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.03), while men outperformed women in visuoconstruction (p = 0.002) and figural memory (p = 0.005). In contrast, gender-corrected Z scores showed that men were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.02; recognition, p = 0.04), while no difference was found for visuospatial tests. This picture could be observed both in the overall analysis of PD patients as well as in a differentiated group analysis. CONCLUSIONS Normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is stronger in women than in men with PD. Future studies are needed to replicate these findings, examine the progression of gender-specific cognitive decline in PD and define different underlying mechanisms of this dysfunction.

The Multiple Object Test as a Performance Based Tool to Assess Cognitive Driven Activity of Daily Living Function in Parkinson’s Disease

BACKGROUND There is need for multidimensional quantitative assessment of cognitive driven activities of daily living (ADL) functions in Parkinsons disease (PD). OBJECTIVE To determine whether there is an ADL profile related to cognitive impairment in PD assessed by the Multiple Object Test (MOT). We assumed MOT performance to be lower in PD patients versus controls and in PD patients with more severe cognitive impairment. METHODS 50 PD patients with no cognitive impairment (PD-NC), 54 patients with PD-mild cognitive impairment (PD-MCI), 29 with Parkinsons disease dementia (PDD), and 40 healthy controls (HC) were investigated. Besides comprehensive cognitive testing, the MOT, a performance based test consisting of five routine tasks (e.g., preparing a cup of coffee), was applied. Quantitative (total errors and time) and qualitative (error type) MOT parameters were analyzed. RESULTS Total time and number of MOT errors was increased in PD patients compared to controls (p < 0.001). These parameters also differentiated PDD patients from other cognitive groups (p < 0.05). No control subject had ≥ 4 errors in the MOT, but 30% of PD patients, especially PDD, scored above this cut-off. Omission (p < 0.001) and mislocation (p < 0.03) errors were more prominent in PDD than other cognitive groups. Perplexity errors did not differ between PD-MCI and PDD but between PD-NC and PDD (p = 0.01). MOT parameters discriminating between cognitive groups correlated mainly with lower test performance in psychomotor speed and executive function. CONCLUSION Performance based testing is promising to identify quantitative and qualitative ADL aspects differentiating between different cognitive groups which might be helpful for an early detection of PDD.

Clinical Characteristics with an Impact on ADL Functions of PD Patients with Cognitive Impairment Indicative of Dementia

Background Dementia in Parkinson’s disease (PD) is defined as cognitive decline severe enough to affect activities of daily living function (ADL). The aim of our exploratory study was to compare two groups of PD patients. Both groups had cognitive deficits severe enough to justify diagnosis of dementia, but they differed according to caregivers’ rating on ADL dysfunction. Parameters which differed between the two groups were interpreted to affect the caregivers’ perception of ADL dysfunction in PD patients with cognitive impairment indicative of Parkinson’s disease dementia. Methodology/Principal Findings Thirty of 131 Parkinson’s disease patients fulfilled the Movement Disorders Society Task Force – recommended, cognitive Level-I-criteria for dementia. According to standardized caregiver ratings, volunteers were grouped into 18 patients with (ADL-) and 12 without instrumental activities of daily living dysfunction (ADL+). Caregiver activities of daily living function ratings closely correlated with self-estimates of patients and those of physician (p<0.001). ADL- patients performed worse on tests assessing visual-construction (p<0.05) and attention (p=0.03) than ADL+ patients. Moreover, the postural instability and gait disorder subtype was more frequent in ADL- patients (p=0.009). ADL- patients tended to have more communication problems (p=0.05), more anxiety (p=0.05) and showed a tendency to be treated more often with neuroleptics (p=0.049) than ADL+. Conclusions/Significance Results indicate that worse attention, visual-construction abilities, the postural instability and gait disorder subtype, communication problems, medication and presence of anxiety are related to activities of daily living dysfunctions in Parkinson’s disease patients with cognitive decline indicative of dementia. Our data suggests that not only cognitive factors but also non-cognitive factors seem to be linked to the diagnosis of Parkinson’s disease dementia associated with significant impact on instrumental activities of daily living function. Further studies with larger sample sizes are needed to verify our results.

