Publications
282 results found
Grimmer T, Faust M, Auer F, et al., 2012, White matter hyperintensities predict amyloid increase in Alzheimer's disease, Neurobiol Aging, Vol: 33, Pages: 2766-2773, ISSN: 1558-1497
Impaired amyloid clearance probably contributes to increased amyloid deposition in sporadic Alzheimer's disease (AD). Diminished perivascular drainage due to cerebral small-vessel disease (CSVD) has been proposed as a cause of reduced amyloid clearance. White matter hyperintensities (WMHs) are considered to reflect CSVD and can be measured using fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Amyloid deposition can be determined in vivo using Pittsburgh compound B ([11C]PiB) positron emission tomography (PET). We aimed to elucidate the association between WMH and the progression of amyloid deposition in patients with AD. Twenty-two patients with probable AD underwent FLAIR-MRI and [11C]PiB-PET examinations at baseline (BL) and after a mean follow-up (FU) interval of 28 months. The relationship between BL-WMH and the progression of cerebral amyloid between BL and FU was examined using a regions-of-interest (ROI) approach. The region-specific variability of this relationship was analyzed using a voxel-based method. The longitudinal analysis revealed a statistically significant association between the amount of BL-WMH and the progression of amyloid load between BL and FU (p = 0.006, adjusted R2 = 0.375, standardized coefficient beta = 0.384). The association was particularly observed in parieto-occipital regions and tended to be closer in regions adjacent to the brain surface. According to our knowledge, this is the first in vivo study in human being supporting the hypothesis that impaired amyloid clearance along perivascular drainage pathways may contribute to beta-amyloid deposition in sporadic AD. The extent of WMH might be a relevant factor to be assessed in antiamyloid drug trials.
Guo LH, Alexopoulos P, Eisele T, et al., 2012, The National Institute on Aging-Alzheimer's Association research criteria for mild cognitive impairment due to Alzheimer's disease: predicting the outcome, Eur Arch Psychiatry Clin Neurosci, ISSN: 1433-8491
The National Institute on Aging-Alzheimer's Association (NIA-AA) clinical research criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) incorporate the use of biomarkers to classify patients according to the likelihood of the presence of AD pathology. The aim of the study was to compare the risk of progression to AD dementia between the four NIA-AA MCI subgroups using data from the AD Neuroimaging Initiative. Patients with MCI were categorised according to the NIA-AA criteria into subgroups with high, intermediate, and low likelihood of the presence of AD pathology (MCI-high, MCI-intermediate, and MCI-unlikely, respectively) or into a group of patients that only met the MCI-core clinical criteria (MCI-core). Data of follow-up visits conducted 6-60 months after baseline were used to compare the relative risk of future AD dementia between the four subgroups employing a Cox regression model. The MCI-high subgroup (N = 22) had a 2.3 times higher risk of developing AD dementia compared with the MCI-core subgroup (N = 327; P = 0.002), while there was a trend for a higher risk in the MCI-high subgroup in contrast to the MCI-intermediate subgroup (N = 31, P = 0.08). No patients in the MCI-unlikely subgroup (N = 17) progressed to AD dementia. Patients with MCI-high have a higher risk for developing AD dementia. The new NIA-AA MCI criteria represent a valuable research instrument that could be incorporated into the diagnostic process of the MCI syndrome after optimisation and refinement.
Guo LH, Westerteicher C, Wang XH, et al., 2012, SORL1 genetic variants and cerebrospinal fluid biomarkers of Alzheimer's disease, Eur Arch Psychiatry Clin Neurosci, Vol: 262, Pages: 529-534, ISSN: 1433-8491
The neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) is involved in amyloidogenesis, and the SORL1 gene is a major risk factor for Alzheimer's disease (AD). We investigated AD-related CSF biomarkers for associations with SORL1 genetic variants in 105 German patients with mild cognitive impairment (MCI) and AD. The homozygous CC-allele of single nucleotide polymorphism (SNP) 4 was associated with increased Tau concentrations in AD, and the minor alleles of SNP8, SNP9, and SNP10 and the haplotype CGT of these SNPs were associated with increased SORL1 concentrations in MCI. SNP22 and SNP23, and the haplotypes TCT of SNP19-21-23, and TTC of SNP22-23-24 were correlated with decreased Ab42 levels in AD. These results strengthen the functional role of SORL1 in AD.
