Lowered Levels of Carbonyl Proteins after Vitamin B Supplementation in Patients with Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: The critical role of neuro-inflammation and oxidative stress in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) has become evident. OBJECTIVE: The aim of this study is to assess the influence of vitamin supplementation on parameters of oxidative stress, inflammation as well as on cognition in patients with AD and mild cognitive impairment. METHODS: In our study, patients with cognitive impairment and healthy controls were enrolled. All patients were intended to receive vitamin supplementation (vitamin B1, B6, B12 and folic acid) for 3 months. Mini Mental State Examination (MMSE) and laboratory markers [carbonyl proteins (CPs), malondialdehyde, tryptophan (Trp), kynurenine (Kyn), neopterin, folic acid, vitamin B12 level] were assessed for patients and controls at baseline and after 3 months. After half of the patients had been treated for 3 months, analyses were performed resulting in 3 subgroups: healthy controls without supplementation (15 subjects, 11 females), patients with vitamin supplementation (17 subjects, 10 females) and patients without vitamin supplementation (16 subjects, 9 females; baseline values prior to supplementation). RESULTS: Age was significantly higher for the supplemented group (76.4 ± 6.7 years) compared to vitamin-naïve patients (63.3 ± 13.7 years; p < 0.01). The MMSE score was higher in the supplemented group (23.1 ± 4.8 vs. 20.3 ± 9.5) but did not reach significance. Levels of CPs were significantly higher in the vitamin-naïve patients (p < 0.05). Levels of Kyn and the Kyn/Trp ratio were significantly lower in vitamin-naïve patients compared to the supplemented group (p < 0.05). No significant difference was seen for the other markers. CONCLUSION: Vitamin supplementation leads to reduced levels of CPs in patients. Pearson's correlation coefficient shows a negative relation (r = -0.69) between CPs and MMSE. Future trials should assess whether CPs might be suitable markers for monitoring of demented patients.

Elevated fecal calprotectin in patients with Alzheimer's dementia indicates leaky gut.

Fecal concentrations of calprotectin were examined in 22 patients with Alzheimer's disease (AD) and compared with serum concentrations of aromatic amino acids. Calprotectin concentrations were mean ± SEM 140 ± 31.9 mg/kg, 16 patients (73%) presented with concentrations outside normal (>50 mg/kg). Concentrations correlated inversely with serum levels of tryptophan, tyrosine and phenylalanine (all p < 0.05). Increased concentrations of fecal calprotectin indicate a disturbed intestinal barrier function in AD patients which could be of relevance for the lowering of essential aromatic amino acids concentrations in the blood.

High frequency repetitive transcranial magnetic stimulation improves cognitive performance parameters in patients with Alzheimer's disease - an exploratory pilot study.

BACKGROUND: Currently available medication for Alzheimer's disease (AD) may slows cognitive decline only transitory, but has failed to bring about long term positive effects. For this slowly progressive neurodegenerative disease so far no disease modifying therapy exists. OBJECTIVE: To find out if non-pharmacologic non-ivasive neuromodulatory repetitive transcranial magnetic stimulation (rTMS) may offer a new alternative or an add on therapeutic strategy against loss of cognitive functions. METHODS: In this exploratory intervention study safety and symptom development before and after frontopolar cortex stimulation (FPC) using intermittent theta burst stimulation (iTBS) at 10 subsequent working days was monitored as add-on treatment in 28 consecutive patients with AD. Out of these, 10 randomly selected patients received sham stimulation as a control. In addition, ​serum concentrations of neurotransmitter precursor amino acids, of immune activation and inflammation markers, of brain derived neurotrophic factor (BDNF) as well as of nitrite were measured. RESULTS: Treatment was well tolerated, no serious adverse effects were observed. Improvement of cognition was detected by an increase of Mini Mental State Examination score (MMSE; p<0.01, paired rank test) and also by an increase in a modified repeat address phrase test, part of the 6-item cognitive ​impairment test (p < 0.01). A trend to an increase in the clock drawing test (CDT; p = 0.08) was also found in the verum treated group. Furtheron, in 10 of the AD patients with additional symptoms of depression treated with iTBS, a significant decrease in the HAMD-7 scale (p <0.01) and a trend to lower serum phenylalanine concentrations (p = 0.08) was seen. No changes of the parameters tested were found in the sham treated patients. CONCLUSION: Our preliminary results may indicate that iTBS is effective in the treatment of AD. Also a slight influence of iTBS on the metabolism of phenylalanine was found after 10 iTBS sessions. An impact of iTBS to influence the enzyme phenylalanine hydroxylase (PAH), as found in previous series of treatment resistant depression, could not be seen in this our first observational trial in 10 AD patients with comorbidity of depression. Longer treatment periods for several weeks in a higher number of AD patients with depression could cause more intense and disease modifying effects visible in different neurotransmitter concentrations important in the pathogenesis of AD.

