Prospective Study on Salivary Evening Melatonin and Sleep before and after Pinealectomy in Humans.

Melatonin is secreted systemically from the pineal gland maximally at night but is also produced locally in many tissues. Its chronobiological function is mainly exerted by pineal melatonin. It is a feedback regulator of the main circadian pacemaker in the hypothalamic suprachiasmatic nuclei and of many peripheral oscillators. Although exogenous melatonin is approved for circadian rhythm sleep disorders and old-age insomnia, research on endogenous melatonin in humans is hindered by the great interindividual variability of its amount and circadian rhythm. Single case studies on pinealectomized patients report on disrupted but also hypersomnic sleep. This is the first systematic prospective report on sleep with respect to pinealectomy due to pinealocytoma World Health Organization grade I without chemo- or radiotherapy. Before and after pinealectomy, 8 patients completed questionnaires on sleep quality and circadian rhythm (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Morningness-Eveningness Questionnaire), 2 nights of polysomnography, salivary evening melatonin profiles, and qualitative assessment of 2 weeks of actigraphy and sleep logs. Six patients were assessed retrospectively up to 4 years after pinealectomy. Before pinealectomy, all but 1 patient showed an evening melatonin rise typical for indifferent chronotypes. After pinealectomy, evening saliva melatonin was markedly diminished, mostly below the detection limit of the assay (0.09 pg/mL). No systematic change in subjective sleep quality or standard measures of polysomnography was found. Mean pre- and postoperative sleep efficiency was 94% and 95%, and mean sleep-onset latency was 21 and 17 min, respectively. Sleep-wake rhythm during normal daily life did not change. Retrospective patients had a reduced sleep efficiency (90%) and more stage changes, although this was not significantly different from prospective patients. In conclusion, melatonin does seem to have a modulatory, not a regulatory, effect on standard measures of sleep. Study output is limited by small sample size and because only evening melatonin profiles were assessed.

Cognitive decline in the behavioral variant of frontotemporal dementia.

BACKGROUND: Only a small number of studies on the natural disease course in behavioral variant frontotemporal dementia (bvFTD) have been conducted. This is surprising because knowledge about the progression of symptoms is a precondition for the design of clinical drug trials. METHODS: The aim of the present study was to examine the cognitive decline of 20 patients with mild bvFTD over one year using the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (CERAD-NAB). RESULTS: Within an average follow-up interval of 13 months, patient scores declined significantly in the Mini-mental-State-Examination (MMSE) and the CERAD-NAB subtests of naming, verbal and nonverbal memory. No significant changes were found in the CERAD-NAB subtests of category fluency, recognition, and visuoconstruction. The average annualized decline on the MMSE was 4.0 ± 4.9 points. Ceiling effects were detected in Figures Copy, Word List Recognition and Modified Boston Naming Test. Though the included patient group was rather homogeneous regarding severity of dementia, the cognitive changes were very heterogeneous. CONCLUSION: Given the heterogeneity of cognitive decline, the design of a test battery for clinical trials in FTD will be challenging. A cognitive battery should definitely include the MMSE, Word List Learning and Word List Delayed Recall.

Accelerated clinical decline in well-educated patients with frontotemporal lobar degenerations.

Education seems to protect against symptoms of neurodegeneration, but highly educated individuals experience faster cognitive decline after the onset of dementia. No studies on the effects of education on the clinical course in frontotemporal lobar degenerations (FTLD) exist. The aim of the study was to explore the effect of education on the rate of clinical deterioration in patients with FTLD. Thirty-five patients with FTLD were recruited and followed up for 20 months in average. A correlation was calculated between years of education and monthly rate of change on the clinical dementia rating scale sum of the boxes (CDR-SOB). A linear regression analysis with the CDR-SOB monthly rate of change as dependent, and the educational years and other variables possibly associated with the rate of clinical decline as independent variables was performed. There was a significant positive association between education and CDR-SOB monthly rate of change, indicating a faster decline in the well-educated. Education was the only significant predictor of clinical deterioration.

