Anatomical and functional changes in the retina in patients with Alzheimer's disease and mild cognitive impairment.

PURPOSE: There is evidence that mild cognitive impairment (MCI) or Alzheimer's disease (AD) is accompanied by alterations in the retina. The current study was performed to investigate structural and functional changes in patients with systemic neurodegenerative disease. METHODS: A total of 47 patients with either MCI or AD and 43 healthy age- and sex-matched control subjects were included. Inclusion criteria for MCI were abnormal memory function and a mini-mental state examination (MMSE) score >26 points, for patients with AD a diagnosis of probable AD of mild to moderate degree and an MMSE score in the range of 20-26. Retinal blood flow was measured using a Doppler optical coherence tomography (OCT) system. Retinal vessel diameter, oxygen saturation and flicker-induced vasodilatation were measured using a Vessel Analyzer. Retinal nerve fibre layer thickness (RNFLT) was assessed using an OCT system. RESULTS: Global RNFLT was lower in patients compared to healthy controls (93.7 ± 12.8 µm versus 99.1 ± 9.0 µm, p = 0.02). The same was found in regards to retinal arterial blood flow, which was 9.3 ± 2.4 and 12.3 ± 3.2 µl/min in the patient and control groups, respectively (p < 0.001). Mean retinal arterial diameter was reduced in patients (76.0 ± 8.9 µm versus 80.6 ± 8.0 µm, p = 0.03). Arteriovenous difference in oxygen saturation was lower in patients (20.4 ± 5.1% versus 23.5 ± 4.0%, p < 0.01). No difference in the flicker response was observed. CONCLUSION: In patients with MCI and AD, arteriovenous difference in oxygen saturation, retinal blood flow and arterial vessel diameter was reduced. No difference was found in flicker response between groups. This indicates alterations in retinal oxygen metabolism in patients with neurodegenerative disease.

Are Pre-Ascent Low-Altitude Saliva Cortisol Levels Related to the Subsequent Acute Mountain Sickness Score? Observations from a Field Study.

Background: The associations among cortisol levels, body water status, and acute mountain sickness (AMS) remain unclear. We investigated associations between AMS prevalence and severity with resting saliva cortisol levels at low altitude (LA) and high altitude (HA) and with fluid balance during a HA stay. Methods: Twenty-two physically fit and healthy participants (12 women, 10 men) were transported to HA (Testa Grigia, 3480 m). In the late afternoon at LA, on the next day 3-4 hours after arrival at HA and in the morning after an overnight stay, heart rate, oxygen saturation, and systolic and diastolic blood pressures were measured in a sitting position after 10 minutes of rest; cortisol levels were quantified in saliva samples taken pre-ascent and 3-4 hours after arrival at HA. AMS was scored with the 1993 Lake Louise Score (LLS, cut-off ≥3). Urine volume and fluid and food intake were recorded during the altitude stay. Results: Pre-ascent cortisol levels were associated with fluid retention during the altitude stay (r2 = 0.33, p < 0.05) and both were positively related to the LLS (r2 = 0.49 and r2 = 0.26, p < 0.05, respectively). Conclusions: In conclusion, resting LA cortisol levels and fluid retention upon rapid exposure to altitude seem to be associated with AMS. This suggests a potential link among cortisol homeostasis, fluid balance, and AMS risk.

FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease.