Polyneuropathy and dementia in old age: common inflammatory and vascular parameters.

Thirty-three inpatients (22 females, 11 males, aged 79.4 ± 9.5 years) were investigated in this prospective cohort study to study the prevalence of polyneuropathy (PNP) and dementia in geriatric inpatients. Clinical and electrodiagnostic investigations, routine laboratory, including thyroid parameters, folic acid, vitamin B(12), homocysteine, neopterin, fibrinogen and glycosylated hemoglobin were measured in serum, the mini-mental state examination and computed tomographic scanning were performed in each patient. PNP was found clinically and electrodiagnostically in 96% of patients. Age was the most precipitating factor for PNP, and was significantly correlated to electrodiagnostic changes in the nerves investigated in both, upper and lower extremities, while clinical symptoms were confined only to the feet. Correlation was seen between homocysteine and the amplitude of the sural nerve (surAmpl) (rs = -0.406, p = 0.029) as well as the sural nerve conduction velocity (surNCV) (rs = -0.389, p = 0.037), and between neopterin and the grade of denervation (rs = 0.445, p = 0.014) in our patients. Neopterin and fibrinogen did not correlate significantly, but there was a trend to higher fibrinogen concentrations in patients with higher neopterin levels (rs = 0.344, p = 0.062). A trend of a correlation was seen between higher homocysteine concentrations and the number of changes in electrodiagnostic measurements (rs = 0.354, p = 0.055). Twenty-one of the 33 patients (64%) were demented, 9 (27%) presented clinically as mild cognitive impairment, 3 (9%) were not demented. Vascular risk factors were found in 83%: hypertension in 58%, hypercholesterinemia in 39%, cardiac disease in 36%, diabetes mellitus (DM) in 21%, peripheral arterial disease (PAD) in 9%. A significant correlation was found between homocysteine and folic acid concentrations (rs = -0.401, p = 0.028). Falls were reported in 48% of cases, indicating PNP as a risk factor in this group of patients. In conclusion, PNP was found very common with a high coincidence with dementia and a female preponderance, suggesting an influence on daily life (falls) in our subjects studied. PNP correlated significantly with markers for vascular disease as well as immune activation (homocysteine and neopterin) similar to earlier findings in patients with neurodegenerative disorders, suggesting common therapeutic options in patients with PNP and dementia.

The Immunopathogenesis of Alzheimer's Disease Is Related to the Composition of Gut Microbiota.

The microbiota-gut-brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and immune system function by the production of lipopolysaccharides and amyloid. Dysbiosis of the intestinal microbiome induces local and consecutively systemic immune-mediated inflammation. Proinflammatory cytokines then trigger neuroinflammation and finally neurodegeneration. Immune-mediated oxidative stress can lead to a deficiency of vitamins and essential micronutrients. Furthermore, the wrong composition of gut microbiota might impair the intake and metabolization of nutrients. In patients with Alzheimer's disease (AD) significant alterations of the gut microbiota have been demonstrated. Standard Western diet, infections, decreased physical activity and chronic stress impact the composition and diversity of gut microbiota. A higher abundancy of "pro-inflammatory" gut microbiota goes along with enhanced systemic inflammation and neuroinflammatory processes. Thus, AD beginning in the gut is closely related to the imbalance of gut microbiota. Modulation of gut microbiota by Mediterranean diet, probiotics and curcumin can slow down cognitive decline and alter the gut microbiome significantly. A multi-domain intervention approach addressing underlying causes of AD (inflammation, infections, metabolic alterations like insulin resistance and nutrient deficiency, stress) appears very promising to reduce or even reverse cognitive decline by exerting positive effects on the gut microbiota.

Carbonyl proteins as a clinical marker in Alzheimer's disease and its relation to tryptophan degradation and immune activation.

