Functional cognitive disorder in subjective cognitive decline-A 10-year follow-up.

OBJECTIVES: In memory clinics, patients with significant memory complaints without objective neuropsychological findings are common. They are classified as subjective cognitive decline (SCD) and, as a group, face a heightened risk for future dementia. However, the SCD group is heterogeneous and comprises patients suffering from a somatoform condition, namely functional cognitive disorder (FCD). These patients make up at least 11% of memory clinics' attendees. The aim of this long-term follow-up study was to investigate if patients diagnosed with FCD also face a higher risk of developing dementia. METHODS: Forty-two Patients were recruited at a university hospital memory clinic. FCD was diagnosed according to the Schmidtke criteria (see Table 1). Ten years later, all were invited again. Participants were interviewed, screened for depression and given neuropsychological tests of verbal memory and information processing speed. Cognitive impairment was defined as performance below 1.5 standard deviations (SD) of the age-related mean. RESULTS: Twenty-eight of 42 patients (67%) took part in this follow-up. The group's mean results in both cognitive measures were stable over time. All individual performances were within 1.5 SD. With 10 patients (24%), brief contact was successful and manifest dementia could be excluded. Four patients (10%) could not be contacted. CONCLUSIONS: In retrospect, the Schmidtke criteria for FCD safely identified memory clinic attendees with SCD who did not proceed to Mild Cognitive Impairment or dementia. None of the patients who could be contacted for this follow-up after a decade (90% of baseline participants) showed signs of dementia.

[Driving ability in mild cognitive impairment and dementia]. / Fahrtauglichkeit bei Leichter Kognitiver Störung und Demenz.

Executive functions, visuo-spatial processing and control of behaviour are pertinent for safe driving. In patients with mild cognitive impairment and dementia, these abilities can be impaired, in addition to age-related impairments, and driving ability can be compromised at an early stage. Neurologists and psychiatrists play an important role in the examination, counseling and, if required, the issuing of a medical driving ban. Mistakes in this process may ensue forensic sequelae for the involved physicians. The present article presents the relevant conditions and associated cognitive impairments, and gives some recommendations on the neuropsychological workup and on the communication with patients and relatives concerning driving.

The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment.

BACKGROUND: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials. OBJECTIVE: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. RESULTS: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aß42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects. CONCLUSION: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.

Subjective cognitive decline is related to CSF biomarkers of AD in patients with MCI.

OBJECTIVE: To test whether, in individuals with mild cognitive impairment (MCI), different measures of subjective cognitive decline (SCD) in the memory domain predict abnormal CSF biomarkers of Alzheimer disease (AD). METHODS: We analyzed the multicenter baseline (cross-sectional) data of 245 patients with MCI. SCD was measured quantitatively with the Subjective Memory Decline Scale (SMDS) and qualitatively by assessing particular concerns associated with self-experienced worsening of memory. Logistic regression models were used to examine associations between SCD and abnormal CSF biomarkers, taking into account objective memory impairment, depressive symptoms, and education as covariates. RESULTS: Abnormal CSF ß-amyloid 1-42 (Aß42) and more depressive symptoms were associated with higher SMDS scores and with the report of memory concerns. Risk of abnormal CSF Aß42 increased by an estimated 57% for a 1-SD increase in SMDS scores and was doubled in patients who had SMDS scores >4 or who reported memory concerns, respectively. In addition, both SCD measures predicted risk of having a biomarker signature indicative of prodromal AD defined as presence of low CSF Aß42 together with either high CSF tau or CSF phosphorylated tau 181 levels. CONCLUSIONS: In MCI, specific aspects of SCD severity and quality are related to CSF biomarkers indicative of AD. This extends findings in pre-MCI samples and calls for an improved operational assessment of SCD in MCI. This might be useful for sample enrichment strategies for increased likelihood of AD pathology.

Combined treatment with memantine and galantamine-CR compared with galantamine-CR only in antidementia drug naïve patients with mild-to-moderate Alzheimer's disease.