Morbelli S, Drzezga A, Perneczky R, et al., 2012, Resting metabolic connectivity in prodromal Alzheimer's disease. A European Alzheimer Disease Consortium (EADC) project, Neurobiol Aging, Vol: 33, Pages: 2533-2550, ISSN: 1558-1497
We explored resting-state metabolic connectivity in prodromal Alzheimer's disease (pAD) patients and in healthy controls (CTR), through a voxel-wise interregional correlation analysis of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) by means of statistical parametric mapping. Baseline 18F-fluorodeoxyglucose-positron emission tomography of 36 patients with amnestic mild cognitive impairment who converted to Alzheimer's disease (AD) dementia after an average time of 2 years (pAD) and of 105 CTR were processed. The area of hypometabolism in pAD showed less metabolic connectivity in patients than in CTR (autocorrelation and correlation with large temporal and frontal areas, respectively). pAD patients showed limited correlation even in selected nonhypometabolic areas, including the hippocampi and the dorsolateral prefrontal cortex (DLFC). On the contrary, in CTR group correlation was highlighted between hippocampi and precuneus/posterior cingulate and frontal cortex, and between dorsolateral prefrontal cortex and caudate nuclei and parietal cortex. The reduced metabolic connections both in hypometabolic and nonhypometabolic areas in pAD patients suggest that metabolic disconnection (reflecting early diaschisis) may antedate remote hypometabolism (early sign of synaptic degeneration).
Perneczky R, Alexopoulos P, Wagenpfeil S, et al., 2012, Head circumference, apolipoprotein E genotype and cognition in the Bavarian School Sisters Study, Eur Psychiatry, Vol: 27, Pages: 219-222, ISSN: 1778-3585
BACKGROUND: The apolipoprotein E (APOE) varepsilon4 allele is correlated with an earlier onset of Alzheimer's disease symptoms; larger head circumference has been associated with an individual resilience against cognitive impairment. METHODS: We explored if larger head circumference attenuates the effect of the APOE varepsilon4 allele on cognition in 380 Catholic sisters covering the spectrum from normal cognitive performance to severe dementia. RESULTS: Linear regression analysis, adjusting for risk factors for cognitive decline, revealed that APOE varepsilon4 was correlated with worse cognition and that larger head circumference attenuated the negative effect of the varepsilon4 allele on cognitive performance. CONCLUSION: Larger head circumference (i.e. larger brain size) seems to be associated with greater resilience against genetic determinants of cognitive impairment, possibly due to enhanced brain or cognitive reserve.
Perneczky R, Kurz A, 2012, Dealing with uncertainty: biomarkers for the early detection of Alzheimer's disease, Int Psychogeriatr, Vol: 24, Pages: 1533-1535, ISSN: 1741-203X
Peters O, Lorenz D, Fesche A, et al., 2012, A combination of galantamine and memantine modifies cognitive function in subjects with amnestic MCI, J Nutr Health Aging, Vol: 16, Pages: 544-548, ISSN: 1760-4788
OBJECTIVES: Mild cognitive impairment (MCI) is etiologically heterogeneous, and a substantial proportion of MCI subjects will develop different dementia disorders. One subtype of this syndrome, amnestic MCI, occurs preferentially but not exclusively in prodromal AD and is characterized by defined deficits of episodic memory. DESIGN, SETTING AND PARTICIPANTS: For a 2-year, double-blinded, placebo-controlled study MCI patients, presenting with an amnestic syndrome but not necessarily based on presumed prodromal AD were randomized. INTERVENTION: Patients received (a) a combination of 16 mg galantamine plus 20 mg memantine, or (b) 16 mg galantamine alone or (c) placebo. MEASUREMENTS: The primary objective was to explore the differential impact of these interventions on the progression to dementia and on cognitive changes as measured by the ADAScog. RESULTS: After recruitment of 232 subjects, the trial was halted before reaching the planned sample size, because safety concerns arose in other studies with galantamine in MCI. This resulted in a variable treatment duration of 2-52 weeks. The statistical analysis plan was amended for studying cognitive effects of discontinuing the study medication, which was done separately for galantamine and memantine, and under double-blind conditions. There was one death, no unexpected severe adverse events, and no differences of severe adverse events between the treatment arms. The cognitive changes on the ADAScog were not different among the groups. Only for the subgroup of amnestic MCI with presumed AD etiology, a significant improvement of ADAScog score over placebo before the discontinuation of medication was observed, while amnestic MCI presumably due to other etiologies showed no cognitive changes with broad variation. Cognitive improvement was numerically larger in the combination treatment group than under galantamine alone. Patients who received placebo declined as expected. Discontinuation of galantamine, either as part of the
Redel P, Bublak P, Sorg C, et al., 2012, Deficits of spatial and task-related attentional selection in mild cognitive impairment and Alzheimer's disease, Neurobiol Aging, Vol: 33, ISSN: 1558-1497
Visual selective attention was assessed with a partial-report task in patients with probable Alzheimer's disease (AD), amnestic mild cognitive impairment (MCI), and healthy elderly controls. Based on Bundesen's "theory of visual attention" (TVA), two parameters were derived: top-down control of attentional selection, representing task-related attentional weighting for prioritizing relevant visual objects, and spatial distribution of attentional weights across the left and the right hemifield. Compared with controls, MCI patients showed significantly reduced top-down controlled selection, which was further deteriorated in AD subjects. Moreover, attentional weighting was significantly unbalanced across hemifields in MCI and tended to be more lateralized in AD. Across MCI and AD patients, carriers of the apolipoprotein E epsilon4 allele (ApoE4) displayed a leftward spatial bias, which was the more pronounced the younger the ApoE4-positive patients and the earlier disease onset. These results indicate that impaired top-down control may be linked to early dysfunction of fronto-parietal networks. An early temporo-parietal interhemispheric asymmetry might cause a pathological spatial bias which is associated with ApoE4 genotype and may therefore function as early cognitive marker of upcoming AD.
