Expanding the Spectrum of Stress-Induced Childhood-Onset Neurodegeneration with Variable Ataxia and Seizures (CONDSIAS).

Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an extremely rare, autosomal recessive neurodegenerative disorder. It is caused by biallelic pathogenic variants in the ADPRS gene, which encodes an enzyme involved in DNA repair, and is characterized by exacerbations in relation to physical or emotional stress, and febrile illness. We report a 24-year-old female, who was compound heterozygous for two novel pathogenic variants revealed by whole exome sequencing. Additionally, we summarize the published cases of CONDSIAS. In our patient, onset of symptoms occurred at 5 years of age and consisted of episodes of truncal dystonic posturing, followed half a year later by sudden diplopia, dizziness, ataxia, and gait instability. Progressive hearing loss, urinary urgency, and thoracic kyphoscoliosis ensued. Present neurological examination revealed dysarthria, facial mini-myoclonus, muscle weakness and atrophy of hands and feet, leg spasticity with clonus, truncal and appendicular ataxia, and spastic-ataxic gait. Hybrid [18F]-fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) of the brain revealed cerebellar atrophy, particularly of the vermis, with corresponding hypometabolism. MRI of the spinal cord showed mild atrophy. After informed consent from the patient, we initiated experimental, off-label treatment with minocycline, a poly-ADP-polymerase (PARP) inhibitor, which has shown beneficial effects in a Drosophila fly model. The present case report expands the list of known pathogenic variants in CONDIAS and presents details of the clinical phenotype. Future studies will reveal whether PARP inhibition is an effective treatment strategy for CONDIAS.

Psychometric properties and reference data for Danish versions of Free and Cued Selective Reminding Test, Category Cued Memory Test and Logical Memory.

Memory assessment is a key element in neuropsychological testing. Gold standard evaluation is based on updated normative data, but in many small countries (e.g. in Scandinavia) such data are sparse. In Denmark, reference data exist for non-verbal memory tests and list-learning tests but there is no normative data for memory tests which capture narrative recall and cued recall. In a nation-wide study, Free and Cued Selective Reminding Test (FCSRT), WMS-III Logical Memory (LM) and a newly developed test Category Cued Memory Test (CCMT-48) were applied in 131 cognitively intact persons (aged 60-96 years). Regression-based reference data for Danish versions of FCSRT, CCMT-48 and LM adjusted for age, education and gender are provided. Gender and age-group had a significant impact on the expected scores, whereas the effect of education had a limited effect on expected scores. Test performances were significantly correlated in the range 0.21-0.51. Based on these findings and previous results it may be relevant to assess both free recall, cued recall and recognition to tap the earliest changes associated with neurodegeneration, and this study therefore provides an important supplement to existing Danish normative data. Future studies should investigate the discriminative validity of the tests and the clinical utility of the presented reference data.

Frequency and severity of semantic deficits in a consecutive memory clinic cohort.

BACKGROUND/AIM: Semantic memory deficits have been shown in dementia and mild cognitive impairment (MCI) by group comparisons. The aim of this study is to investigate the frequency of impairments on tests with semantic content in patients with dementia, MCI (amnestic and non-amnestic) and affective disorders. METHODS: A Famous faces test, Boston Naming Test and Category fluency were applied in 114 consecutive memory clinic patients and 95 healthy participants (all participants were 60 years old or older; dementia/MCI patients had Mini-Mental State Examination scores ≥20). RESULTS: Fifty-three patients were classified with dementia, 36 with MCI (14 amnestic, 22 non-amnestic) and 25 with affective disorders. Dementia and MCI patients differed significantly from the control group on all tests. Patients with dementia and MCI had impairments in about 40% of the cases (on the most sensitive tests). However, patients with affective disorders also had mild impairments on tests tapping semantic memory (25% were impaired on the most sensitive tests). Impairments on the Famous faces test were more frequently found in dementia and MCI as compared to patients with affective disorders. CONCLUSION: Short tests with semantic memory content are sensitive to changes in dementia and MCI, but impairments on such tests may also be found in other diseases, e.g. affective disorders.

Cognitive impairment in the preclinical stage of dementia in FTD-3 CHMP2B mutation carriers: a longitudinal prospective study.