BACKGROUND: The question arises whether oxidative stress is connected with systemic immune activation in Alzheimer's disease (AD) and mild cognitive impairment (MCI). During immune response interferon-gamma stimulates the kynurenine (Kyn) pathway, a major route of L-tryptophan (Trp) degradation. METHODS: Plasma Kyn, Trp and the Kyn to Trp ratio (Kyn/Trp), carbonyl proteins (CP) as oxidative stress parameter and homocysteine, neopterin, folate and vitamin B12 were measured from patients with AD and MCI (n = 16: 6 females and 4 males with AD, 3 females and 3 males with MCI; 63.3 +/- 13.7 years), and an age matched healthy control group (n = 15: 11 females and 4 males; 62.8 +/- 3.6 years). We correlated the oxidative stress parameter CP with the degradation of Trp creating a new quotient CP/Trp and calculated the sensitivity, specificity, and cut-off values for CP, Trp, CP/Trp, and Kyn/Trp using discriminate analysis. RESULTS: CP was significantly higher in AD/MCI (930 +/- 265 pmol/mg; p < 0.001) compared to controls (300 +/- 120 pmol/mg), Trp was significantly lower in AD/MCI (48.9 +/- 9.0 micromol/L; p < 0.001) than controls (65.2 +/- 10.7 micromol/L). While Kyn showed no significant difference between AD/MCI (1.72 +/- 0.56 micromol/L) and controls (1.53 +/- 0.29 micromol/L), Kyn/Trp was significantly higher in AD/MCI (35.2 +/- 8.8 micromol/mmol; p < 0.001) than in controls (23.7 +/- 4.2 micromol/mmol). CP/Trp ratio was more than 4 fold higher in the AD/MCI group (19.8 +/- 7.76 [(pmol/mg)/(micromol/L)]; p < 0.001) compared to controls (4.79 +/- 2.26 [(pmol/mg)/(micromol/L)]). Homocysteine, folate, vitamin B12, and neopterin showed no significant difference. Discriminant analysis provided CP alone as the best clinical marker with highest sensitivity and highest specificity for AD/MCI followed by the ratio of CP/Trp. ROC curve analysis provided the best result for CP/Trp. CONCLUSIONS: These preliminary results support the hypothesis that oxidative damage to proteins is directly connected with Trp degradation and Kyn pathway in the systemic immune activation.

On the Possible Relevance of Bottom-up Pathways in the Pathogenesis of Alzheimer's Disease.

Dementia is an increasing health problem in older aged populations worldwide. Age-related changes in the brain can be observed decades before the first symptoms of cognitive decline appear. Cognitive impairment has chronic inflammatory components, which can be enhanced by systemic immune activation. There exist mutual interferences between inflammation and cognitive deficits. Signs of an activated immune system i.e. increases in the serum concentrations of soluble biomarkers such as neopterin or accelerated tryptophan breakdown along the kynurenine axis develop in a significant proportion of patients with dementia and correlate with the course of the disease, and they also have a predictive value. Changes in biomarker concentrations are reported to be associated with systemic infections by pathogens such as cytomegalovirus (CMV) and bacterial content in saliva. More recently, the possible influence of microbiome composition on Alzheimer's disease (AD) pathogenesis has been observed. These observations suggest that brain pathology is not the sole factor determining the pathogenesis of AD. Interestingly, patients with AD display drastic changes in markers of immune activation in the circulation and in the cerebrospinal fluid. Other data have suggested the involvement of factors extrinsic to the brain in the pathogenesis of AD. However, currently, neither the roles of these factors nor their importance has been clearly defined.

Correction to: Knock-on effect of periodontitis to the pathogenesis of Alzheimer's disease?

The original version of this article unfortunately contained a mistake. There was an error in Fig. 2. The original article has been corrected. We apologize for the mistake.The correct Fig. 2 is given ….

Knock-on effect of periodontitis to the pathogenesis of Alzheimer's disease?