Cognitive rehabilitation in patients with mild cognitive impairment.

OBJECTIVE: To explore the benefits of a multi-component cognitive rehabilitation programme in patients with mild cognitive impairment (MCI). METHODS: Patients with MCI (n = 18) and patients with mild dementia in Alzheimer's disease (n = 10) participated in a 4-week cognitive rehabilitation programme in a day clinic setting. The intervention was provided in group format and included activity planning, self-assertiveness training, relaxation techniques, stress management, use of external memory aids, memory training, and motor exercise. RESULTS: After 4 weeks, MCI patients showed significant improvements on activities of daily living, mood, verbal and nonverbal episodic memory. In contrast, patients with mild dementia exhibited a non-significant increase in verbal memory but no other changes. MCI subjects allocated to the waiting list control condition (n = 12) showed a significant re-test effect on verbal episodic memory, but no improvement of everyday activities or mood. CONCLUSIONS: The study demonstrates that patients with MCI benefit from a multi-component cognitive rehabilitation programme with regard to activities of daily living, mood, and memory performance.

Pest controllers: a high-risk group for Multiple Chemical Sensitivity (MCS)?

INTRODUCTION: Based on the assumption that professional groups with frequent chemical exposure are at an increased risk for developing Multiple Chemical Sensitivity (MCS), a sample of 45 professional pest controllers was investigated. METHODS: The examination of the pest controllers consisted of a physical and laboratory examination with urine screening for pyrethroid metabolites, a psychiatric interview, a neuropsychological test battery, and a chemical sensitivity questionnaire. RESULTS: Persistent or serious work related health problems and chemical sensitivity were not reported. In urine, cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (Br(2)CA) was detected in 11%, 4-fluoro-3-phenoxybenzoic acid (F-PBA) in 7%. 3-phenoxybenzoic acid (3-PBA) exceeded the reference range in 9%, cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid (Cl(2)CA) in 20%. Increased liver enzymes and blood count deviations were rather common. 38% had psychiatric disorders. With few exceptions, neuropsychological testing results were normal. CONCLUSIONS: The results do not support the hypothesis that work-related insecticide exposure promotes chemical sensitivity.

A 6-month, open-label study of memantine in patients with frontotemporal dementia.

OBJECTIVE: To evaluate safety and effects on cognition and behavior of memantine 20 mg/day in the treatment of patients with frontotemporal dementia (FTD). METHODS: This was a single-center, 6-month, open, uncontrolled study. Sixteen outpatients with a diagnosis of FTD were enrolled. RESULTS: On the CIBIC plus 26 weeks after baseline four of the 16 patients were minimally improved, four were unchanged, seven were minimally worse and one patient was moderately worse. Neither the Neuropsychiatric Inventory nor the Frontal Behavioral Inventory demonstrated statistically significant differences in behavior between baseline and final visit. There was an increase in the total Alzheimer's Disease Assessment Scale score, reflecting a decline in cognitive performance. Executive functions as well as activities of daily living and extrapyramidal motor symptoms (EPMS) remained unchanged during the trial. CONCLUSION: The number of patients was small, so that the evidence given by statistical tests is limited. Thus, the present study can only show trends regarding drug effects. As memantine is well-tolerated, further randomized and controlled studies should be conducted to evaluate drug efficacy.

The Ekman 60 Faces Test as a diagnostic instrument in frontotemporal dementia.

