Compensatory mechanisms of the human brain have been suggested in recent studies investigating language functions in dementia with neuroimaging techniques (Vandenbulcke et al., 2005; Nelissen et al., 2007). In slowly progressing diseases like degenerative dementias, longitudinal studies might help to further elucidate the underlying dynamics. In a group of patients with clinically diagnosed mild cognitive impairment (MCI) or degenerative dementia (Alzheimer's Dementia (AD) or frontotemporal lobar degeneration (FTLD)), we longitudinally investigated fMRI activation patterns during confrontation naming and concomitant language performance with a standardized language test battery (Aachen Aphasia Test Battery; Huber et al., 1983). 16 patients from the MCI-AD-continuum participated (11 MCI, 5 AD), as well as 8 patients with FTLD (6 primary progressive aphasia (PPA), 2 behavioral variant FTLD (bvFTLD)). Applying voxel-based morphometry analyses, we detected a clearly left-lateralized atrophy pattern, mainly within the temporal lobes, compared to 16 healthy elderly control subjects. Examination of patients at baseline and six months later allowed for subdivision into two groups of patients (by use of a median split), whose development of naming deficits differed significantly: One group of patients showed a decrease in naming test performance (Decliners; N = 12), the other group remained rather stable (NonDecliners; N = 12). Comparing brain activation patterns between Decliners and NonDecliners, we observed a significant interaction between factors ‘time’ and ‘group’, with activation strength being higher at follow-up in NonDecliners vs. Decliners: In the right temporal pole activation increased in NonDecliners, while it decreased in Decliners. Further correlational analyses revealed that activation level in this region was related to better performance in the naming subtest from the language test battery. Our data indicate that recruitment of the right temporal pole during object naming was beneficial for task performance, and it was specific to the patient group who showed no performance decline. This suggests a successful, compensatory mechanism of the contralesional, right hemisphere when the left hemisphere is primarily, and progressively, affected by degenerative disease.
Significance Cognitive decline during aging impairs life quality and may lead to dementia. It is associated with a dysfunction of the brain acetylcholinergic system. Here we demonstrate that pharmacological stimulation of neurokinin3 receptors improves learning and memory in aged rats by enhancing acetylcholinergic function in the brain. In a human association study we show that a single-nucleotide polymorphism in the neurokinin3-receptor–coding gene TACR3 can predict learning and memory in elderly patients with cognitive impairments and their hippocampus volume. These findings suggest the neurokinin3 receptor as a potential biomarker and treatment target for cognitive enhancement in the elderly.
Background: Consideration of many tests from different cognitive domains in defining mild cognitive impairment (MCI) is clinical routine, but guidelines for a neuropsychological operationalization of MCI are lacking. Objective: Among different operational MCI criteria, to identify those which are best in predicting either conversion to dementia, or a biomarker profile indicative for Alzheimer’s disease (AD). Methods: Memory clinic patients without dementia ( N = 558; mean age = 66; up to 3 years of follow-up; n = 360 with baseline CSF biomarkers) were included in an observational study using most liberal criteria of cognitive impairment. Four operational definitions of MCI were retrospectively applied: 1) amnestic MCI (CERAD word list delayed recall), 2) CERAD total score, 3) comprehensive criteria and 4) base rate corrected CERAD. We compared their accuracy in predicting incident all-cause dementia or AD dementia within three years, or a concurrent CSF Aβ 42 /tau-ratio indicative of AD. Results: The four definitions overlapped considerably, classified 35–58% of the original sample as impaired and were associated with markedly increased PPVs regarding incident all-cause dementia (39–46% versus 26% of the original sample), AD dementia and AD biomarker positivity. The base rate corrected MCI definition had the highest prognostic accuracy. Conclusion: he operational criteria examined seem suitable to specify MCI in memory clinic settings, as they identify subjects at high risk of clinical progression. Depending on the neuropsychological battery in use, one or several of these criteria could help to calibrate the clinical judgment of test results, reduce false-positive decisions, and define risk-enriched groups for clinical trials.
Large studies on cognitive profiles of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD-MCI) compared to Parkinson's disease (PD-MCI) are rare.Data from two multicenter cohort studies in AD and PD were merged using a unified base rate approach for the MCI diagnosis. Cognitive profiles were compared using scores derived from the Consortium to Establish a Registry for Alzheimer's Disease battery.Patients with AD-MCI showed lower standardized scores on all memory test scores and a language test. Patients with PD-MCI showed lower standardized scores in a set-shifting measure as an executive task. A cross-validated logistic regression with test scores as predictors was able to classify 72% of patients correctly to AD-MCI versus PD-MCI.The applied test battery successfully discriminated between AD-MCI and PD-MCI. Neuropsychological test batteries in clinical practice should always include a broad spectrum of cognitive domains to capture any cognitive changes.