BACKGROUND: Neurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer's disease and non-Alzheimer's tauopathies. Targeting pathological tau proteins via immunotherapy is a promising strategy for disease-modifying treatment of Alzheimer's disease. Previously, we reported a 24-week phase 1 trial on the active vaccine AADvac1 against pathological tau protein; here, we present the results of a further 72 weeks of follow-up on those patients. METHODS: We did a phase 1, 72-week, open-label study of AADvac1 in patients with mild to moderate Alzheimer's disease who had completed the preceding phase 1 study. Patients who were previously treated with six doses of AADvac1 at monthly intervals received two booster doses at 24-week intervals. Patients who were previously treated with only three doses received another three doses at monthly intervals, and subsequently two boosters at 24-week intervals. The primary objective was the assessment of long-term safety of AADvac1 treatment. Secondary objectives included assessment of antibody titres, antibody isotype profile, capacity of the antibodies to bind to AD tau and AADvac1, development of titres of AADvac1-induced antibodies over time, and effect of booster doses; cognitive assessment via 11-item Alzheimer's Disease Assessment Scale cognitive assessment (ADAS-Cog), Category Fluency Test and Controlled Oral Word Association Test; assessment of brain atrophy via magnetic resonance imaging (MRI) volumetry; and assessment of lymphocyte populations via flow cytometry. RESULTS: The study was conducted between 18 March 2014 and 10 August 2016. Twenty-six patients who completed the previous study were enrolled. Five patients withdrew because of adverse events. One patient was withdrawn owing to noncompliance. The most common adverse events were injection site reactions (reported in 13 [50%] of vaccinated patients). No cases of meningoencephalitis or vasogenic oedema were observed. New micro-haemorrhages were observed only in one ApoE4 homozygote. All responders retained an immunoglobulin G (IgG) antibody response against the tau peptide component of AADvac1 over 6 months without administration, with titres regressing to a median 15.8% of titres attained after the initial six-dose vaccination regimen. Booster doses restored previous IgG levels. Hippocampal atrophy rate was lower in patients with high IgG levels; a similar relationship was observed in cognitive assessment. CONCLUSIONS: AADvac1 displayed a benign safety profile. The evolution of IgG titres over vaccination-free periods warrants a more frequent booster dose regimen. The tendency towards slower atrophy in MRI evaluation and less of a decline in cognitive assessment in patients with high titres is encouraging. Further trials are required to expand the safety database and to establish proof of clinical efficacy of AADvac1. TRIAL REGISTRATION: The studies are registered with the EU Clinical Trials Register and ClinicalTrials.gov : the preceding first-in-human study under EudraCT 2012-003916-29 and NCT01850238 (registered on 9 May 2013) and the follow-up study under EudraCT 2013-004499-36 and NCT02031198 (registered 9 Jan 2014), respectively.

Secondary dementia due to Lyme neuroborreliosis.

Dementia-like syndromes are rare manifestations of Lyme neuroborreliosis. The clinical patterns are summarized using our own cases and case reports from the literature, which were diagnosed as definite Lyme neuroborreliosis according to the European guidelines. The cases disclose signs of subcortical dementia that occur more rapidly than in patients suffering from primary dementia. Gait disturbances early in the disease course is another frequently observed characteristic feature. The response to 2-4 weeks of antibiotic treatment with ceftriaxone was excellent. There were no indications for a prolonged antibiotic treatment. It is essential to be aware of this manifestation of Lyme neuroborreliosis, because early antibiotic treatment will prevent permanent sequelae that may occur throughout the further course of the untreated disease.

Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau proteins is therefore a promising strategy for disease-modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial. METHODS: We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50-85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov, number NCT01850238; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov, number NCT02031198. FINDINGS: This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 [53%] vaccinated patients [92 individual events]). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres. INTERPRETATION: AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1. FUNDING: AXON Neuroscience SE.

Evolution of clinical features in possible DLB depending on FP-CIT SPECT result.

OBJECTIVE: To test the hypothesis that core and suggestive features in possible dementia with Lewy bodies (DLB) would vary in their ability to predict an abnormal dopamine transporter scan and therefore a follow-up diagnosis of probable DLB. A further objective was to assess the evolution of core and suggestive features in patients with possible DLB over time depending on the (123)I-FP-CIT SPECT scan result. METHODS: A total of 187 patients with possible DLB (dementia plus one core or one suggestive feature) were randomized to have dopamine transporter imaging or to follow-up without scan. DLB features were compared at baseline and at 6-month follow-up according to imaging results and follow-up diagnosis. RESULTS: For the whole cohort, the baseline frequency of parkinsonism was 30%, fluctuations 29%, visual hallucinations 24%, and REM sleep behavior disorder 17%. Clinician-rated presence of parkinsonism at baseline was significantly (p = 0.001) more frequent and Unified Parkinson's Disease Rating Scale (UPDRS) score at baseline was significantly higher (p = 0.02) in patients with abnormal imaging. There was a significant increase in UPDRS score in the abnormal scan group over time (p < 0.01). There was relatively little evolution of the rest of the DLB features regardless of the imaging result. CONCLUSIONS: In patients with possible DLB, apart from UPDRS score, there was no difference in the evolution of DLB clinical features over 6 months between cases with normal and abnormal imaging. Only parkinsonism and dopamine transporter imaging helped to differentiate DLB from non-DLB dementia.