BACKGROUND: Alzheimer's disease has chronic inflammatory components, which can be enhanced by systemic immune activation resulting in inflammation or vice versa. There is growing evidence that chronic periodontitis drives systemic inflammation and finally Alzheimer's disease. Thus, a link might exist between oral pathogens and Alzheimer's disease. This may be of special significance as there is an age-related incidence of chronic periodontitis. METHODS: In this study, 20 consecutive patients with probable Alzheimer's disease were investigated. Diagnosis was established by cognitive tests, routine laboratory tests and cerebral magnetic resonance tomography. In 35% of these patients with cognitive impairment pathogenic periodontal bacteria were found. RESULTS: The presence of Porphyromonas gingivalis, the key pathogen and one of the species involved in chronic periodontitis, was found to be associated with lower mini mental state examination scores (p < 0.05) and with a tendency to lower scores in the clock drawing test (p = 0.056). Furthermore, association between lower serum concentrations of the immune biomarker neopterin and the presence of Treponema denticola (p < 0.01) as well as of kynurenine were found in Alzheimer patients positive vs. negative for Tannerella forsytia (p < 0.05). CONCLUSIONS: Data indicate a possible association of specific periodontal pathogens with cognitive impairment, Treponema denticola and Tannerella forsytia may alter the host immune response in Alzheimer's disease. Albeit still preliminary, findings of the study may point to a possible role of an altered salivary microbiome as a causal link between chronic periodontitis and cognitive impairment in Alzheimer's disease.

Value of cerebral blood flow quantification in the diagnosis of dementia.

BACKGROUND: Quantifying hemispheric cerebral blood flow (CBF) may improve diagnostic accuracy when combined with perfusion SPECT. AIM: To explore the impact of measuring mean CBF on the differential diagnosis of dementia under clinical conditions. METHODS: CBF was calculated from anterior planar dynamic images acquired over 100 s after i.v. bolus injection of 550 MBq of (99m)Tc-HMPAO using Patlak linearization of normalized time-activity curves derived from right and left hemispheric, and aortic ROIs. Regional perfusion was evaluated from SPECT imaging carried out 20 min later. ANCOVA was applied to compare age-dependent differences of CBF; model differences at P<0.05 were considered significant. Study populations consisted of controls, 34 patients with no focal or vascular abnormality or mood disorder and with normal MR or CT brain images (F:M, 16:18; age+/-SD; 54.3+/-20.2 years); and patients with probable dementia comprised two subgroups. The first consisted of 33 patients with primary degenerative aetiology (PDD) (DAT or mixed-type microvascular and DAT, Lewy body and fronto-temporal atrophy), F/M; 17:16, age+/-SD; 68.4+/-8.8 years. The second subgroup consisted of 13 patients with dementia related to subcortical microvascular leuco-encephalopathy (vLEP), M/F 7:6, age+/-SD; 71.7+/-12.6 years. Classification was mainly based on clinical findings according to DMS-IV criteria, combined with follow-up or functional and anatomical imaging. RESULTS: Computation of CBF on 100 consecutive patients showed excellent inter-user reproducibility in trained hands (variation coefficient <5%). Mean CBF in controls showed an age dependent decrease, the first order linear regression was CBF(left)=58.9-0.2 x age (r=-0.648, P<0.001) and CBF(right)=57.9-0.02 x age (r=-0.645). In comparison to controls, a slightly more pronounced but statistically insignificant age-dependent decrease in mCBF was found in the vLEP group, CBF(left)=55.5-0.21 x age (r=-0.56) and CBF(right)=64.2-0.32 x age (r=-0.645). In the PDD group CBF, after adjusting for age, was significantly lower than control values (P<0.001); CBF(left)=37-0.025 x age and CBF(right)=39-0.057 x age. More importantly, better discrimination between PDD and controls in patients of younger age (45-65 years) was found. In older patients (65-85 years) overlap slightly increased. ROC analysis of the cohort of dement patients and controls older than 46 years revealed a 93-94% sensitivity and a specificity of 73% and 77% for the left and right hemispheres, respectively, at a CBF cut-off value of 39.5 ml.min(-1).100 g(-1). CONCLUSION: Routine quantification of mean CBF by HMPAO-RNA is a simple and reproducible method which can be easily added to the standard brain perfusion SPECT without additional cost or increasing patient's radiation burden. Combined with regional perfusion it provides an additional tool for the aetiological classification of dementia.

Probiotic Supplementation in Patients with Alzheimer's Dementia - An Explorative Intervention Study.

