Jette Stokholm

Awareness of Deficits in Mild Cognitive Impairment and Alzheimer’s Disease: Do MCI Patients Have Impaired Insight?

In this study we investigated impaired awareness of cognitive deficits in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Very few studies have addressed this topic, and methodological inconsistencies make the comparison of previous studies difficult. From a prospective research program 36 consecutive patients with mild AD (MMSE above 19), 30 with amnesic MCI and 33 matched controls were examined. Using three methods for awareness assessment we found no significant differences in the level of awareness between MCI and AD. Both groups had impaired awareness and significant heterogeneity in the clinical presentation of awareness. The results demonstrate that subjective memory problems should not be a mandatory prerequisite in suspected dementia or MCI, which makes reports from informants together with thorough clinical interview and observation central when assessing suspected dementia disorders.

Semantic Memory Impairment in the Earliest Phases of Alzheimer’s Disease

The presence and the nature of semantic memory dysfunction in Alzheimer’s disease (AD) have been widely debated. This study aimed to determine the frequency of impaired semantic test performances in mild AD and to study whether incipient semantic impairments could be identified in predementia AD. Five short neuropsychological tests sensitive to semantic memory and easily applicable in routine practice were administered to 102 patients with mild AD (Mini-Mental State Examination score above 19), 22 predementia AD patients and 58 healthy subjects. ‘Category fluency’ and ‘naming of famous faces’ were the most frequently impaired tests in both patient groups. The study demonstrated that impairments on semantically related tests are common in mild AD and may exist prior to the clinical diagnosis. The results imply that assessment of semantic memory is relevant in the evaluation of patients with suspected AD.

Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation.

We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer’s disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre‐symptomatic and affected family members underwent multidisciplinary (clinical, molecular, neuroimaging and neuropathological) examinations. Treatment with memantine in a family member with early symptoms, based on the clinical phenotype and the lack of specific treatment, appears to stabilize the disease course and increase the glucose metabolism in cortical and subcortical areas, as determined by serial [F18]FDG‐PET scanning before and after initiation of treatment. Neuropathological examination of a second affected and mutation‐positive family member showed moderate atrophy of the temporal lobes including the hippocampi. Microscopy revealed abundant numbers of tau‐positive neurofibrillary tangles in all cortical areas and in some brainstem nuclei corresponding to a diagnosis of frontotemporal lobe degeneration on the basis of a MAPT mutation. The clinical and genetic heterogeneity of autosomal dominant inherited dementia must be taken into account in the genetic counselling and genetic testing of families with autosomal dominantly inherited dementia in general.

Heterogeneity in executive impairment in patients with very mild Alzheimer's disease.

Background/Aims: The presence of executive impairment in mild Alzheimer’s disease (AD) has primarily been demonstrated by means of group comparison. Whether executive dysfunction is a common feature of mild AD or only present in a subgroup of patients remains unclear. The aim of this study was to describe the frequency of impairment on a set of internationally well-known executive tests in patients with very mild AD. Methods: Thirty-six patients with very mild AD (MMSE scores above 23) and 32 healthy control subjects were administered a battery of 7 executive tests: Trail Making part B, Stroop Interference Test, modified Wisconsin Card Sorting Test (WCST), category- and letter-based verbal fluency, a design fluency task and the Similarities subtest from WAIS. Impairment was defined as a score of 2 SD or more below control means. Results: Executive impairment on at least 1 measure was seen in 76% of the patients, and 50% were impaired on 2 or more tests. Trail Making B and Stroop Interference Test were impaired in more than 40%, whereas only few patients were impaired on Similarities, WCST and design fluency. A wide variation of executive test profiles was seen among the patients. Conclusion: Executive impairments are common in early AD and not just a feature characteristic of a subgroup of patients. Complex attentional skills are more frequently affected than other executive functions. There is, however, considerable heterogeneity among AD patients in the pattern of executive dysfunction.

The Executive Interview as a Screening Test for Executive Dysfunction in Patients with Mild Dementia

Objectives: To validate the Executive Interview (EXIT25) as a screening instrument for executive cognitive dysfunction in patients with mild dementia.