INTRODUCTION: Several studies have tested the N-methyl-D-aspartate-receptor antagonist memantine as an add-on to pre-existing treatment with acetylcholinesterase inhibitors. The objective of this study was to evaluate the efficacy and safety of a combined memantine and galantamine-CR de novo regimen compared with galantamine-CR only treatment in never treated patients with mild-to-moderate Alzheimer's disease (AD). METHODS: Antidementia drug-naïve participants (n = 232) with probable, mild-to-moderate AD, and mini-mental state examination scores between 15 and 26 (inclusive) were randomized to receive either 20 mg/day memantine plus 24 mg/day galantamine-CR or 24 mg/day galantamine-CR plus placebo in a 52-week, prospective, double-blind, controlled trial. The primary outcome measurement was the change on the Alzheimer's disease assessment scale-cognition score. Secondary measures comprised the Alzheimer's Disease Cooperative Study-activities of daily living inventory and the clinical dementia rating. RESULTS: At the end of the trial, there were no statistically significant differences between the galantamine-CR/memantine combination and galantamine-CR only group in primary and secondary outcome measurements. The incidence and the severity of adverse events were similar between the groups. DISCUSSION: In this trial, memantine in combination with galantamine-CR did not show an advantage with respect to cognition, function, and behavior in previously never treated patients with mild-to-moderate AD. There were no significant differences in tolerability and safety between the groups. Thus, a de novo combination treatment results in no significant improvement in disease progression (current controlled trials number: NCT01921972).

Are There Any Connections between Language Deficits and Cognitive Slowing in Alzheimer's Disease?

BACKGROUND: Speech disorders already occur in the early phases of Alzheimer's disease (AD). As a possible cause, problems of executive processes are discussed. Cognitive slowing is also repeatedly addressed. AIMS: Are there any connections between cognitive slowing and speech disorders in AD? And is there a relationship between cognitive slowing and executive processes? METHODS: The data of 72 healthy controls and 52 AD patients were examined with regard to their language performance and their response times in a computerized Stroop paradigm. RESULTS: The AD patients showed significantly worse results in all language tests as well as much longer reaction times in all Stroop conditions, especially in the interference condition (Stroop 3). Speech errors and response times correlated with severity (MMSE), and the speech errors correlated with the reaction times in Stroop 3 (interference condition, which reflects the processing time of executive processes). CONCLUSION: The most interesting question now is: How are language processing and executive processing time (Stroop 3) related?

Memory concerns, memory performance and risk of dementia in patients with mild cognitive impairment.

BACKGROUND: Concerns about worsening memory ("memory concerns"; MC) and impairment in memory performance are both predictors of Alzheimer's dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations. We examined the risk of incident AD by MC and memory performance in patients with mild cognitive impairment (MCI). METHODS: We analyzed data of 417 MCI patients from a longitudinal multicenter observational study. Patients were classified based on presence (n = 305) vs. absence (n = 112) of MC. Risk of incident AD was estimated with Cox Proportional-Hazards regression models. RESULTS: Risk of incident AD was increased by MC (HR = 2.55, 95%CI: 1.33-4.89), lower memory performance (HR = 0.63, 95%CI: 0.56-0.71) and ApoE4-genotype (HR = 1.89, 95%CI: 1.18-3.02). An interaction effect between MC and memory performance was observed. The predictive power of MC was greatest for patients with very mild memory impairment and decreased with increasing memory impairment. CONCLUSIONS: Our data suggest that the power of MC as a predictor of future dementia at the MCI stage varies with the patients' level of cognitive impairment. While MC are predictive at early stage MCI, their predictive value at more advanced stages of MCI is reduced. This suggests that loss of insight related to AD may occur at the late stage of MCI.

CSF-tau and CSF-Abeta(1-42) in posterior cortical atrophy.

OBJECTIVE: Our purpose was to measure Abeta(1-42), T-tau and P-tau(181) in the cerebrospinal fluid (CSF) of patients with posterior cortical atrophy (PCA), a presenile dementia likely to represent a variant of Alzheimer's disease (AD). METHODS: CSF samples from 34 subjects including 9 patients with PCA, 11 age-matched patients with AD and 14 age-matched cognitively healthy controls were analyzed using commercially available ELISA kits. RESULTS: The Abeta(1-42), T-tau and P-tau(181) levels in PCA patients differed significantly (p < 0.02) from those in healthy controls but were indistinguishable from subjects with a clinical diagnosis of AD. CONCLUSION: High T-tau and P-tau(181) and low Abeta(1-42) levels in PCA - typically observed in AD - indicate that the underlying pathology of PCA is usually AD. If these findings are replicated in PCA patients with autopsy-confirmed AD neuropathology, PCA patients may be eligible for disease-modifying AD treatments.