Sorg C, Myers N, Redel P, et al., 2012, Asymmetric loss of parietal activity causes spatial bias in prodromal and mild Alzheimer's disease, Biol Psychiatry, Vol: 71, Pages: 798-804, ISSN: 1873-2402
BACKGROUND: In Alzheimer's disease (AD), loss of effective neuronal activity is reflected by cortical glucose hypometabolism. Hypometabolism in the posterior parietal cortex (PPC) is among the first in vivo signs of AD; however, its functional impact on large-scale brain mechanisms and behavior is poorly understood. The lateral PPC contributes to spatial attention constituting a basic function of the human brain. We hypothesized 1) that lateral PPC hypometabolism is associated with impaired spatial attention in very early AD and 2) that impaired competition of effective neuronal activity across hemispheres might underlie this deficit in terms of brain mechanisms. METHODS: A model-based imaging approach was applied to assess patients with prodromal (n = 28) and mild (n = 7) AD. Quantitative attention parameters, derived from performance on simple psychophysical tasks and analyzed by Bundesen's computational theory of visual attention, were related to brain metabolism, measured by (18)F-fluorodeoxyglucose positron emission tomography. RESULTS: Patients' left and right lateral PPC metabolism was reduced. Nine patients had significant spatial attentional bias on the left side and two patients on the right. Direction and degree of spatial bias was correlated with direction and degree of an interhemispheric metabolism bias in the inferior parietal lobe and temporoparietal junction. CONCLUSIONS: Our data provide evidence that in very early AD, asymmetric hypometabolism of the lateral PPC causes spatial attentional bias. Results are broadly consistent with the model that asymmetrically impaired effective neuronal PPC activity in AD biases the competition of visual objects for cortical representation and access to awareness to one side.
Wagner M, Wolf S, Reischies FM, et al., 2012, Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease, Neurology, Vol: 78, Pages: 379-386, ISSN: 1526-632X
OBJECTIVE: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). METHODS: Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale-Revised. CSF was obtained from all patients. RESULTS: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Abeta(1-42)/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD- patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. CONCLUSIONS: Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.
Alexopoulos P, Tsolakidou A, Roselli F, et al., 2012, Clinical and neurobiological correlates of soluble amyloid precursor proteins in the cerebrospinal fluid, Alzheimers Dement, Vol: 8, Pages: 304-311, ISSN: 1552-5279
BACKGROUND: According to a widely accepted hypothesis, the amyloid precursor protein (APP) is processed by two competing pathways: the amyloidogenic beta-secretase-mediated pathway or the nonamyloidogenic alpha-secretase-mediated pathway. APP is cleaved preferentially through the nonamyloidogenic pathway in normal brain, whereas the balance shifts to the amyloidogenic pathway in Alzheimer's disease (AD). The levels of the alpha-secretase-cleaved soluble APP (sAPPalpha) and beta-secretase-cleaved soluble APP (sAPPbeta) in cerebrospinal fluid (CSF) are likely to reflect these competing mechanisms. METHODS: We investigated the levels and the relationship between sAPPalpha and sAPPbeta in the CSF of 64 patients with mild AD, 76 patients with mild cognitive impairment, and 12 cognitively healthy control subjects, as well as the effect of apolipoprotein E genotype and sex on soluble APP levels. RESULTS: There was a significant positive correlation between sAPPalpha and sAPPbeta levels in all three groups. sAPPalpha and sAPPbeta concentrations were higher in patients with mild cognitive impairment compared with patients with AD. In the AD group, females exhibited higher sAPPalpha and sAPPbeta levels than males. No influence of the apolipoprotein E genotype on soluble APP concentrations was detected. DISCUSSION: The positive correlation between sAPPalpha and sAPPbeta challenges the hypothesis that AD is caused by an imbalance of the alpha- and beta-secretase APP proteolysis through competing mechanisms. Moreover, the differences in CSF levels of sAPPalpha and sAPPbeta between male and female patients with AD may reflect a "sexual dimorphism" in the activity of the two APP processing pathways in AD.