OBJECTIVE AND METHODS: A longitudinal study spanning over 8 years and including 17 asymptomatic individuals with CHMP2B mutations was conducted to assess the earliest neuropsychological changes in autosomal dominant neurodegenerative disease frontotemporal dementia (FTD) linked to chromosome 3 (FTD-3). Subjects were assessed with neuropsychological tests in 2002, 2005 and 2010. RESULTS: Cross-sectional analyses showed that the mutation carriers scored lower on tests of psychomotor speed, working memory, executive functions and verbal memory than a control group consisting of not-at-risk family members and spouses. Longitudinal analyses showed a gradual decline in psychomotor speed, working memory capacity and global executive measures in the group of non-demented mutation carriers that was not found in the control group. In contrast, there were no significant group differences in domain scores on memory or visuospatial functions. On an individual level the cognitive changes over time varied considerably. CONCLUSION: Subjects with CHMP2B mutation show cognitive changes dominated by executive dysfunctions, years before they fulfil diagnostic criteria of FTD. However, there is great heterogeneity in the individual cognitive trajectories.

Severe and rapidly progressing cognitive phenotype in a SCA17-family with only marginally expanded CAG/CAA repeats in the TATA-box binding protein gene: a case report.

BACKGROUND: The autosomal dominant spinocerebellar ataxias (SCAs) confine a group of rare and heterogeneous disorders, which present with progressive ataxia and numerous other features e.g. peripheral neuropathy, macular degeneration and cognitive impairment, and a subset of these disorders is caused by CAG-repeat expansions in their respective genes. The diagnosing of the SCAs is often difficult due to the phenotypic overlap among several of the subtypes and with other neurodegenerative disorders e.g. Huntington's disease. CASE PRESENTATION: We report a family in which the proband had rapidly progressing cognitive decline and only subtle cerebellar symptoms from age 42. Sequencing of the TATA-box binding protein gene revealed a modest elongation of the CAG/CAA-repeat of only two repeats above the non-pathogenic threshold of 41, confirming a diagnosis of SCA17. Normally, repeats within this range show reduced penetrance and result in a milder disease course with slower progression and later age of onset. Thus, this case presented with an unusual phenotype. CONCLUSIONS: The current case highlights the diagnostic challenge of neurodegenerative disorders and the need for a thorough clinical and paraclinical examination of patients presenting with rapid cognitive decline to make a precise diagnosis on which further genetic counseling and initiation of treatment modalities can be based.

Performances on Rey Auditory Verbal Learning Test and Rey Complex Figure Test in a healthy, elderly Danish sample--reference data and validity issues.

This study presents Danish data for Rey Auditory Verbal Learning Test (RAVLT) and Rey Complex Figure Test (RCFT) from 100 subjects aged 60-87 years. Education and estimated verbal intelligence (DART score) had a significant impact on the RAVLT trial 1-5 score but not on other RAVLT measures. The RCFT copy score was significantly related to age and the DART score. On RCFT recall a highly significant difference was found between persons who could make a faultless copy and persons with incomplete copy performance. Thus, this study presents separate data for RCFT recall scores according to the subjects' copying performance (in separate tables for age and education groups). For all measures on both RAVLT and RCFT wide distributions of scores were found and the impact of this broad score range on the tests' discriminative validity is discussed. RAVLT performances for elderly were similar to previous published meta-norms, but the included sample of elderly Danes performed better on RCFT (copy and recall) than elderly from the United States.

Huntington's disease: effect of memantine on FDG-PET brain metabolism?

In this open-label pilot study, the authors evaluated the effect of memantine on the distribution of brain glucose metabolism in four Huntington's disease (HD) patients as determined by serial 18-fluoro-deoxyglucose [F(18)]FDG-PET scans over a period of 3-4 months (90-129 days, with one patient choosing to continue treatment over the 18-month follow-up period). The treatment regimen was well tolerated. No significant differences on neuropsychological parameters before and after treatment were detected; but the patient who continued treatment did not deteriorate at 18 months' reevaluation, whereas the three patients who had stopped treatment after 3 to 4 months had minor progression in all cognitive domains on re-evaluation 12 months after the end of treatment.

Allogenic hematopoietic stem cell transplantation in two siblings with adult metachromatic leukodystrophy and a systematic literature review.