Die Alzheimer Krankheit ist bei über 1 Million der ca. 1,5 Millionen von einer Demenz in Deutschland betroffenen Menschen die Hauptursache. Die Prävalenz der Erkrankung steigt von 5 % der 75-Jährigen auf 40 % der 90-Jährigen. Die Diagnosestellung ist im mittleren Krankheitsstadium mit wenigen klinischen Tests sicher möglich. Für das frühe Stadium stehen neue laborchemische und nuklearmedizinische Verfahren mit hoher diagnostischer Sicherheit zur Verfügung. Krankenhausaufenthalte bei Menschen mit Demenz entstehen oft im Gefolge deliranter Episoden und Stürzen. Die Berücksichtigung der erhöhten Unverträglichkeit für anticholinerge Medikamente, die Bevorzugung tagesklinischer Angebote sowie die Einbeziehung pflegender Angehöriger sind im Krankenhaus wichtig.
Ziele: Ziel dieser Studie war es, mit verschiedenen Bildgebenden Verfahren den Temporal- sowie den Parietallappen bei Patienten mit progressiver nichtflüssiger Aphasie (PNA) zu untersuchen und mit Patienten mit Alzheimer Krankheit (AD) zu vergleichen. Methode: Positronenemissionstomographie mit (F-18)-Fluordeoxyglukose (FDG-PET), voxelbasierte Morphometrie (VBM) und Chemical Shift Imaging (CSI) wurden bei 5 Patienten mit PNA, 10 alters- und MMSE-adaptierten AD-Patienten und 10 Normalpersonen angewandt. Es wurden Auswertungen mittels Statistical Parametric Mapping (SPM2) als Gruppenvergleiche und auf Einzelfallbasis durchgeführt. Ergebnis: Die Gruppenvergleiche zeigten links anterolaterale temporale Veränderungen (BA20/21) in PET, VBM and CSI bei PNA-Patienten im Vergleich zu Normalpersonen (SPM2, P<0.001). In der PET zeigten AD-Patienten in diesem Bereich einen umschriebeneren Hypometabolismus. Zusätzlich fanden sich in der PET bei unseren PNA- und AD-Patienten Veränderungen im links lateralen Parietalkortex (BA 40), in der VBM nur in der AD Gruppe. Wenn man die Information von allen drei Bildgebenden Verfahren auf Einzelfallebene auswertet, findet man häufig Pathologien im links anterolateralen Temporallappen (PNA: 5/5; AD: 8/10; P=0.43) und lateralen Parietallappen (PNA: 5/5; AD: 9/10; P=0.66). PNA- und AD-Patienten unterscheiden sich jedoch signifikant hinsichtlich der Häufigkeit in der Beteiligung des medialen Temporallappens (PNA: 1/5; AD: 9/10; P=0.02) und des posterioren Cingulums/Präcuneus (PNA: 0/5; AD: 9/10; P=0.002). Schlussfolgerung: Obwohl unsere Ergebnisse nicht auf alle Subgruppen von PNA-Patienten übertragen werden können, ist mit PET, VBM und CSI eine Differenzierung von PNA und AD möglich. Entscheidend sind Veränderungen im medialen Temporallappen und im posterioren Cingulum/Präcuneus, nicht jedoch in lateralen temporalen und parietalen Bereichen, die bei beiden Krankheiten beteiligt sind.
Abstract To determine mechanisms of structural plasticity in adult CNS neurons, we investigated the expression of immediate early genes (IEGs) in the rat retina. Gene products of different IEG families (JUN and FOS proteins) and cAMP‐responsive element binding protein (CREBP) were examined by immunohistochemistry under three different paradigms. Normal rats which were not axotomized were compared with axotomized animals, where retinal ganglion cells (RGCs) were axotomized by intraorbital optic nerve cut and retrogradely labeled with fluorogold (FG). Under these circumstances, RGCs show only transient sprouting, followed by continuous retrograde RGC degeneration. In the third group, after the optic nerve lesion, adult rats additionally received a sciatic nerve graft to the transected optic nerve stump. This allows some RGCs to regenerate an axon into the grafted nerve. In both groups, the time course of RGC survival and JUN, CREB, and FOS protein expression was monitored. In normal animals, JUN‐Immunoreactivity (JUN‐Ir) was not detectable in the retinal ganglion cell layer. JUN‐Ir was induced in about 70% of all FG‐positive RGCs 5 days after axotomy. The expression of JUN‐Ir started to decline 8 days after axotomy. Only a few JUN‐Ir‐positive RGCs were found after 2 weeks. In transplanted animals, however, the numbers of JUN‐Ir‐positive RGCs were significantly higher 2 and 3 weeks after transplantation compared to animals that exclusively received axotomy. Furthermore, in grafted rats about 70% of the regenerating RGCs expressed JUN‐Ir 2 weeks after grafting as compared to only 38% JUN‐positive RGCs among the surviving but not regenerating RGCs. In normal animals CREBP‐Ir was constitutively expressed in nearly all cells of the retinal ganglion cell layer. The decline in number of CREBP‐Ir‐positive cells paralleled the axotmy‐induced RGC death. FOS‐Ir‐positive cells were not found in the ganglion cell layer at any time. These results demonstrate a selective and transient JUN expression of RGCs after axotomy which is sustained during axonal regeneration. This suggests that sciatic nerve grafts are able to regulate the expression of JUN proteins in axotomized RGCs of adult rats. 1994 John Wiley & Sons, Inc.