Guo LH, Alexopoulos P, Wagenpfeil S, et al., 2012, Brain size and the compensation of Alzheimer's disease symptoms: A longitudinal cohort study, Alzheimers Dement, ISSN: 1552-5279
BACKGROUND: Greater intracranial volume (ICV) has been associated with less severe Alzheimer's disease (AD) symptoms at a given level of cerebral pathology. In this study we examine whether ICV modulates the association between clinical disease progression on the one hand and brain atrophy or the apolipoprotein E genotype on the other. METHODS: Six hundred seventy-four subjects were studied from the AD Neuroimaging Initiative (ADNI). Subjects included 204 controls, 144 patients with AD dementia, and 326 with amnestic mild cognitive impairment (aMCI). Longitudinal analyses were conducted applying generalized estimating equations to examine the influence of ICV on clinical deterioration and atrophy progression. Follow-up data were available for up to 60 months after the baseline visit (mean 31.42 months, SD 13.12 months). RESULTS: ICV was not directly associated with clinical worsening or atrophy progression. However, ICV attenuated the impact of atrophy and the apolipoprotein E epsilon4 allele on clinical disease progression in aMCI. CONCLUSION: Greater ICV, that is, premorbid brain size, seems to protect against clinical deterioration in the face of AD-related brain atrophy in aMCI. The results support the theory of a compensatory role of brain reserve in contrast to a neuroprotective role. The protective effects of morphologic reserve seem to be limited to early clinical AD; once a certain threshold of neurodegenerative burden is passed, a larger premorbid brain no longer offers an advantage in this context.
Tsolakidou A, Alexopoulos P, Guo LH, et al., 2012, beta-Site amyloid precursor protein-cleaving enzyme 1 activity is related to cerebrospinal fluid concentrations of sortilin-related receptor with A-type repeats, soluble amyloid precursor protein, and tau, Alzheimers Dement, ISSN: 1552-5279
BACKGROUND: beta-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity determines the rate of APP cleavage and is therefore the main driver of amyloid beta production, which is a pathological hallmark of Alzheimer's disease (AD). METHODS: The present study explored the correlation between BACE1 activity and cerebrospinal fluid (CSF) markers of APP metabolism and axonal degeneration in 63 patients with mild AD and 12 healthy control subjects. RESULTS: In the AD group, positive correlations between BACE1 activity and soluble APP beta, the APP sorting receptor sortilin-related receptor with A-type repeats (also known as SorLA or LR11), and tau were detected. BACE1 activity was not associated with amyloid beta(1-42) or soluble APP alpha concentrations in the AD group, and no associations between BACE1 activity and any of the protein concentrations were found in the control group. CONCLUSION: Our results confirm the relevance of BACE1 and sortilin-related receptor with A-type repeats within the amyloid cascade and also provide a further piece of evidence for the link between amyloid and tau pathology in AD.
Li R, Hapfelmeier A, Schmidt J, et al., 2011, A case study of stacked multi-view learning in dementia research, Pages: 60-69, ISSN: 0302-9743
Classification of different types of dementia commonly involves examination from several perspectives, e.g., medical images, neuropsychological tests, etc. Thus, dementia classification should lend itself to so-called multi-view learning. Instead of simply combining several views, we use stacking to make the most of the information from the various views (PET scans, MMSE, CERAD and demographic variables). In the paper, we not only show the performance of stacked multi-view learning on classifying dementia data, we also try to explain the factors contributing to its performance. More specifically, we show that the correlation of views on the base and the meta level should be within certain ranges to facilitate successful stacked multi-view learning. © 2011 Springer-Verlag.