Careful neuropsychological testing reveals a novel genetic marker, GSTO1*C, linked to the pre-stage of Alzheimer's disease.

Approximately 30 million people currently suffer from late-onset Alzheimer's disease (LOAD) worldwide. Twin studies demonstrated that 60 to 80% of LOAD is genetically determined, 20% of which remaining unassigned. This case-control study included 118 cognitively healthy controls, 52 patients with mild cognitive impairment (MCI; the pre-stage of LOAD) and 71 LOAD patients. The participants were genotyped for the genetic LOAD marker apolipoprotein E4 (APOE4) and the single-nucleotide polymorphism rs4925 in glutathione S-transferase omega-1 (GSTO1). Additive logistic regression showed a novel, statistically significant association of the major allele GSTO1*C with MCI (OR1.9; p = 0.032). However, identification of significant SNP-disease relations required well-defined study groups. When classifying participants solely by the short Mini Mental State examination (MMSE), the associations of GSTO1*C and the reference marker APOE4 with MCI were cancelled. Moreover, even identifying only the control group by MMSE nullified a statistically significant association (OR1.8; p = 0.045) between GSTO1*C and LOAD. In contrast, these statistical relations were retained when the detailed Consortium to Establish a Registry for Alzheimer's Disease (CERAD-Plus) test battery was used. Hence, besides proposing rs4925 as a genetic marker for cognitive impairment, this work also emphasized the importance of carefully characterized controls in addition to well-diagnosed patients in case-control studies.

Clinical usefulness of dopamine transporter SPECT imaging with 123I-FP-CIT in patients with possible dementia with Lewy bodies: randomised study.

BACKGROUND: Dementia with Lewy bodies (DLB) is underrecognised in clinical settings. AIMS: To investigate whether performing a (123)I-ioflupane injection ((123)I-FP-CIT also called DaTSCAN™) single photon emission computed tomography (SPECT) scan in patients with possible DLB would lead to a more certain diagnosis (probable DLB or non-DLB dementia). METHOD: We randomised 187 patients with possible DLB 2:1 to have a scan or not (control group). The outcome measure was a change in diagnosis to probable DLB or non-DLB. RESULTS: There were 56 controls and 114 scanned patients, of whom 43% had an abnormal scan. More patients in the imaging group had a change in diagnosis compared with controls at 8 and 24 weeks (61% (n = 70) v. 4% (n = 2) and 71% (n = 77) v. 16% (n = 9); both P<0.0001). Clinicians were more likely to change the diagnosis if the scan was abnormal (82%) than if it was normal (46%). CONCLUSIONS: Imaging significantly contributed to a more certain diagnosis, proving to be a useful adjunct in the work-up of patients with possible DLB.

Ginkgo biloba extract EGb 761 in the treatment of dementia: a pharmacoeconomic analysis of the Austrian setting.

OBJECTIVE: We used efficacy data from three clinical trials to investigate the pharmacoeconomic implications of treating noninstitutionalized Austrian dementia patients with a drug based on EGb 761R, a standardized extract from Gingkgo biloba. In a separate analysis, we compared the pharmacoeconomic aspects of achieving treatment success with EGb 761R and cholinesterase inhibitors. METHODS: A fixed-effect model was used to conduct a metaanalysis of activities of daily living data from 1,201 patients diagnosed with dementia and treated with either EGb 761R (240 mg/day) or matched placebo for 22 or 24 weeks under double-blind conditions. From this analysis, the delay in activities of daily living (ADL)-based disease progression was estimated. Current Austrian drug reimbursement prices, physician fees, and federal subsidies for seven stages of home care were applied to calculate overall costs in four scenarios. For the comparison with cholinesterase inhibitors, metaanalysis data pertaining to overall clinical impression as published by the Cochrane Group were compared to corresponding data from our EGb 761R studies. RESULTS AND DISCUSSION: The benefit of treatment with EGb 761R (240 mg/day) corresponds to a delay in ADL deterioration by 22.3 months compared to placebo. Overall net savings with EGb 761R treatment ranged from EUR 3,692 to EUR 29,577, mainly driven by delays in progression towards higher home care subsidies. For one additional therapy success with EGb 761R, EUR 530.88 was required. In a tentative cost comparison, cholinesterase inhibitors required higher expenses to achieve treatment success.

