Bernd Ibach

Acetylcholinesterase inhibition in Alzheimer's Disease

Alzheimers Disease (AD) is the most common cause for dementia in our ageing population, which leads to a slowly progressive, irretrievable ruination of mental function. The destructive, primarily degenerative condition is neuropathologically characterized by the formation of amyloid plaques, neurofibrillary tangles and loss of neurons and synapses as well. Research during the past twenty years revealed early in the disease course a degeneration of cholinergic nuclei localised in the basal forebrain. Impairment of this cholinergic system, which projects into large areas of the limbic system and the neocortex is followed by disturbance of attentional processes and cognitive decline. The link between the cholinergic dysfunction and cognitive impairment has focused large scientific efforts to understand the neurobiology of cognition and to develop therapeutic tools for the fight against Alzheimers Disease. Acetylcholinesterase inhibitors are currently the best established treatment for this devastating disease. This review describes historical aspects and the vast range of use of cholinesterase inhibitors in traditional societies and industrial nations. Second, the rational basis will be outlined for their development as medication, the so-called cholinergic hypotheses of AD. Third, acetylcholinesterase inhibitors currently available for the treatment of AD will be reviewed. This includes donepezil, galanthamine and rivastigmine. Tacrine, the first acetylcholinesterase inhibitor who became available in 1993 as a treatment for AD, does not play an essential role anymore besides his historical value, because of its hepatotoxicity. Although acetylcholinesterase inhibitors are no cure, these drugs can delay the progress of mental deterioration, reduce neuropsychiatric symptoms and therefore represent a rational therapeutic approach to the treatment of Alzheimers Disease.

Cerebrospinal fluid tau and β-amyloid in Alzheimer patients, disease controls and an age-matched random sample

We prospectively evaluated the diagnostic accuracy of cerebrospinal fluid (CSF)-beta-amyloid1-42 (Abeta42), -total-tau (tau) and -phosphorylated-tau181 (p-tau181) as measured by sandwich ELISAs in the clinical routine of a community state hospital to discriminate between patients with Alzheimers disease (AD), healthy controls (HC), non-AD-dementias, a group composed of various psychiatric disorders (non-AD-dementias, mental diseases) and an age-matched random sample (RS) (total N=219). By comparing patients with AD to HC as reference, tau revealed sensitivity (sens)/specificity (spec) of 88%/80%, p-tau(181) 88%/80%, tau/Abeta42-ratio 81%/85% and phospho-tau(181)/Abeta42-ratio 81%/78%. Discriminative power between HC and all dementias under investigation was estimated lower for tau (78%/77%) and p-tau(181) (73%/79%). Relative to patients with AD, ROC analysis for the RS revealed highest sens/spec for p-tau181 (79%/77%) and p-tau181/Abeta42 ratio (78%/75%). Differentiation between AD versus a group made of patients with various psychiatric disorders was optimised by using CSF-p-tau181 (80%/77%). Under clinical routine conditions current CSF-biomarkers show a substantial capacity to discriminate between AD and HC as reference and to mark off AD patients from RS and heterogeneous diagnostic groups composed of non-AD dementias and other psychiatric conditions. Despite a residual substantial overlap between the groups, we conclude that current CSF markers are well suited to support AD-related diagnostic procedures in every-day clinics.

Neural correlates of emotional working memory in patients with mild cognitive impairment

Emotional stimuli can have beneficial effects on memory in healthy aged subjects and partly on patients with dementia. So far, no experimental study has explored the effects of memory for emotional stimuli in patients with mild cognitive impairment (MCI), a concept that describes a transitional state between normal aging and dementia. The present fMRI study explored working memory for emotional stimuli in 16 patients with amnestic MCI (aMCI) and 16 healthy aged participants. Subjects performed an n-back task (2-back) with neutral, positive, and negative emotional pictures. The analysis focused on target processing. Results showed that groups did not differ in working memory performance. In healthy aged participants emotional targets had no significant impact on working memory. In patients with aMCI a negativity bias was observed, indicating that negative targets were better remembered compared to neutral and positive targets. Regarding fMRI results, both groups showed an increase in functional activity in prefrontal and lateral parietal brain regions associated with target processing. As a key result, we observed significant group by emotion interaction effects in the precuneus. Healthy aged participants showed a signal decrease in the left precuneus for positive compared to neutral targets. The precuneus deactivation in healthy aged participants may indicate a disengagement of self-referential processes towards task-related processes. Patients with aMCI revealed a signal increase in the right precuneus for negative compared to neutral targets. This increase in precuneus activity, combined with a behavioural facilitation effect, may indicate a mechanism to compensate disease related processes in aMCI.

No association of TDP-43 with sporadic frontotemporal dementia.

A hyperphosphorylated, ubiquitinated form of TDP-43, known as pathologic TDP-43, was shown to be a central component of ubiquitin-positive, tau-negative and alpha-synuclein-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amytrophic lateral sclerosis (ALS). To investigate the role of the TDP-43 gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 10 single nucleotide polymorphisms covering the entire TDP-43 genomic region, including the MASP2 gene in 173 patients with sporadic FTD (including 7 patients that were diagnosed with FTD and ALS) and 184 matched controls from Germany. Although we could observe a weak trend towards a potential disease association in a few FTD/ALS patients, no significant association with sporadic FTD could be demonstrated. There is no evidence, that common variants in TDP-43 confer a strong risk to the development of sporadic FTD.

Hospital admission circumstances and prevalence of frontotemporal lobar degeneration: a multicenter psychiatric state hospital study in Germany.