Validation of the Danish Addenbrooke's Cognitive Examination as a Screening Test in a Memory Clinic

Background: Addenbrooke’s Cognitive Examination (ACE) is a cognitive screening test developed to detect dementia. It has been validated in several countries. Validation studies have predominantly included patients with various degrees of dementia and healthy controls. Objective: The aim of this study was to evaluate the Danish version of ACE as a screening test for early dementia in an outpatient memory clinic. Further, we wanted to investigate the ability of the ACE to discriminate patients with early Alzheimer’s disease (AD) from patients with depression. Method: 78 patients with mild AD (MMSE ≥20), 30 non-demented patients diagnosed with depression (originally referred for evaluation of cognitive symptoms), and 63 healthy volunteers, all between 60 and 85 years of age, were included. All patients were given the ACE as a supplement to the standard diagnostic work-up. Results: The cut-off points for optimal trade-off between sensitivity and specificity for ACE were 85/86 (sensitivity 0.99, specificity 0.94). When these cut-off points were applied to the group of depressive patients, the specificity dropped to 0.64, indicating a great overlap in individual test scores for demented and depressed patients. Conclusion: The optimal cut-off points for ACE found in this Danish study were close to what is reported in most other European studies. The great overlap in ACE scores for demented and depressed patients emphasize that test scores must be interpreted with great caution when used in diagnostic work-up.

Overdiagnosis of dementia in young patients - a nationwide register-based study.

Background: Little is known about the quality of the diagnostic evaluation and the validity of dementia diagnoses in young patients established in routine clinical practice. The aim of this study was to investigate the validity of the diagnosis of dementia registered in the Danish nationwide hospital registers in young patients. Methods: Two hundred patients were randomly selected from 891 patients <65 years registered with a dementia diagnosis for the first time in 2008. The patients’ medical records were reviewed to evaluate if they fulfilled ICD-10 and/or DSM-IV criteria for dementia and current clinical criteria for specific dementia subtypes. Results: A registered diagnosis was found to be correct in only 59%. A misdiagnosis of dementia occurred primarily in patients with depression or alcohol abuse. Conclusion: Our results suggest that dementia is overregistered and overdiagnosed in young patients. This may be due to a different symptom profile of dementia in young patients, lack of knowledge among clinical physicians and the wide range of conditions which may be misinterpreted as dementia.

Performances on five verbal fluency tests in a healthy, elderly Danish sample

ABSTRACT Verbal fluency tests are widely used as measures of language and executive functions. This study presents data for five tests; semantic fluency (animals, supermarket items and alternating between cities and professions), lexical fluency (s-words), and action fluency (verbs) based on a sample of 100 cognitively intact elderly Danish subjects aged 60–87 years. We found mean scores similar to what has been reported from other countries. There was little influence of background variables: in four out of fives tests less than 20% of the variance could be explained by age, education, and estimated intelligence. Age had a greater impact than education on category based performance, while the opposite was the case for lexical- and action-based fluency. Overall, intelligence was of little importance. There was a positive and significant correlation between all tests, but with only low to moderate strength of association, indicating that various fluency tasks draw on different cognitive abilities and are not interchangeable.

A novel presenilin 2 mutation (V393M) in early‐onset dementia with profound language impairment

Background:  Mutations in the Presenilin 2 gene (PSEN2) are rare causes of Alzheimer’s disease (AD). Pathogenic mutations in the genes associated with autosomal dominant inherited AD have been shown to alter processing of the amyloid precursor protein (APP) resulting in a relative increase of the amount of Aβ42 peptide.

Atypical early-onset Alzheimer's disease caused by the Iranian APP mutation.

BACKGROUND Approximately 1% of all cases of Alzheimers disease are inherited autosomal dominantly, and to date, three causative genes have been found, the Presenilin 1 (PSEN1) gene, the Presenilin 2 (PSEN2) gene and the Amyloid precursor protein (APP) gene. We describe atypical phenotypic features in a family with a pathogenic APP gene mutation and discuss possible explanations for these atypical features. METHODS AND RESULTS We report a family with a history of dementia compatible with autosomal dominant transmission. The disease course in the proband was not typical for Alzheimers disease as the diagnosis was preceded by 8 years of an isolated amnesia. Further, the proband had epilepsy with complex partial seizures and central degenerative autonomic failure as determined by clinical physiology. Sequencing the three known causative Alzheimer genes revealed a pathogenic missense mutation, APP Thr714Ala (the Iranian mutation). CONCLUSIONS The atypical clinical phenotype with long prodromal phase, autonomic failure and seizures in this new proband with the APP Thr714Ala mutation illustrates the clinical heterogeneity in families with identical pathogenic mutations.