Multicentre variability of MRI-based medial temporal lobe volumetry in Alzheimer's disease.

Magnetic resonance imaging (MRI)-based volumetry of medial temporal lobe regions is among the best established biomarker candidates of Alzheimer's disease (AD) to date. This study assessed the effect of multicentre variability of MRI-based hippocampus and amygdala volumetry on the discrimination between patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and on the association of morphological changes with ApoE4 genotype and cognition. We studied 113 patients with clinically probable AD and 150 patients with amnestic MCI using high-resolution MRI scans obtained at 12 clinical sites. We determined effect sizes of group discrimination and random effects linear models, considering multicentre variability. Hippocampus and amygdala volumes were significantly reduced in AD compared with MCI patients using data pooled across centres. Multicentre variability did not significantly affect the power to detect a volume difference between AD and MCI patients. Among cognitive measures, delayed recall of verbal and non-verbal material was significantly correlated with hippocampus and amygdala volumes. Amygdala and hippocampus volumes were not associated with ApoE4 genotype in AD or MCI. Our data indicate that multicentre acquisition of MRI data using manual volumetry is reliable and feasible for cross-sectional diagnostic studies, and they replicate essential findings from smaller scale monocentre studies.

[Development and evaluation of a group therapy for functional memory and attention disorder]. / Konzeption und Erprobung eines gruppentherapeutischen Behandlungskonzepts für die funktionelle Gedächtnis- und Konzentrationsstörung.

OBJECTIVES: Functional Memory and Attention Disorder (FMD) is regularly seen in patients presenting in psychosomatic or memory clinics. The aim of this study was the evaluation of a novel group therapy for FMD in a randomized controlled trial. METHODS: 40 FMD patients were randomly assigned to either the experimental (EG) or the wait-list control group (CG). Out of these 35/31 were analysed (intent to treat vs. observed cases respectively). The intervention consisted of psychoeducation, cognitive restructuring, stress management, relaxation and mindfulness techniques. Data were collected at baseline, three months (post-intervention) and six months (follow-up). Primary outcome was the memory self-efficacy measure of the Metamemory in Adulthood Questionnaire (MSE). Secondary outcomes were the sum scores of the Perceived Stress Questionnaire (PSQ) and the SCL-90-R. RESULTS: The EG showed a significantly higher improvement on MSE at follow-up than the CG. No significant group differences emerged on PSQ or SCL-90-R. The CG showed stable MSE scores during the waiting period without intervention. However, after the CG received their therapy the same pattern on MSE scores as seen in the EG emerged. CONCLUSIONS: This study provides preliminary evidence for an improvement of memory self efficacy in FMD through a newly devised group therapy program consisting of different modules. This result ought to be replicated in larger studies.

Validation of two inventories for the diagnosis and monitoring of functional memory disorder.

OBJECTIVE: Functional memory disorder (FMD) is an acquired nonorganic condition characterized by significant deficits of memory and concentration that occur in daily living and are thought to be caused by psychosocial burden and distress. FMD is an important differential diagnosis to organic mild cognitive impairment. Although frequent, FMD is under-researched and mostly diagnosed by exclusion rather than by positive diagnostic criteria. Diagnosis can be difficult in patients with borderline cognitive test results. METHODS: To aid in the clinical diagnosis and monitoring of FMD, a short 10-item FMD questionnaire and a 22-item FMD rating scale were developed. They asses a range of memory complaints thought to be indicative of FMD. Each of the two inventories was applied and evaluated in a separate study involving FMD patients and control groups. In one study, the natural course of FMD was observed. In the other study, the effect of a therapeutic intervention was assessed. Here, we present the full text of the two FMD inventories and data on test quality characteristics. RESULTS: Internal consistency and split-half-reliability indices were excellent throughout. At suitable cutoffs, both versions discriminated FMD patients from control subjects with high accuracy. Both also demonstrated discriminant construct validity. Moreover, the long version demonstrated high test-retest reliability and convergent construct validity and proved to be sensitive to change. CONCLUSION: The short version of the FMD inventory is a helpful tool in the clinical diagnosis of FMD. The longer version is suitable for monitoring of FMD severity in the context of therapeutic interventions and observational studies. To determine whether the inventories can discriminate FMD from organic mild cognitive impairment, further studies are required.