Home-Based Physical Behavior in Late Stage Parkinson Disease Dementia: Differences between Cognitive Subtypes

Background: For the early diagnosis of Parkinson disease dementia (PDD), objective home-based tools are needed to quantify even mild stages of dysfunction of the activities of daily living (ADL). Objectives: In this pilot study, home-based physical behavior was assessed to examine whether it is possible to distinguish mild cognitive impairment (PD-MCI) from PDD. Methods: Fifty-five patients with mild to severe Parkinson disease (PD) participated in this cross-sectional study. Based on comprehensive neuropsychological testing, PD patients were classified as cognitively nonimpaired (PD-NC), PD-MCI or PDD. For physical behavior assessments, patients wore the accelerometer DynaPort® (McRoberts) for 3 days. Ordinal logistic regression models with continuous Y were applied to correct results for motor impairment and depressive symptoms. Results: After excluding 7 patients due to insufficient wearing time, 48 patients with a mean of 2 recorded days were analyzed (17 PD-NC, 22 PD-MCI, 9 PDD). ADL-impaired PDD patients showed fewer sedentary bouts than non-ADL-impaired PD-MCI (p = 0.01, odds ratio [OR] = 8.9, 95% confidence interval [CI] = 1.8-45.2) and PD-NC (p = 0.01, OR = 10.3, CI = 1.6-67.3) patients, as well as a longer sedentary bout length (PD-NC: p = 0.02, OR = 0.1, CI = 0.02-0.65; PD-MCI: p = 0.02, OR = 0.14, CI = 0.03-0.69). These differences were mainly caused by fewer (PD-NC: p = 0.02, OR = 9.6, CI = 1.5-62.4; PD-MCI: p = 0.01, OR = 8.5, CI = 1.5-37.3) but longer sitting bouts (PD-NC: p = 0.03, OR = 0.12, CI = 0.02-0.80; PD-MCI: p = 0.04, OR = 0.19, CI = 0.04-0.93). Tests assessing executive function, visuoconstruction and attention correlated significantly with specific activity parameters (ρ ≥ 0.3; p < 0.05). Conclusion: Objective assessment of physical behavior, in particular the detection of sedentary bouts, is a promising contributor to the discrimination between PD-MCI and PDD.

Cognitive Performance Patterns in Healthy Individuals with Substantia Nigra Hyperechogenicity and Early Parkinson's Disease.

Introduction: Hyperechogenicity of the substantia nigra (SN+) is a risk marker for Parkinson’s disease (PD) which can be detected before the diagnosis. In healthy individuals, SN+ has been associated with slight deficits in specific cognitive functions, suggesting cognitive impairment as a possible pre-diagnostic marker for PD. However, the pattern of cognitive deficits associated with SN+ has not yet been compared with those present in PD. Methods: Data of 262 healthy individuals with normal echogenicity (SN-) and 48 healthy individuals with SN+ were compared with 82 early stage PD patients using the “Consortium to Establish a Registry for Alzheimer’s disease” test battery. First, the test clusters (factors) were identified using a principal component analysis (PCA). Mean group performance of cognitive tests belonging to distinct factors, according to the PCA, and single subtest performances were compared using analyses of variance. Second, the number of individuals with abnormal cognitive performances (z-score < -1.0) were compared between groups. Results: Verbal memory, semantic and executive function, and praxis were identified as components of cognitive performances. The SN+ group performed significantly worse than the SN- group in tests assessing semantic and executive function, with a non-significant decrease in verbal memory. On the subtest level, individuals of the SN+ group scored significantly lower than the SN- group on the Boston Naming Test (BNT; p = 0.008). In all subtests, the percentages of PD patients with values below the cut-off for abnormal performance were higher than in the SN- group. Moreover, more individuals from the SN+ group scored below the cut-off in the BNT (SN- = 8.4%, SN+ = 20.8%, p = 0.01) and TMT-B (SN- = 6.9%, SN+ = 16.7%, p = 0.02), compared to the SN- group. Conclusion: This study confirms poorer performance of healthy individuals with SN+ compared to SN- in specific cognitive domains. However, against the SN- group, the cognitive profile of the SN+ group was not fully consistent with the profile of early PD patients. Our data argues that cognitive impairment associated with SN+ might differ slightly from that seen in early PD. Compensational mechanisms in the early phases of neurodegeneration, and the fact that only a subgroup of SN+ will develop PD, may partly explain these differences.

Post-cueing deficits with maintained cueing benefits in patients with Parkinson's disease dementia

In Parkinson’s disease (PD), internal cueing mechanisms are impaired leading to symptoms like hypokinesia. However, external cues can improve movement execution by using cortical resources. These cortical processes can be affected by cognitive decline in dementia. It is still unclear how dementia in PD influences external cueing. We investigated a group of 25 PD patients with dementia (PDD) and 25 non-demented PD patients (PDnD) matched by age, sex, and disease duration in a simple reaction time task using an additional acoustic cue. PDD patients benefited from the additional cue in similar magnitude as did PDnD patients. However, withdrawal of the cue led to a significantly increased reaction time in the PDD group compared to the PDnD patients. Our results indicate that even PDD patients can benefit from strategies using external cue presentation but the process of cognitive worsening can reduce the effect when cues are withdrawn.