Are specific symptoms of depression predictive of Alzheimer's dementia?

OBJECTIVE: To investigate whether specific symptoms of major depression are associated with later development of possible or probable Alzheimer's dementia. METHOD: The analysis is part of the Vienna Transdanube Aging Study, a prospective, community-based cohort study of all 75-year-old inhabitants of 2 Viennese districts. Current depressive symptoms were captured with a DSM-IV-TR-based questionnaire. Diagnosis of possible or probable Alzheimer's dementia was performed according to criteria by the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. The baseline sample included 437 not-demented and not previously depressed individuals. At 60-month follow-up, 65 of the remaining 296 subjects had possible or probable Alzheimer's dementia. The primary outcome measure was the probability of diagnosis of Alzheimer's dementia related to baseline depressive symptoms. Baseline data were collected between May 2000 and December 2002; 60-month follow-up data were collected between June 2005 and February 2008. RESULTS: 10.8% of those who were diagnosed with possible or probable Alzheimer's dementia at 60-month follow-up had shown loss of interest versus 2.2% in the nondemented group. The analysis showed a significant association of loss of interest only with the later occurrence of possible or probable Alzheimer's dementia (adjusted P value <.05, OR = 5.27 [95% CI, 1.62-17.2], area under the receiver operating characteristic curve = 0.541). The specificity of this symptom in predicting Alzheimer's dementia was 97.8, and the sensitivity was 10.4. CONCLUSIONS: Of 9 symptoms of depression, only loss of interest was associated with the development of Alzheimer's dementia over a period of 5 years in a sample of 75-year-old not-demented, never-depressed subjects, suggesting that depressive symptoms in the elderly are mostly symptoms of genuine depression.

Effect of six months of treatment with V0191 in patients with suspected prodromal Alzheimer's disease.

New criteria related to prodromal Alzheimer's disease (AD) have been proposed to overcome the issue of heterogeneity of patients with mild cognitive impairment (MCI) and to better define patients in early stage AD. Only few therapeutic trials, if any, have been reported using this newly defined population. The objective of this study was to assess the clinical efficacy and safety of a novel pro-cholinergic drug (V0191) in patients with prodromal AD. Two hundred forty two (242) patients with a diagnosis of prodromal AD were randomized in an approximately 1 : 1 ratio to receive either 1500 mg V0191 or matching placebo once daily for 24 weeks. Changes in global cognitive functioning were assessed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog; responder rate as primary efficacy measure). Standardized measures of memory, executive function, attention, functional capacity, and apathy were also obtained. Despite some interesting trends at week 12 and conversion rates favoring V0191, no statistically significant differences in cognitive function between V0191 and placebo were noted. In addition to the absence of drug efficacy on this population, several design features may have hindered this study, including insufficient powering to assess changes in cognition over time, a relatively short duration of treatment, and the lack of validated clinical trial measures designed to assess the prodromal AD population. Lessons learned in AD study design optimization, including those presented in this paper, could be valuable for further investigation with pro-cholinergic drugs such as V0191.

Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzyme gene.