Alexopoulos P, Guo LH, Kratzer M, et al., 2011, Impact of SORL1 single nucleotide polymorphisms on Alzheimer's disease cerebrospinal fluid markers, Dement Geriatr Cogn Disord, Vol: 32, Pages: 164-170, ISSN: 1421-9824
BACKGROUND: Recently, genetic variants of the neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) have emerged as risk factors for the development of Alzheimer's disease (AD). METHODS: In this study, SORL1 gene polymorphisms, which have been shown to be related to AD, were analyzed for associations with cerebrospinal fluid (CSF) amyloid beta1-42 (Abeta(1-42)), phosphorylated tau181, and total tau levels in a non-Hispanic Caucasian sample, which encompassed 100 cognitively healthy elderly individuals, 166 patients with mild cognitive impairment, and 87 patients with probable AD. The data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). Moreover, the impact of gene-gene interactions between SORL1 single nucleotide polymorphisms (SNPs) and the apolipoprotein E (APOE) epsilon4 allele, the major genetic risk factor for sporadic AD, on Abeta(1-42) concentrations was investigated. RESULTS: Significant associations between CSF Abeta(1-42) levels and the SORL1 SNPs 23 (rs3824968) and 24 (rs2282649) were detected in the AD group. The latter association became marginally statistically insignificant after Bonferroni correction for multiple comparisons. Carriers of the SORL1 SNP24 T allele and the SNP23 A allele both had lower CSF Abeta(1-42) concentrations than non-carriers of these alleles. The analysis of the impact of interactions between APOE epsilon4 allele and SORL1 SNPs on CSF Abeta(1-42) levels unraveled significant influences of APOE. CONCLUSIONS: Our findings provide further support for the notion that SORL1 genetic variants are related to AD pathology, probably by regulating the amyloid cascade.
Friedrich P, Feulner TM, Laws SM, et al., 2011, No association of Tachykinin receptor 2 (TACR2) polymorphisms with Alzheimer's disease, Neurobiol Aging, Vol: 32, Pages: 544-545, ISSN: 1558-1497
The Tachykinin Receptor 2 (TACR2) located at chromosome 10q21.3 belongs to a class of receptors that bind members of the tachykinin neurotransmitter family. The TACR2 binds neurokinin A, also known as substance K, and is expressed in distinct parts of the human brain. Functionally, the TACR2 has been implicated in stress induced hippocampal acetylcholine release and the gene TACR2 is located within a previously identified linkage region for Alzheimer's disease (AD) on chromosome 10q21. Together, both facts make the TACR2 a reasonable positional and functional candidate gene for AD. Genotyping of 13 single nucleotide polymorphisms (SNPs) covering the entire gene and haplotypic analysis revealed no association with AD. Thus, we conclude that TACR2 can be excluded as a major susceptibility gene conferring risk to AD.
Hamann J, Bronner K, Margull J, et al., 2011, Patient participation in medical and social decisions in Alzheimer's disease, J Am Geriatr Soc, Vol: 59, Pages: 2045-2052, ISSN: 1532-5415
OBJECTIVES: To analyze the preferences of people with amnestic mild cognitive impairment (aMCI) and mild dementia in Alzheimer's disease (AD) regarding different aspects of healthcare-related decisions, to correlate these findings with different measures of decision-making capacity, and to explore the views of relatives and referring physicians. DESIGN: Cross-sectional survey. SETTING: University-based memory clinic in Munich, Germany. PARTICIPANTS: One hundred people with aMCI or mild AD, their relatives (N = 99), and their referring physicians (N = 93). MEASUREMENTS: Participation preferences and decisional capacity and assessment of these measures according to relatives and physicians. RESULTS: Patients had a preference for participation in healthcare-related decisions, especially in social ones. Overall, individuals wanted their relatives to play a secondary role in decision-making. Relatives and referring physicians performed poorly in predicting the individuals' participation preferences, and relatives wanted to attribute less decision-making power to patients than the patients did themselves. Patients refrained from participation if they had lower Mini-Mental State Examination scores or were unsure about their decisional capacity. There were deficits in decision-making capacity, which mostly related to understanding of the information presented. There was only weak correlation between the different measures (patient's, relative's, and physician's estimate, MacArthur Competence Assessment Tool for Treatment) of the patients' decisional capacity. CONCLUSION: The combination of marked participation preferences and impairments in the decisional capacity of individuals with aMCI and early AD constitute an ethical and practical challenge. A thorough implementation of structured probes of the patients' decisional capacity combined with interventions that aid patients in their decision-making capability might help to overcome some of these challenges.