Frequency of progranulin mutations in a German cohort of 79 frontotemporal dementia patients.

Mutations of the progranulin gene lead to progranulin haploinsufficiency and to frontotemporal lobar degeneration (FTD) with TDP-43 positive inclusions. It is assumed that unknown genetic, epigenetic and environmental factors are responsible for the observed marked degree of phenotypic variability among mutation carriers. This is the first published series of German FTD cases screened for progranulin mutations. Mean age at onset was 62 years, 19 patients (24%) had a positive family history of dementia, and 11 patients (14%) had a positive family history for probable FTD. Data on FTD subtypes are presented. Two mutations were identified (3%), one of which has been described previously. Clinically, both patients showed the frontal-behavioural variant type of FTD. Remarkably, a sibling of one case presented with progressive nonfluent aphasia, clinically distinct from the brother. We also performed quantitative PCR analyses to detect potential whole progranulin gene and exon deletions. Here, results were negative.

Early and differential diagnosis of dementia and mild cognitive impairment: design and cohort baseline characteristics of the German Dementia Competence Network.

BACKGROUND: The German Dementia Competence Network (DCN) has established procedures for standardized multicenter acquisition of clinical, biological and imaging data, for centralized data management, and for the evaluation of new treatments. METHODS: A longitudinal cohort study was set up for patients with mild cognitive impairment (MCI), patients with mild dementia and control subjects. The aims were to establish the diagnostic, differential diagnostic and prognostic power of a range of clinical, laboratory and imaging methods. Furthermore, 2 clinical trials were conducted with patients suffering from MCI and mild to moderate Alzheimer's Disease (AD). These trials aimed at evaluating the efficacy and safety of the combination of galantamine and memantine versus galantamine alone. RESULTS: Here, we report on the scope and projects of the DCN, the methods that were employed, the composition and flow within the diverse groups of patients and control persons and on the clinical and neuropsychological baseline characteristics of the group of 2,113 subjects who participated in the observational and clinical trials. CONCLUSION: These data have an impact on the procedures for the early and differential clinical diagnosis of dementias, the current standard treatment of AD as well as on future clinical trials in AD.

How are memory complaints in functional memory disorder related to measures of affect, metamemory and cognition?

OBJECTIVE: Memory complaints are a common finding in outpatients, especially in psychosomatic and neurological practice. In a substantial group of patients persistent memory complaints are found in the absence of abnormal neuropsychology. Different labels such as "functional memory complaint" have been suggested for this phenomenon. We characterise a group of patients with such memory complaints, which we termed functional memory disorder (FMD). The aim of the present study is to describe patients with FMD. METHODS: Thirty-nine patients with FMD were compared to 38 control subjects. Data were collected on the German version of the Rey Auditory Verbal Learning test and the Zahlenverbindungstest (cognitive speed), subscales of the Metamemory in Adulthood questionnaire (MIA), the Perceived Stress Questionnaire (PSQ), the Global Severity Index (GSI) of the Symptom Checklist, the Beck Depression Inventory (BDI), and other psychological questionnaire measures. RESULTS: We found significant group differences on all psychological questionnaire measures, with more pathological scores in the patient group. GSI and PSQ were the best predictors of memory self-efficacy. MIA-Memory Self-Efficacy (MSE), MIA-Achievement, and BDI were the best predictors of group membership (FMD vs. control group). When MSE was excluded, MIA-Achievement and BDI or GSI were the only predictors of group membership. Neuropsychological measures predicted neither MSE nor group membership. CONCLUSIONS: Pathological scores on measures of metamemory, stress, and depression are typical of FMD. Low MSE and a high memory-related achievement motivation seem to be key features of FMD. Other important features are increased perceived stress, general psychosomatic complaint, and elevated depression scores. Neuropsychological test performance is not associated with FMD symptoms.

The syndrome of functional memory disorder: definition, etiology, and natural course.

