Neuronavigated repetitive transcranial magnetic stimulation as novel mapping technique provides insights into language function in primary progressive aphasia

Navigated repetitive transcranial magnetic stimulation (nrTMS) is an innovative technique that provides insight into language function with high accuracy in time and space. So far, nrTMS has mainly been applied in presurgical language mapping of patients with intracranial neoplasms. For the present study, nrTMS was used for language mapping in primary progressive aphasia (PPA). Seven patients (median age: 70 years, 4 males) with the non-fluent variant of PPA (nfvPPA) were included in this pilot study. Trains of nrTMS (5 Hz, 100% resting motor threshold) caused virtual lesions at 46 standardized cortical stimulation targets per hemisphere. Patients’ errors in a naming task during stimulation were counted. The majority of errors induced occurred during frontal lobe stimulation (34.3%). Timing errors and non-responses were most frequent. More errors were induced in the right hemisphere (58%) than in the left hemisphere (42%). Mapping was tolerated by all patients, however, discomfort or pain was reported for stimulation of frontal areas. The elevated right-hemispheric error rate in our study could be due to a partial shift of language function to the right hemisphere in neurodegenerative aphasia during the course of disease and therefore points to the existence of neuronal plasticity in nfvPPA. While this is an interesting finding for neurodegenerative disorders per se, its promotion might also harbor future therapeutic targets

An Explorative Note on Apraxia Tests

Apraxia is stated independent of primary motor disorders. However, patient groups suffering from stroke or dementia can reveal motor impairments. In this study we examined the dependence of apraxia tests of imitation and pantomime on a latent motor component using a principal component analysis. With samples sizes of 11 patients suffering from dementia of the Alzheimer's type and 15 healthy control subjects, clear limitations concerning the validity of the results are given. Nevertheless, we could observe strong dependence of the three apraxia tests, especially the imitation of finger and hand gestures, on a latent motor component in this preliminary examination. We suggest confirmation by larger samples sizes and to control for the basic motor capacity when testing for signs of apraxia in such patient samples

Speech motor profiles in primary progressive aphasia

Purpose: Previous research on motor speech disorders (MSDs) in primary progressive aphasia (PPA) has largely focused on patients with the nonfluent/agrammatic variant of PPA (nfvPPA), with few systematic descriptions of MSDs in variants other than nfvPPA. There has also been an emphasis on studying apraxia of speech, whereas less is known about dysarthria or other forms of MSDs. This study aimed to examine the qualitative and quantitative characteristics of MSDs in a prospective sample of individuals with PPA independent of subtype. Method: We included 38 participants with a root diagnosis of PPA according to current consensus criteria, including one case with primary progressive apraxia of speech. Speech tasks comprised various speech modalities and levels of complexity. Expert raters used a novel protocol for auditory speech analyses covering all major dimensions of speech. Results: Of the participants, 47.4% presented with some form of MSD. Individual speech motor profiles varied widely with respect to the different speech dimensions. Besides apraxia of speech, we observed different dysarthria syndromes, special forms of MSDs (e.g., neurogenic stuttering), and mixed forms. Degrees of severity ranged from mild to severe. We also observed MSDs in patients whose speech and language profiles were incompatible with nfvPPA. Conclusions: The results confirm that MSDs are common in PPA and can manifest in different syndromes. The findings emphasize that future studies of MSDs in PPA should be extended to all clinical variants and should take into account the qualitative characteristics of motor speech dysfunction across speech dimensions

Therapeutic drug monitoring of rivastigmine and donepezil under consideration of CYP2D6 genotype-dependent metabolism of donepezil

Background: The efficacy of acetylcholinesterase inhibitors (AChE-I) might depend on blood concentration. While rivastigmine metabolism is independent of the cytochrome P450 system, its isoenzymes, especially CYP2D6, metabolize donepezil. CYP2D6 polymorphisms can cause altered enzyme activity resulting in lower or higher than expected drug concentrations of donepezil. Objective: We investigated correlations between clinical efficacy and serum concentrations of rivastigmine and donepezil under special consideration of CYP2D6 genotype or gene dose-dependent metabolism of donepezil. Methods: Serum concentrations of donepezil and rivastigmine were measured by liquid chromatography - tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR) and allele-specific PCR were performed to assess CYP2D6 genotype and gene dose. Results: Patients treated with rivastigmine (n=28) or donepezil (n=48) were included in the study. Both gene dose and metabolism type significantly predicted the level of donepezil serum concentration (p=0.019 and p=0.013, respectively). In the rivastigmine group, changes of the word list delayed recall subtest before treatment and under stable medication were significantly associated with rivastigmine serum levels (beta=0.465;p=0.018). Drug serum concentrations were outside the recommended range in a substantial percentage of participants, which might have contributed to poor correlations between changes in cognitive measures and drug concentrations. Donepezil serum concentrations significantly depended on CYP2D6 gene dose. Conclusion: Testing AChE-I serum concentration should be considered in patients without clinical response to treatment or those with severe side effects. Patients with donepezil drug levels outside the recommended range might additionally profit from CYP2D6 genotyping or treatment with an AChE-I independent of CYP metabolism