Kurz A, Perneczky R, 2011, Amyloid clearance as a treatment target against Alzheimer's disease, J Alzheimers Dis, Vol: 24 Suppl 2, Pages: 61-73, ISSN: 1875-8908
An imbalance between production and clearance of the amyloid-beta peptide (Abeta) is a key momentum of the complex pathological cascade of Alzheimer's disease (AD). It is caused by overproduction of Abeta or, more frequently, by impaired clearance from brain. Clearance can be reduced by increased aggregation, defective degradation, disturbed balance of transport across the blood-brain barrier, or inefficient peripheral removal of the peptide. In recent years these mechanisms have become targets of pharmacological interventions. Although several compounds have been discarded on the grounds of limited clinical efficacy, all major clearance-related approaches still hold promise. Some drug candidates have advanced to Phase III trials including anti-Abeta antibodies, metal complexing agents, ginseng extracts, and intravenous immunoglobulins. Data are currently not available from these studies that might allow an evaluation of efficacy and safety. Phase II trials on active and passive immunization have demonstrated a striking discrepancy between significant neurobiological effects regarding the removal of Abeta deposits and minor clinical outcomes. This does not preclude the possibility that clearance-related strategies have the potential of saving neurons and synapses via reducing the levels of soluble and particularly toxic Abeta species in brain. It may take longer than projected in ongoing trials for such neurobiological effects to translate into measurable changes of clinical progression.
Kurz A, Perneczky R, 2011, Novel insights for the treatment of Alzheimer's disease, Prog Neuropsychopharmacol Biol Psychiatry, Vol: 35, Pages: 373-379, ISSN: 1878-4216
The development of treatments for Alzheimer's disease (AD) is currently shifting away from the correction of neurotransmitter abnormalities and from attempts to remove the pathognomonic protein deposits. Drug discovery is heading towards novel types of pharmacological interventions which are aimed at more central and upstream pathophysiological events. The large number of upcoming treatment targets can be grouped into two major categories. The first category consists of antecedents of beta amyloid peptide (Abeta) and TAU deposition including Abeta production, degradation and clearance, TAU hyperphosphorylation and aggregation. The second consists of protectors against neuronal dysfunction and premature death such as mitochondrial functioning, nerve growth and regeneration, and neuronal membrane integrity. It is hoped that some of these strategies will not only have larger symptomatic effects than the currently available drugs but also an impact on the underlying neurodegeneration. Since the novel treatments will be typically administered over years they must meet high standards of safety, drug-drug compatibility, and tolerability. Probably the most important target groups for novel treatments are carriers of mutations causing AD, and individuals with minor cognitive impairment representing a pre-dementia stage of the disease. To minimise incorrect case identifications, drug development must be paralleled by improved diagnostic techniques. Novel pharmacological strategies may be cost-effective if disability and need of full-time care can be postponed or prevented without prolonging time lived with dementia or extending survival. We are uncertain whether the advent of novel disease-retarding strategies will revolutionise the management of AD. Symptomatic treatments will continue to be needed, and psychosocial approaches will retain an essential role in supporting affected individuals and their families.
Perneczky R, Alexopoulos P, Schmid G, et al., 2011, [Cognitive reserve and its relevance for the prevention and diagnosis of dementia], Nervenarzt, Vol: 82, Pages: 325-335, ISSN: 1433-0407
Progressive brain damage is undoubtedly the main cause of clinical symptoms of dementia in neurodegenerative disorders such as Alzheimer's disease. However, the association between brain damage and cognitive symptoms is not linear. Certain interindividual differences such as a good school education or a greater brain volume are associated with a higher resilience against brain damage that is usually referred to as cognitive reserve (CR). Individuals with high CR have a diminished risk for dementia and both active and passive concepts for this phenomenon are discussed. In the concept of passive CR, peculiarities of brain structure such as higher synapse or neuron counts are regarded as buffers against brain damage. Symptoms of dementia do not occur until a certain threshold of damage is passed. In addition to the passive concepts, active mechanisms are also discussed that are associated with the ability to maintain a certain level of cognitive performance in the face of progressive neurodegeneration for a longer period. In subjects with healthy cognitive function, these active mechanisms contribute to the adaptation of brain activity when task difficulty level is increased. Confronted with progressive neurodegeneration, these active mechanisms help to compensate for brain damage. Individuals with higher CR show more efficient activation for solving the same task, which helps them to preserve normal levels of cognitive performance for a longer period.