BACKGROUND: Insulin-degrading enzyme (IDE) is the ubiquitously expressed enzyme responsible for insulin and amyloid beta (Aß) degradation. IDE gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with Type 2 diabetes mellitus (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for Alzheimer's disease (AD), however with controversial results. METHODS: We examined associations of three IDE polymorphisms (IDE2, rs4646953; IDE7, rs2251101 and IDE9, rs1887922) with AD, Aß42 plasma level and T2DM risk in the longitudinal Vienna Transdanube Aging (VITA) study cohort. RESULTS: The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Aß42 plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9. CONCLUSIONS: Based on our SNP and haplotype results, we delineate the model that IDE promoter and 3' untranslated region/downstream variation may have different effects on IDE expression, presumably a relevant endophenotype with disorder-specific effects on AD and T2DM susceptibility.

Memantine in moderate to severe Alzheimer's disease: an observational post-marketing study.

Memantine is an N-methyl-D: -aspartate (NMDA) receptor antagonist, approved for the treatment of moderate to severe Alzheimer's disease (AD). We conducted a 4-month observational, post-marketing, Austrian study of memantine in 377 outpatients with moderate to severe AD. In this 'real-life' setting, memantine was well-tolerated, and produced benefits in cognition (Mini-Mental State Examination), activities of daily living (Activities of Daily Living score), and global function (Clinical Global Impression scale). Treatment effects were apparent in both pre-treated and treatment-naïve patient subgroups.

[Memory clinics in Austria - characteristics and patterns of practice]. / Gedächtnisambulanzen in Österreich - Charakteristika und diagnostisch-therapeutische Praxis.

OBJECTIVE: To compile a cross-sectional overview of Austria's Memory Clinics, their staffing, diagnostic and therapeutic programs, and their acceptance and use. METHODS: In April and May 2009 27 out of the 29 Austrian Memory Clinics participated in a telephone survey based on a standardized questionnaire. RESULTS AND CONCLUSIONS: The number of Austrian Memory Clinics has risen in an essentially linear fashion between 1987 and 2009. A large majority (85%) had public sponsors. The fact that 57% of all patients seen at these institutions had been referred by their physician (while 25% were self-referrals) illustrates that Memory Clinics enjoy considerable acceptance and reputation among physicians, patients and caregivers. The psychometric tools that are employed conform to the state of the art in depression and cognitive screening in this type of population. In the large majority of Memory Clinics blood chemistry, cell counts, and medical imaging is mandatory, and frequently includes cerebral SPECT or PET radioimaging. Psychosocial counseling was the single most frequent therapeutic program feature (44%), followed by cognition training (15%) and caregiver counseling groups with or without explicit training (6% and 23%, resp.). Interest in a potential cross-border collaboration of Memory Clinics in German-speaking countries is almost universal.

Genetic variation in the choline O-acetyltransferase gene in depression and Alzheimer's disease: the VITA and Milano studies.

Linkage studies point to the long arm of chromosome 10 being a susceptibility region for Alzheimer's disease (AD). Additionally, the gene choline O-acetyltransferase (CHAT) located on chromosome 10 was discussed for conveying risk towards AD, but the results are ambiguous. We examined a possible association of nineteen single-nucleotide polymorphisms (SNPs) in the CHAT gene in a longitudinal cohort study, the Vienna Tansdanube Aging (VITA)-study, in which all subjects were 75 years old at baseline. For replication, we used a more heterogeneous case-control sample from Milano with early and late AD. Nominal allelic and genotypic associations with AD risk in the cross-sectional VITA sample were found for rs3810950 (p = 0.038 for genotype, OR = 1.66 95% CI 1.03-2.68, p = 0.052 allele-wise). When combining both VITA- and Milano study rs3810950 was significantly associated with AD (p(combined) = 0.01634; power = 82%). This association was highly significant for APOEε4 carriers (p = 0.009 for genotype, OR = 3.21 95% CI 1.43-7.19 p = 0.007 allele-wise). Furthermore, an association of rs1880676 with AD was specific to carriers of the APOEε4 risk allele (p = 0.008, genotype; OR = 3.47 95% CI 1.50-8.01 p = 0.005 allele-wise). For depressive symptoms, we found a nominally significant association of rs3810950 with minor and major depression (p = 0.023, genotype; p = 0.008, allele). Applying Benjamini and Hochberg correction these associations could not be confirmed and also not be replicated in the more heterogeneous Milano sample. While our data therefore do not seem to support a major role for CHAT genetic variation in geriatric depression and AD, there might be a minor contribution in geriatric patients with depression and late onset AD, in particular those carrying the APOEε4 genotype.