Two siblings were diagnosed with adult metachromatic leukodystrophy (MLD) and treated with hematopoietic stem cell transplantation (HSCT). While the older sibling was symptomatic at the time of diagnosis, her younger brother was diagnosed and transplanted at the presymptomatic state. We describe patients' clinical, biochemical, and genetic features, as well as neuropsychological and neurophysiological test results, and brain magnetic resonance imaging from pretransplantation and posttransplantation assessments. Both patients converted to complete donor chimerism and arylsulfatase A levels normalized 3 months posttransplantation. Twelve months posttransplantation, neurological and neuropsychological assessment for both patients showed stabilization, and they remained stable for the 38 months long observation period. To assess the effect of HSCT used as treatment for the rare, adult MLD subtype on survival and stabilization, we performed a systematic literature review and included 7 studies with a total of 26 cases. Of these 26 cases, 6 patients died of HSCT-related complications and 2 patients had graft rejection. Of the remaining 18 patients, 2 patients improved after HSCT, 13 patients stabilized, and 3 patients progressed, suggesting that HSCT potentially benefits adult MLD patients. Larger studies focusing on this subtype are needed and recommendations on criteria for HSCT in adult MLD need to be evolved.

Hereditary spastic paraplegia caused by the PLP1 'rumpshaker mutation'.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterised by progressive spasticity and weakness in the lower limbs. Mutations in PLP1 on the X chromosome cause spastic paraplegia type 2 (SPG2) or the allelic Pelizaeus-Merzbacher Disease (PMD). The PLP1 protein is a major myelin protein involved in stabilisation and maintenance of the myelin sheath. The function of the protein has been studied in the rumpshaker mouse, which is a model of SPG2/PMD. OBJECTIVE: To characterise the phenotype of patients with the 'rumpshaker mutation.' PATIENTS: A family with HSP caused by the 'rumpshaker mutation.' RESULTS: The patients showed nystagmus during infancy and had early onset of HSP. They had normal cognition, and cerebral MRI showed relatively unspecific white matter abnormalities on T2 sequences without clear progression. Urinary urgency was reported among the female carriers. MRS of both patients showed increased myo-inositol in the white matter, while decreased N-acetylaspartate was found exclusively in the oldest patient. All evoked potential examinations were compatible with severe central demyelination, while no signs of peripheral demyelination or axonal degeneration were found. (18)F-FDG-PET scans were normal. CONCLUSION: The phenotypes of the patients reported here are the mildest described to be caused by the rumpshaker mutation and represent the mildest form among the spectrum of PLP1 related disorders. No definite symptoms in the female carriers could be ascribed to the mutation. These data suggest the pathology to be an underlying dysmyelinating disorder in combination with a central axonal degeneration.

Normative data for eight verbal fluency measures in older Danish adults.

Verbal fluency tests are quickly administered, easy to use, and regularly used in the neuropsychological assessment. The aim of this study was to present regression-based reference data for eight different verbal fluency tests in a Danish sample (aged 60-96 years) to determine the influence of age, gender, and education on test-performances. The results showed that age and education were significantly associated with both categories, lexical and alternating fluency tests, and gender had a significant impact on two tests. All tests were significantly correlated, but there was a much stronger association between tests of the same type (lexical versus category) than between different types of tests indicating that various fluency tasks draw on different cognitive abilities. Specific patterns of impairment can be analyzed using these normative data and may be important in the assessment of dementia spectrum disorders.

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 >or=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.

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

BACKGROUND: Approximately 1% of all cases of Alzheimer's 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 Alzheimer's 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.

Inflammatory markers of CHMP2B-mediated frontotemporal dementia.

Histopathological studies and animal models have suggested an inflammatory component in the pathomechanism of the CHMP2B associated frontotemporal dementia (FTD-3). In this cross-sectional study, serum and cerebrospinal fluid were analyzed for inflammatory markers in CHMP2B mutation carriers. Serum levels of CCL4 were increased throughout life. Serum levels of IL-15, CXCL10, CCL22 and TNF-α were significantly associated with cognitive decline, suggesting a peripheral inflammatory response to neurodegeneration. CSF levels of sTREM2 appeared to increase more rapidly with age in CHMP2B mutation carriers. The identification of a peripheral inflammatory response to disease progression supports the involvement of an inflammatory component in FTD-3.

[Frontotemporal dementia].

Frontotemporal dementia (FTD) refers to the clinical syndromes caused by various neurodegenerative diseases in the frontal and temporal lobes. Advances in the knowledge and understanding of these diseases have resulted in changes in the clinical as well as the genetic and pathological classification. This is a short review of the current classification and understanding of FTD.