Perneczky R, Ghosh BC, Hughes L, et al., 2011, Saccadic latency in Parkinson's disease correlates with executive function and brain atrophy, but not motor severity, Neurobiol Dis, Vol: 43, Pages: 79-85, ISSN: 1095-953X
Brain regions related to saccadic control are affected by Parkinson's disease (PD) pathology and a relationship between abnormal saccades and cognitive features of PD has been suggested. We measured the latency of visually-evoked saccades, and correlated best-fit parameters in a LATER neuronal decision model mu and sigma (mean and SD of the distribution of reciprocal latency, i.e. speed of response), and sigma(E) (SD of the early component) with motor function, cognition and grey matter volume in 18 patients with PD and 17 controls. There was a negative correlation between verbal fluency and sigma; no correlation was found between motor function and any of the latency parameters. Higher mu (shorter latency) positively correlated with grey matter volume in the prefrontal cortex, the cerebellar vermis, and the fusiform gyrus. There was a negative correlation between sigma and grey matter volume in the frontal and parietal eye fields, the premotor cortex, and the lateral prefrontal cortex. sigma(E) negatively correlated with grey matter volume in the frontal eye fields and the middle frontal gyrus. Our behavioural and imaging findings point to an association between saccade latency, executive function and the structural integrity within a well-defined oculomotor network.
Preibisch C, Sorg C, Forschler A, et al., 2011, Age-related cerebral perfusion changes in the parietal and temporal lobes measured by pulsed arterial spin labeling, J Magn Reson Imaging, Vol: 34, Pages: 1295-1302, ISSN: 1522-2586
PURPOSE: To investigate age-related regional perfusion changes focused on the medial temporal lobes and related parietal areas using a pulsed arterial spin labeling technique. MATERIALS AND METHODS: Resting cerebral blood flow (CBF) maps were obtained from 44 healthy volunteers (18 male, 26 female; age range, 19 to 79 years) using a pulsed arterial spin labeling (PASL) MRI technique at 3 Tesla focused on the parietal and temporal lobes. Repeated measurements were performed in 20 subjects to assure the reliability and reproducibility of the applied PASL technique. RESULTS: Focal age-related CBF decreases were detected in the parietal cortex, cuneus and caudate, whereas increases were seen in the lateral and medial temporal lobe such as hippocampus, the calcarine gyrus and the thalamus. Moreover, repeated measurements demonstrated a high reliability and reproducibility of the applied PASL technique. CONCLUSION: Data provide evidence for regionally dissociated patterns of perfusion increases and decreases during ageing in the temporal and parietal lobes.
Richter-Schmidinger T, Alexopoulos P, Horn M, et al., 2011, Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults, J Neural Transm, Vol: 118, Pages: 249-257, ISSN: 1435-1463
Unravelling the impact of genetic variants on clinical phenotypes is a challenging task. Apolipoprotein E (ApoE) and brain-derived neurotrophic factor (BDNF) play an important role in cell growth, regeneration, synaptic plasticity, learning and memory processes. The aim of the present study was to examine the impact of BDNF Val66Met- and ApoE-polymorphisms and their interactions on hippocampal morphology and memory functions in healthy young adults. Hippocampal volume and memory performance of 135 healthy individuals, aged 24.6 +/- 3.2 years, were assessed, using magnetic resonance imaging and the Inventory for Memory diagnostics. The performance of BDNF-Met66 carriers was significantly lower in working memory (P = 0.03) compared with non carriers, whereas no further differences were observed either in cognitive performance or in hippocampal volumes between the groups. Age, BDNF Val66 Met polymorphism and the interaction factor BDNF genotype x age were significantly associated with the variation of working memory scores (P = 0.01, 0.01, 0.02 respectively). No statistically significant differences were detected in the volumes of hippocampi and in memory phenotypes between individuals carrying the ApoE E4 allele and those without it. The analysis did not reveal an impact of gene-gene interaction between BDNF and ApoE genes on hippocampal volumes or memory performance. BDNF Val66Met polymorphism seems to influence working memory function and modulate the effects of ageing on working memory in healthy young adults.
Spreng RN, Drzezga A, Diehl-Schmid J, et al., 2011, Relationship between occupation attributes and brain metabolism in frontotemporal dementia, Neuropsychologia, Vol: 49, Pages: 3699-3703, ISSN: 1873-3514
Occupation has been associated with cognitive reserve in healthy aging and Alzheimer's disease. Here we assess the relationship between cerebral metabolic deficits in behavioral variant frontotemporal dementia (bvFTD) and occupation characteristics. Using factor analysis, we derived verbal, physical and visuospatial occupation scores from the US Department of Labor, Occupational Information Network and related these scores to regional cerebral metabolic rate of glucose utilization in 31 patients diagnosed with behavioral variant bvFTD, controlling for cognitive status (CERAD neuropsychological assessment battery), gender and education. Regression analyses showed a marked inverse association between glucose metabolism and (a) verbal occupation scores in left prefrontal cortex and, (b) physical occupation characteristics in right supplementary motor area. We concluded that, consistent with the cognitive reserve hypothesis, lifelong occupation characteristics are related to focal cerebral metabolic deficits in bvFTD. Specific occupation demands spanning decades may strengthen cognitive resistance to pathology.