OBJECTIVES: Nonorganic, functional memory disorder (FMD) is frequent in memory clinic patients, and is an important differential diagnosis to prodromal dementia. The authors propose a definition of FMD as an acquired medical and psychological condition that is closely related to psychosocial burden and distress. DESIGN: Prospective follow-up study, aimed to evaluate the natural course of FMD. SETTING: University hospital memory clinic. PARTICIPANTS: Seventy-three patients who suffered memory deficits and psychological distress and had normal test results. Forty-six attended a follow-up examination after a mean delay of 20.1 months. MEASUREMENTS: FMD severity was assessed with a structured inventory and an overall self-rating scale. Objective performance was assessed by standardized tests of memory and attention. RESULTS: Identified causes of distress were overwork, interpersonal conflicts, somatic illness, adjustment disorder, dysthymia, and Alzheimer phobia. At follow-up, FMD had resolved in only six patients, and persisted in 39. Average symptom severity showed only a minor reduction. CONCLUSION: FMD is, in many instances, a long-term rather than transient problem. Possible reasons include the persistence of burden factors and the failure to evade the "stress spiral" of mutual reinforcement of distress and cognitive dysfunction.

High rate of conversion to Alzheimer's disease in a cohort of amnestic MCI patients.

BACKGROUND: A large proportion of patients with amnestic mild cognitive impairment (MCI) progress to Alzheimer's disease (AD), but the rate of conversion is highly variable, depending on selection and inclusion criteria. In the present prospective study, amnestic MCI criteria were applied in order to enrich the study population with prodromal AD patients. METHODS: A composite CERAD word list learning z-score of -1 was applied as a cut-off for memory performance at baseline. Competing causes of memory impairment other than prodromal AD were actively excluded. A cohort of 88 amnestic MCI patients was included; 75 were available for follow-up. RESULTS: After a mean delay of 19 months, 44% were found to have converted to AD, corresponding to an annualized conversion rate of 28%. The rate of new diagnoses other than stable MCI or AD was 6%. Baseline neuropsychological variables were not instrumental to predict progression. CONCLUSION: Amnestic MCI patients, as identified by the present set of criteria, carry a high risk of median-term progression to AD.

The Clock Reading Test: validation of an instrument for the diagnosis of dementia and disorders of visuo-spatial cognition.

BACKGROUND: The 12-item Clock Reading Test (CRT) allows a fine-graded assessment of clock-reading ability. It has a strong focus on visuo-spatial processing and requires no executive processing. This study evaluated the reliability, validity, sensitivity and specificity of the CRT for the diagnosis of dementia and visuo-spatial dysfunction. METHODS: The CRT, the Clock Drawing Test (CDT) and other tests were applied to groups of 200 subjects with dementia, 105 subjects with mild cognitive impairment (MCI), 20 subjects with focal parietal lesions and 64 elderly control subjects. RESULTS: The CRT was found to be reliable and sensitive for the detection of cognitive impairment in parietal lesions, Alzheimer-, mixed- and Lewy Body dementia. Normal subjects and patients with MCI, frontotemporal dementia or cerebral small vessel disease showed little or no impairment. CONCLUSION: CRT and CDT are clock-processing tests with different demand profiles. They can supplement each other in the neuropsychological diagnosis of dementia and visuo-spatial dysfunction.

Multiple chemical sensitivity syndrome (MCS)--suggestions for an extension of the U.S. MCS-case definition.

PURPOSE: To validate and extend the US case definition for the Multiple Chemical Sensitivity Syndrome (MCS) from 1999 by a systematic literature-review. DATA SOURCE: MEDLINE-research from 1997 to August 2003, research in the Cochrane-Library in August 2003, earlier reviews since 1997. STUDY SELECTION: Headings and abstracts were screened by one reviewer. All references dealing with multiple chemical sensitivities (MCS) which covered topics of interest such as symptom-profiles, differential diagnostic procedures, etc. were included in the analysis. DATA EXTRACTION AND SYNTHESIS: Topic-specific data extraction and synthesis was done by one reviewer. Data interpretation was discussed by all other authors. RESULTS: Out of 1429 references 36 publications proved to be suitable for the review. The results can be summarized as follows: exposure-related symptoms associated with self-reported multiple chemical sensitivities can be divided into non-specific complaints of the central nervous system--CNS (main characteristics) and functional disturbances in other organ systems (optional complaints). There is a significant overlap of MCS, CFS and fibromyalgie. At present no standards for a diagnostic procedure based on the criteria outlined above are existing CONCLUSIONS: MCS should only be diagnosed in patients who are mainly suffering from exposure-related non-specific complaints of the Central nervous system. The suggested diagnostic procedure follows the guidelines for CFS which are extended by diagnostic clarification of functional disturbances in other organ systems.