Serum Concentrations of Cholinesterase Inhibitors in Patients With Alzheimer's Dementia Are Frequently Below the Recommended Levels

Background: Acetylcholinesterase inhibitors (AChE-I) are recommended for the treatment of cognitive symptoms but also of behavioral and psychological symptoms in dementia. They are widely used not only in Alzheimer's disease, but also in other forms of dementia. Efficacy of treatment might depend on serum concentration of the respective AChE-I. Objective: In patients with mild to moderate Alzheimer's dementia, we measured serum concentrations of hepatically metabolized donepezil and renally excreted rivastigmine and investigated possible modifiers. Additionally, we looked at correlations between serum concentrations and efficacy for both drugs. Methods: Serum concentrations of donepezil and rivastigmine were measured by liquid chromatography – tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR). Allele specific PCR were performed to determine CYP2D6 genotype and gene dose. Clinical efficacy was assessed by changes of the subtest wordlist delayed recall of the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB). Results: Sixty-seven patients treated with a stable dosage of donepezil 10 mg (n=41) or rivastigmine 9.5 mg (n=26) were included. Mean serum concentration of donepezil and rivastigmine were 41.2 and 6.5 ng/ml, respectively. Serum concentrations were below the recommended range in 73% of the subjects in the donepezil group and in 65% of the participants in the rivastigmine group. When applying a dose-related reference, ranges 63% of patients in the donepezil group and 32% in the rivastigmine group had concentrations below the expected range. Gene dose, sex, and duration of treatment significantly predicted donepezil serum concentration (p=0.046, p=0.001, p=0.030 respectively). Only for rivastigmine did the serum concentration significantly contribute to the regression model predicting changes on the subtest word list delayed recall (β=0.472; p=0.019). Conclusions: Serum concentrations of about two thirds of the patients were below the recommended range. When not looking at absolute values but at the dose-related reference ranges, these numbers improved but still 32%, respectively 63% of patients had low serum concentrations. High serum concentrations of rivastigmine predicted clinical response to cognition. Therapeutic drug monitoring might help to identify the cause of poor clinical response to cognition and behavioral and psychological symptoms in patients with AChE-I treatment

Dementia care in the Danube Region. A multi-national expert survey

Background: Dementia is a particularly severe societal challenge in several countries of the Danube Region due to higher-than-average increment in population longevity, disproportionate increase of the old-age dependency ratio, and selective outward migration of health care professionals. A survey was conducted among dementia experts to obtain a deeper understanding of the dementia care structures and services in this geographical area, and to identify the educational needs of health care professionals, and the availability of assistive technology. ------ Subjects and methods: A standardized questionnaire was sent out to 15 leading dementia experts/clinicians in 10 Danube Region countries inquiring about professional groups involved in dementia care, availability and reimbursement of services, inclusion of dementia in professional education and training, acceptability of Internet-based education, and availability of assistive technology. The authors are the survey respondents. ----- Results: The majority of individuals with dementia receive care in the community rather than in institutions. The roles of medical specialties are disparate. General practitioners usually identify dementia symptoms while specialists contribute most to clinical diagnosis and treatment. Health care professionals, particularly those who work closely with patients and carers, have limited access to dementia-specific education and training. The greatest need for dementia-specific education is seen for general practitioners and nurses. An Internetbased education and skill-building program is considered to be equivalent to traditional faceto- face but offer advantages in terms of convenience of access. Assistive technology is available in countries of the Danube Region but is significantly underused. ----- Conclusion: Dementia care in the Danube Region can be improved by an educational and skill-building program for health care professionals who work in the frontline of dementia care. Such a program should also attempt to enhance interdisciplinary and intersectorial collaboration, to intensify the interaction between primary care and specialists, and to promote the implementation of assistive technology