Frontotemporal lobar degeneration (FTLD) is a heterogenous, non-Alzheimer’s disease, dementia complex with variable clinical presentation. We carried out a prospective nationwide hospital-based clinico-epidemiologic study in geriatric psychiatry to estimate the prevalence and admission circumstances of patients with FTLD. During a 4-week period 33 patients with clinical FTLD were prospectively ascertained in 36 psychiatric state hospitals in Germany with a total catchment area of >20,000,000 people. The relative portion of FTLD patients within the primary dementia population accounted for 1.9%. The estimated prevalence of FTLD in Germany was 47.9/100,000 population aged between 45 and 79 years. The admission circumstances were mainly behavioral disturbances (54.5%), unclear syndromes of dementia (18.1%) and further remarkably heterogeneous psychiatric syndromes. FTLD is a common cause of dementia in geriatric psychiatry with a variable clinical presentation that could mimic most of the major psychiatric diseases. Patients with FTLD may be older than previously assumed (mean age at admission 63.9 years) and show their maximum age-related prevalence between 60 and 70 years (78.7/100,000).

Patterns of referring of patients with frontotemporal lobar degeneration to psychiatric in- and out-patient services: Results from a prospective multicentre study

Dementia with frontotemporal lobar degeneration (FTLD) is clinically characterized by the occurrence of various psychiatric symptoms. In a recent study, the hospital-based prevalence of FTLD and the circumstances of the patients’ admission to German psychiatric state hospitals were estimated. On the basis of further continuous assessment, this original FTLD group (n = 33) has been enlarged to 58 patients. The authors here present demographic and clinical data, and reasons for admission to geriatric psychiatry hospitals in comparison with 17 patients, who primarily attended the Memory Disorders Clinic of the University of Regensburg. The results implicate that both institutions see patients with different clinical syndromes: (1) patients were primarily referred to the Memory Disorders Clinic presenting memory and/or speech difficulties as the leading symptoms; (2) major reasons for hospitalisation of patients with FTLD in geriatric psychiatry hospitals were behavioural disturbances; (3) late-onset FTLD (>65 years) was more common than previously assumed in both institutions, and (4) increasing age at admission increased the likelihood to obtain a limited diagnostic approach of brain imaging (only cranial computer tomography) to evaluate the cause of dementia.

Domain-specific improvement of cognition on memantine in patients with Alzheimer's disease treated with rivastigmine.

Objective: Cholinergic therapy is used in mild-to-moderate Alzheimer’s disease (AD) and antiglutamatergic therapy in moderate-to-severe AD. Global scales, as commonly used in clinical trials, blur specifics of disease progression and drug effects. The objective was to assess combination therapy of rivastigmine plus memantine by specific neuropsychological tests in patients with mild-to-moderate AD. Methods: 12-week-short multicenter open-label pilot study. Ninety patients with mild-to-moderate AD already on stable medication with rivastigmine (3–6 mg b.i.d.) additionally received memantine for 12 weeks. Subscales of the Alzheimer’s Disease Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE) and additional neuropsychological tests (e.g. span tasks, semantic fluency) were assessed. Results: The scores in the ADAS-cog memory subscale, the MMSE score, and digit span and semantic fluency significantly improved on combination therapy. Conclusion: Memory improvement was correlated with ADAS-cog memory score at baseline and inversely with age at onset of treatment. The data suggest that improvement on combination therapy results from an improvement of attention/executive function with secondary memory improvement, which will need to be confirmed in a subsequent double-blind study on a larger number of patients.

No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia

Mutations of the chromatin modifying protein 2B gene (CHMP2B) were identified, in a Danish pedigree, to cause familial frontotemporal dementia (FTD). To explore the possible genetic contribution of common CHMP2B variants in sporadic FTD, we analyzed 14 single nucleotide polymorphisms covering the entire genomic region of CHMP2B. After adjustment for multiple testing single marker and haplotype analysis revealed no significant association with sporadic FTD. Thus, we conclude that CHMP2B can be excluded as a susceptibility gene conferring risk to sporadic forms of FTD.

Does the Pattern of Atrophy of the Corpus callosum Differ between Patients with Frontotemporal Dementia and Patients with Alzheimer’s Disease?

The pattern of callosal atrophy might be useful for the differentiation between frontotemporal dementia (FTD) and Alzheimer’s disease (AD) in advanced cases. However, it is unclear whether the pattern of callosal atrophy differs between patients with FTD and patients with AD in mild to moderate stages. Volumetric MR images were recorded from 48 probands (12 with FTD, 12 with late-onset AD, and 24 controls). All patients were in a mild or in a moderate stage. The corpus callosum was divided into five segments. A repeated-measures analysis of variance showed that there was no difference in the pattern of callosal atrophy between the groups. We provide evidence that patients with FTD and patients with late-onset AD do not differ in the pattern of callosal atrophy on condition that: (1) FTD patients and AD patients are in a mild to moderate stage and (2) FTD patients and AD patients differ in age.

Genetic analysis of MAPT haplotype diversity in frontotemporal dementia

The H1 haplotype of the tau gene, MAPT, has been linked to the sporadic tauopathies corticobasal degeneration and progressive supranuclear palsy; however, there have been inconsistent findings regarding association with frontotemporal dementia (FTD). We investigated MAPT haplotype diversity, in 171 sporadic FTD and 186 healthy controls individuals, and report no single marker or haplotype association with increased risk or changes in age at onset. These findings do not support an association of MAPT with FTD but do not rule out its association with other tauopathies.