Frontotemporal dementia (FTD) is characterized by dramatic changes of personality and behaviour. Impaired ability of emotional processing could contribute to these symptoms, as it may lead to misinterpretation of emotional cues that would normally guide behaviour. The aim of the present study was to investigate if the Ekman 60 Faces Test, an instrument to test the recognition of basic facial emotions, enables the differentiation between patients with mild FTD and cognitively healthy subjects (HC). We found that compared to 33 cognitively healthy subjects, 25 patients with mild FTD were impaired in the recognition of basic emotions. At a cut-off score from 46 out of 60 points, the Ekman 60 Faces Test discriminated between patients with mild FTD and HC with 97% diagnostic accuracy (sensitivity: 94%; specificity: 100%). The results of the present study were consistent with the findings of prior studies on smaller patient samples.

Non-fluent progressive aphasia: cerebral metabolic patterns and brain reserve.

Functional imaging studies suggest that brain reserve allows patients with Alzheimer's disease with more years of schooling to cope better with brain damage. No studies exist on patients with non-fluent progressive aphasia (NFPA). We aimed to explore metabolic patterns of patients with NFPA and to provide evidence for brain reserve in NFPA. 11 right-handed patients with NFPA and 16 age-matched controls underwent (18)F-FDG PET imaging. Scans of patients and controls were compared in SPM2. A linear regression analysis with glucose metabolism as dependent variable and years of schooling as the independent variable, adjusted for age, gender, and a total score of the CERAD neuropsychological battery was conducted. The NFPA group showed a hypometabolism of the left hemisphere including the middle frontal, and inferior temporal and angular gyri, and the bilateral caudate nuclei and thalami (p(corr)<0.05). The regression analysis revealed a significant inverse association between education and glucose metabolism in the left inferior temporal, parahippocampal, and supramarginal gyri (p(corr)<0.05). We conclude that brain reserve is also present in NFPA.

Complex activities of daily living in mild cognitive impairment: conceptual and diagnostic issues.

BACKGROUND: The impact of cognitive impairment on activities of daily living (ADL) is being used as a major criterion for differentiating between mild cognitive impairment (MCI) and dementia. The concept of an ADL threshold that separates MCI from dementia, however, appears to be improbable for several reasons. OBJECTIVES: To determine whether complex ADL are impaired in patients with MCI; to examine the usefulness of the assessment of ADL impairment for the diagnosis of MCI; to explore whether both cognitive testing and assessment of impaired ADL are significant predictors of the diagnosis according to the diagnostic gold standard of MCI. DESIGN: Cross-sectional study. SETTING: University-based outpatient clinic. SUBJECTS: A total of 45 elderly MCI patients diagnosed according to research diagnostic criteria and 30 age-matched cognitively unimpaired controls. METHODS: Clinical assessment - Alzheimer's disease Assessment scale, cognitive subscale (ADAS-cog) for the assessment of cognitive functions, Alzheimer's disease Cooperative Study scale for ADL in MCI (ADCS-MCI-ADL) for the assessment of impairments of complex ADL. Statistical evaluation - Mann-Whitney U tests for significant differences on measures of cognition and everyday functioning. Non-parametric correlations for associations between ADL and cognitive ability. Receiver operator curve (ROC) analyses to identify optimal cut-off scores on the ADCS-MCI-ADL and ADAS-cog scales to differentiate between MCI patients and controls. Binary logistic regression analyses to predict the diagnosis of MCI on the basis of the above-mentioned instruments. RESULTS: Patients scored significantly higher than controls on the ADAS-cog scale and significantly lower on the ADCS-MCI-ADL scale. There was a significant negative correlation of the above-mentioned scales in MCI patients (r = -0.46, P < 0.01). Both instruments discriminated well between patients and controls (ADCS-MCI-ADL: optimal cut-off 52 points, sensitivity 0.89, specificity 0.97; ADAS-cog: optimal cut-off 10 points, sensitivity 0.78, specificity 1.0). With regard to the linear predictor in the logistic regression built, both instruments were strong predictors of the diagnosis according to the diagnostic gold standard (ADCS-MCI-ADL: P = 0.002; ADAS-cog: P = 0.041). CONCLUSION: Impairment of ADL is already present in MCI. Therefore, intact ADL cannot be used as a criterion to define the syndrome of MCI and to distinguish it from mild dementia. The assessment of complex ADL is probably useful for the diagnosis of MCI.