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. DESIGN: Validation using group comparison and correlation studies. SETTING: The Copenhagen University Hospital Memory Clinic, a multidisciplinary outpatient clinic based in a neurological setting. PARTICIPANTS: Thirty-three patients with mild dementia (MMSE score > or =20) and 30 healthy controls. MEASUREMENTS: The EXIT25, a 25-item screening instrument for executive dysfunction, was administered to all participants. Global cognitive function was measured using the MMSE. Patients were evaluated using traditional neuropsychological tests for executive dysfunction (Wisconsin Card Sorting Test, Trail Making Part B, Stroop Test, verbal fluency, design fluency, and verbal abstraction). Changes in behavior and functional impairment in activities of daily living were assessed using the Frontal Behavioral Inventory (FBI) and the Disability Assessment for Dementia Scale. RESULTS: EXIT25 scores were significantly higher in patients than in the healthy controls; MMSE scores could not account for the differences. Thirteen of the 25 items separated the two groups. EXIT25 was found to correlate significantly with the Stroop Test, the verbal fluency tests, and the FBI. CONCLUSION: The EXIT25 is able to capture executive cognitive deficits not primarily related to the general level of intellectual reduction in patients with mild dementia. In clinical practice, the EXIT25 might be a valuable supplement to the MMSE.

Diagnostic profile of young and middle-aged memory clinic patients.

With the objective of characterizing the underlying conditions in younger patients with cognitive symptoms, 314 consecutive patients were studied, aged <60 years, referred to a multidisciplinary memory clinic over a period of 54 months. Fifteen percent of the patients fulfilled Diagnostic and Statistical Manual IV criteria for dementia, 17% had selective cognitive deficits, and 55% had no cognitive deficits. Cognitive symptoms in younger patients rarely reflect dementia but more often other medical and psychiatric conditions.

[Frontotemporal dementia--new understanding of Pick disease]. / Frontotemporal demens--ny viden om Picks sygdom.

Frontotemporal dementia is a relatively new term, which encompasses several degenerative diseases involving the frontal and anterior temporal lobes. The article gives a short overview of new knowledge in this field. Clinical criteria are in focus, but neuropathological aspects are also mentioned.

Inadequate diagnostic evaluation in young patients registered with a diagnosis of dementia: a nationwide register-based study.

BACKGROUND: Establishing a diagnosis of dementia in young patients may be complex and have significant implications for the patient. The aim of this study was to evaluate the quality of the diagnostic work-up in young patients diagnosed with dementia in the clinical routine. METHODS: Two hundred patients were randomly selected from 891 patients aged ≤65 years registered with a diagnosis of dementia for the first time in 2008 in Danish hospitals, and 159 medical records were available for review. Three raters evaluated their medical records for the completeness of the diagnostic work-up on which the diagnosis of dementia had been based, using evidence-based guidelines for the diagnostic evaluation of dementia as reference standards. RESULTS: According to the rater review, only 111 (70%) patients met the clinical criteria for dementia. An acceptable diagnostic work-up including all items of recommended basic diagnostic evaluation was performed in only 24%, although more often (28%) in the subgroup of patients where dementia was confirmed by raters. CONCLUSION: This first nationwide study of unselected young patients registered with a diagnosis of dementia indicated that the concept of dementia may be misinterpreted by clinicians and that a diagnosis of dementia in the young is only rarely based on a complete basic diagnostic work-up, calling for increased competency.

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

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.

Performances on Symbol Digit Modalities Test, Color Trails Test, and modified Stroop test in a healthy, elderly Danish sample.

This study presents Danish data for the Symbol Digit Modalities Test (SDMT), Color Trails Test (CTT), and a modified Stroop test from 100 subjects aged 60-87 years. Among the included demographic variables, age had the highest impact on test performances. Thus, the study presents separate data for different age groups. For SDMT and CTT1, Danish Adult Reading Test (DART) score also had a significant impact on test performances. The incongruent version of the modified Stroop test was significantly correlated to education. Moderate and significant correlations were found between the three tests. Even though the three tests are commonly used, few normative data for elderly exists. SDMT and CTT performances from this study were in the same range as previously published international norms, but the validity of the result from the modified Stroop test could not be investigated.