Sustained effects of once-daily memantine treatment on cognition and functional communication skills in patients with moderate to severe Alzheimer's disease: results of a 16-week open-label trial.

The present study evaluated the effects of once-daily memantine (20 mg) treatment on cognition and communication in patients with moderate to severe Alzheimer's disease (AD). In a multicenter, single-arm open-label study, outpatients diagnosed with AD (MMSE < 20; n = 97) were titrated from 5 mg to 20 mg once-daily memantine over 4 weeks. Once-daily memantine treatment (20 mg) was then continued for 8 weeks, followed by a 4-week wash-out period. The primary efficacy endpoint was the change from baseline in the Consortium to Establish a Registry for Alzheimer's Disease -Neuropsychological Battery (CERAD-NP) total score. Secondary efficacy endpoints included change from baseline in Functional Communication Language Inventory (FLCI) and ADCS-ADL19 total score, and the response from baseline in Clinical Global Impression of Change (CGI-C). The CERAD-NP total score improved significantly after 12 weeks of once-daily memantine treatment compared with baseline (5.9 ± 8.8; p < 0.0001). The FLCI total score improved significantly after 12 weeks compared with baseline (4.4 ± 6.8; p < 0.0001). These significant improvements were already observed after 4 and 8 weeks of once-daily memantine treatment and persisted after a 4-week wash-out period. ADCS-ADL19 total scores showed only slight increases from baseline, and CGI-C indicated that the majority of patients experienced an improvement or stabilization of the disease after 12 weeks. At least one Treatment-Emergent Adverse Event was reported by 38 (39.2%) patients. In patients with moderate to severe AD, once-daily memantine (20 mg) treatment significantly improved cognition and functional communication and was found to have a favorable safety and tolerability profile.

Association of a functional NOS1 promoter repeat with Alzheimer's disease in the VITA cohort.

NO synthase, type I (NOS-I) has been suggested to play a role in the etiology of Alzheimer's disease (AD). The gene encoding NOS-I harbors at least nine alternative first exons; in the promoter region of exon 1f, a polymorphic repeat (NOS1 ex1f-VNTR) has been described which influences gene expression and neuronal transcriptome. We have shown that short alleles of this repeat are associated with AD. Here, we sought to further explore this finding by investigating a longitudinal cohort sample from the Vienna-Transdanube-Aging (VITA) study consisting of 606 subjects enrolled at the age of 75 (of these, genotypes were available for 574 subjects) and followed up for 60 months. The ex1f-VNTR risk genotype was associated with AD in the total sample and at the second follow-up. Thus, either long alleles of NOS1 ex1f-VNTR are protective against disease or conversely, short alleles predispose to earlier onset of disease. As demonstrated, ex1f-VNTR interacted with the apolipoprotein E ε4 risk allele (OR in the presence of both risk alleles 3.63; 95% CI: 1.45-9.12). These findings provide further evidence for an association of NOS1 with AD.

[Memantine for treatment of behavioural disturbances and psychotic symptoms in moderate to moderately severe Alzheimer dementia: a naturalistic study in outpatient services in Austria]. / Memantin in der Behandlung von Verhaltensauffälligkeiten und psychotischen Symptomen bei moderater bis mittelschwerer Alzheimer-Demenz: Eine naturalistische Studie im ambulanten Bereich in Osterreich.

We conducted an open, 16-week study on the efficacy of memantine on behavioral disturbances and psychotic symptoms in moderate to moderately severe Alzheimer s disease in daily routine. Fifty-three patients of 20 outpatient centers in Austria were recruited. The Neuropsychiatric Inventory (NPI) was defined as main outcome measure. After 16 weeks the total NPI score improved by 4,6 points (p<0.01). The caregiver distress score was also significantly reduced. The most pronounced improvements were seen in the NPI components depression (-24,6%), aberrant motor behavior (-16,9%), agitation/agression, fear, apathy, disinhibition and disturbances in appetite and eating behavior (-11,3%, each). Our naturalistic study is in line with the results of controlled trials in moderate and severe Alzheimer dementia stages. Controlled clinical trials which have behavioral disturbances and psychotic symptoms as primary endpoint are needed to define the true potential of memantine in mild dementia stages.