Impairment of activities of daily living requiring memory or complex reasoning as part of the MCI syndrome.

BACKGROUND: Mild Cognitive Impairment (MCI) is a borderline state between age-associated cognitive decline and mild dementia. MCI is separated from mild dementia by an absence of global intellectual deterioration and the preservation of activities of daily living (ADL). However, even mild degrees of cognitive deterioration are known to have negative effects on complex ADL. OBJECTIVES: To examine whether patients with MCI have impaired ADL as compared to healthy controls, which areas of ADL are particularly involved, and whether limitations on ADL are associated with demographical or clinical data. METHODS: Forty-eight patients with MCI diagnosed according to research criteria and 42 cognitively unimpaired controls were enrolled. Cognitive function was inter alia assessed by the MMSE, complex ADL by the ADCS-MCI-ADL scale. Frequency distributions were compared between patients and controls using chi-square tests. Mean values were examined for statistically significant differences using Kruskal-Wallis tests. A Bonferroni correction for multiple comparisons was applied to the comparison of the 18 areas of the ADCS-MCI-ADL scale. Associations between ADL and biographical or clinical data were analysed using non-parametric correlations. RESULTS: The overall score on the ADCS-MCI-ADL scale was significantly lower in the MCI group. Patients performed significantly worse on 14 out of 18 activities. Activities involving memory or complex reasoning were particularly impaired, whereas more basic activities were unimpaired. There were no statistically significant associations of the ADCS-MCI-ADL overall score with age, years of formal education, gender, or number of cognitive domains affected in the group of MCI patients. However, there was a statistically significant association between the ADCS-MCI-ADL and the MMSE score. CONCLUSION: MCI patients may be impaired in complex ADL.

Executive dysfunction in early stages of Huntington's disease is associated with striatal and insular atrophy: a neuropsychological and voxel-based morphometric study.

BACKGROUND: Huntington's disease (HD) is characterized by a progressive multisystem neuronal atrophy in the brain. Apart from motor signs, cognitive symptoms, particularly executive dysfunctions, are proposed to be recognizable in early stages of disease. The aim of the present study was to clarify if cognitive dysfunction in early stages of HD is correlated with loco-regional structural changes in 3D-MRI. METHODS: Twenty-five patients with genetically confirmed HD in early clinical stages were included in the study and underwent neuropsychological testing, i.e., the executive tasks Tower of Hanoi (ToH), Stroop Colour Word Interference Test (STROOP), and modified Wisconsin Card Sorting Test (mWCST). High-resolution volume-rendering MRI scans (MP-RAGE) were acquired on a 1.5 T scanner in all patients and were analyzed by statistical parametric mapping and voxel-based morphometry (VBM) in comparison to an age-matched control group. RESULTS: Group analysis of HD patients demonstrated robust regional decreases of gray matter volumes (p<0.05, corrected for multiple comparisons) in the caudate and the putamen bilaterally with a global maximum at Talairach coordinates 11/4/11 (Z-score=7.06). Executive dysfunction was significantly correlated with the areas of highest significant differences out of VBM results which were located bilaterally in the caudate (ToH: r=0.647, p<0.001; STROOP: r=0.503, p<0.01; mWCST: r=0.452, p<0.05). Moreover, subgroup analyses revealed marked insular atrophy (Talairach coordinates 43/-3/1; Z-score=5.64) in HD patients who performed worse in the single executive tasks. CONCLUSION: Two aspects were most remarkable in this correlational study: (i) striatal atrophy in HD patients in early stages plays an important role not only in impaired motor control but also in executive dysfunction, and (ii) extrastriatal cortical areas, i.e., the insular lobe, seem to be involved in executive dysfunction as assessed by neuropsychological tests requiring for planning and problem solving, stimulus response selectivity and concept formation.