Perneczky R, Tsolakidou A, Arnold A, et al., 2011, CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease, Neurology, Vol: 77, Pages: 35-38, ISSN: 1526-632X
OBJECTIVE: To explore if soluble amyloid precursor proteins (sAPP) in CSF improve the identification of patients with incipient Alzheimer disease (AD) in a group of patients with mild cognitive impairment (MCI). METHODS: A cohort study with follow-up assessments of 58 patients with MCI with baseline CSF sampling was conducted: 21 patients had progressed to probable AD (MCI-AD), 27 still had MCI, 8 had reverted to normal (MCI-NAD), and 2 patients with frontotemporal dementia (FTD) were excluded. Sixteen additional patients with FTD were included to explore the specificity of the CSF markers. CSF concentrations of sAPPalpha, sAPPbeta, tau, and Abeta(1-42) were measured with sensitive and specific ELISAs. Associations between diagnostic status, CSF protein concentrations, and other patient characteristics were explored using multiple logistic regression analyses with stepwise variable selection. The optimal sensitivity and specificity of the best models were derived from receiver operating characteristic curves. RESULTS: The MCI-AD group had significantly higher sAPPbeta concentrations than the MCI-NAD and the FTD groups. A combination of sAPPbeta, tau, and age differentiated the MCI-AD and the MCI-NAD groups with a sensitivity of 80.00% and a specificity of 81.00%. The best model for the differentiation of the MCI-AD and the FTD groups included sAPPbeta and tau, and showed a sensitivity of 95.20% and a specificity of 81.20%. Abeta(1-42) and sAPPalpha did not significantly contribute to the models. CONCLUSION: These findings suggest that sAPPbeta may be clinically useful, and superior to Abeta(1-42), in the early and differential diagnosis of incipient AD.
Perneczky R, Alexopoulos P, Kurz A, et al., 2011, Cognitive reserve, homocysteine, and cognition in the Bavarian School Sisters Study, J Am Geriatr Soc, Vol: 59, Pages: 1754-1756, ISSN: 1532-5415
Perneczky R, Sorg C, Förstl H, 2010, Functional Imaging of the Ageing Brain, Principles and Practice of Geriatric Psychiatry: Third Edition, Pages: 28-35, ISBN: 9780470747230
Morbelli S, Drzezga A, Perneczky R, et al., 2010, Resting-state brain metabolic connectivity in amnestic MCI-AD converters and healthy controls. A joint project of the European Alzheimer's Disease Consortium (EADC), 23rd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S259-S260, ISSN: 1619-7070
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Schmidt J, Hapfelmeier A, Mueller M, et al., 2010, Interpreting PET scans by structured patient data: a data mining case study in dementia research, KNOWLEDGE AND INFORMATION SYSTEMS, Vol: 24, Pages: 149-170, ISSN: 0219-1377
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- Citations: 12
Alexopoulos P, Topalidis S, Irmisch G, et al., 2010, Homocysteine and cognitive function in geriatric depression, Neuropsychobiology, Vol: 61, Pages: 97-104, ISSN: 1423-0224
BACKGROUND/OBJECTIVES: Cognitive dysfunction is a common aspect of the spectrum of symptoms of geriatric depression. High homocysteine levels have been linked to cognitive decline in neuropsychiatric disorders. The present study investigated possible associations between cognitive impairment observed in geriatric depression and homocysteine levels. METHODS: The performance of 25 mentally healthy individuals and 40 patients with geriatric depression in terms of language processing, processing speed, concentration and attention was assessed with the Stroop Test and the d2 Test of Attention. Serum homocysteine was determined with an enzyme immunoassay. RESULTS: The performance of depressed patients was significantly worse in language processing (p = 0.001) and processing speed (p < 0.0001). Depressed patients with high levels of homocysteine performed better than patients with homocysteine concentrations <or=11.7 micromol/l in both cognitive domains (p = 0.006 and 0.009, respectively). Moreover, homocysteine level was positively associated with language processing (p = 0.002) and processing speed (p = 0.002). CONCLUSIONS: These findings indicate that under the special circumstances of geriatric depression (perturbation of glutamatergic transmission and glutamate metabolism), homocysteine is positively associated with the performance in language processing and processing speed.
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