Late-onset depression in elderly subjects from the Vienna Transdanube Aging (VITA) study.

OBJECTIVES: To assess whether prevalence of depression increases with age. To determine possible risk factors of late-onset depression. METHOD: The Vienna Transdanube Aging (VITA) study is a community-based cohort study investigating every inhabitant of the area on the left shore of the river Danube, in Vienna, Austria, born between May 1925 and June 1926. It includes a thorough neurologic, psychiatric, and neuropsychological battery. Occurrence of a current depressive episode was diagnosed according to a DSM-IV-based questionnaire, the Hamilton Rating Scale for Depression, and the Short Geriatric Depression Scale. A gerontopsychiatric life events scale was used for the assessment of life events. 1505 subjects were contacted and 606 participated. At baseline, 406 nondemented and never-depressed individuals were included in the study. Follow-up after 30 months was possible in 331 of the 406 participants. Baseline data were collected from May 2000 to December 2002, and 30-month follow-up data were collected from November 2002 to September 2005. RESULTS: Of the 331 participants who were not depressed at baseline, 31.4% had developed a subsyndromal, minor, or major depressive episode at the 30-month follow-up; 14.2% were diagnosed with mild cognitive impairment at follow-up, 42.5% of whom were also diagnosed with new-onset depression. In the multiple analyses, "troubles with relatives" was a significant variable (p = .018, OR = 0.5, 95% CI = 0.28 to 0.89, R(2) = 0.16). Summative scores on the Fuld Object Memory Evaluation showed a significant influence (p = .048, OR = 0.9, 95% CI = 0.88 to 0.99, R(2) = 0.01) on the occurrence of newly onset depression. None of the other investigated possible risk factors had a significant influence on the new occurrence of depression. CONCLUSION: Prevalence of late-onset depression increases with age. Having severe troubles with relatives and pre-existing cognitive impairments may enhance the probability of developing a late-onset depression.

[The pupillary response test as a method to differentiate various types of dementia]. / Der Rezeptortest bei der Pupillometrie als Methode zur Differenzierung des dementiellen Syndroms.

AIM: Pupillometry is a non-invasive measurement technique based on the pupillary response to specific sensoric, mental and emotional variables. After topical application of a cholinergic antagonist (tropicamide) an increased pupillary dilatation response in Alzheimers s disease patients was described ("receptor test"). The aim of the present study was to evaluate the usefulness of the 0.01% tropicamide receptor test in differentiating types of dementia. METHOD: 425 patients (159 men, 266 women, mean age 75 years) of the Memory Clinic of the SMZ Ost Vienna, Austria were included in the study. 195 patients suffered from a dementia in Alzheimer's disease with late onset (ICD-10: F00.1), 42 from dementia in Alzheimer's disease with early onset (F00.0), 71 from vascular dementia (F01), 34 from Lewy-Body dementia (F03) and 83 from mixed dementia (F00.2). All patients were investigated by means of a computer-assisted pupillometer. The pupillary diameter of the left eye was measured 4 times (baseline=0 minutes, after 20, 40 and 60 minutes). 4 minutes after baseline one drop of 0.01% tropicamide solution was installed onto the left eye of the patients. RESULTS: At baseline the pupillary diameter was largest in Lewy-Body dementia, smallest in vascular dementia. Significant differences were observed between vascular dementia and early-onset dementia in Alzheimer's disease as well as between Lewy-Body dementia and all other dementia syndromes (except dementia in Alzheimer's disease with early onset). The 0.01% tropicamide receptor test made it possible to differentiate early-onset dementia in Alzheimer's disease from vascular and mixed dementia. CONCLUSION: Utilizing pupillometry in combination with the 0.01% tropicamide receptor test allows to discriminate between different dementia types of, as demonstrated in our study.