BACKGROUND: Dysbiosis of intestinal microbiota in the elderly can cause a leaky gut, which may result in silent systemic inflammation and promote neuroinflammation - a relevant pathomechanism in the early course of Alzheimer's disease. OBJECTIVE: The rebalancing of the microbiome could benefically impact on gut inflammation and immune activation. METHODS: In this study, routine laboratory tests in twenty outpatients (9 females, 11 males, aged 76.7 ± 9.6 years) with Alzheimer's disease were investigated. The mean Mini Mental State Examination score was 18.5 ± 7.7. Biomarkers of immune activation - serum neopterin and tryptophan breakdown - as well as gut inflammation markers and microbiota composition in fecal specimens were analyzed in 18 patients before and after probiotic supplementation for 4 weeks. RESULTS: After treatment a decline of fecal zonulin concentrations and an increase in Faecalibacterium prausnitzii compared to baseline were observed. At the same time, serum kynurenine concentrations increased (p <0.05). Delta values (before - after) of neopterin and the kynurenine to tryptophan ratios (Kyn/Trp) correlated significantly (p <0.05). CONCLUSION: Results show that the supplementation of Alzheimer's disease patients with a multispecies probiotic influences gut bacteria composition as well as tryptophan metabolism in serum. The correlation between Kyn/Trp and neopterin concentrations points to the activation of macrophages and/or dendritic cells. Further studies are warranted to dissect the potential consequences of Probiotic supplementation in the course of Alzheimer's disease.

Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer's disease.

In the last decade an important role for the progression of neuronal cell death in Alzheimer's disease (AD) has been ascribed to oxidative stress. trans-4-Hydroxy-2-nonenal, a product of lipid peroxidation, forms conjugates with a variety of nucleophilic groups such as thiols or amino moieties. Here we report for the first time the quantitation of glutathione conjugates of trans-4-hydroxy-2-nonenal (HNEGSH) in the human postmortem brain using the specific and very sensitive method of electrospray ionization triple quadrupole mass spectrometry (ESI-MS-MS). Levels of HNEGSH conjugates calculated as the sum of three chromatographically separated diastereomers were determined in hippocampus, entorhinal cortex, substantia innominata, frontal and temporal cortex, as well as cerebellum from patients with AD and controls matched for age, gender, postmortem delay and storage time. Neither age, nor postmortem delay, nor storage time did correlate with levels of HNEGSH conjugates which ranged between 1 and 500 pmol/g fresh weight in the brain areas examined. The brain specimen from patients with clinically and neuropathologically probable AD diagnosed according to criteria of the consortium to establish a registry for AD (CERAD) show increased levels of HNEGSH in the temporal and frontal cortex, as well as in the substantia innominata. Classification of disease severity according to Braak and Braak, which takes into consideration the amount of neurofibrillary tangles and neuritic plaques, revealed highest levels of HNEGSH in the substantia innominata and the hippocampus, two brain regions known to be preferentially affected in AD. These results substantiate the link between conjugates of glutathione with a product of lipid peroxidation and Alzheimer's disease and justify further studies to evaluate the role of HNE metabolites as potential biomarkers for disease progression in AD.

Increasing production of homocysteine and neopterin and degradation of tryptophan with older age.

OBJECTIVES: Aging is associated with an increased frequency of abnormal immune system function, which may cause infections, autoimmune diseases, and cardiovascular or neurodegenerative disorders. Th1-type cytokine interferon-gamma (IFN-gamma) induces neopterin production as well as tryptophan degradation via indoleamine (2,3)-dioxygenase (IDO), and quantification of these biochemical alterations allows one to monitor immune system activation. Homocysteine is known to be elevated in the elderly, which is possibly due to an insufficient availability of folate, B6, and/or B12. DESIGN AND METHODS: Serum concentrations of neopterin, homocysteine, tryptophan and kynurenine, and of vitamins folate and B12 were measured in 43 healthy individuals (21 females, 22 males) aged 34-93 years. The ratio of the concentration of the product of IDO, kynurenine, versus the substrate tryptophan (kyn/trp) was calculated to estimate IDO activity. RESULTS: Comparing three age groups of similar size (34-60, 61-71, and 72-93 years), neopterin and homocysteine concentrations as well as the kyn/trp ratio were found to increase with older age (all P < 0.01). Folate concentrations were lower in the middle-aged group as compared with the other two subgroups of individuals. Vitamin B12 concentrations did not differ between groups. Positive correlations were found between kyn/trp and neopterin and homocysteine concentrations (all P < 0.01). CONCLUSIONS: Increasing neopterin concentrations and kyn/trp with older age are in line with the view that aging in healthy people is associated with immune activation especially of the T-cell/macrophage system.

Activated immune system and inflammation in healthy ageing: relevance for tryptophan and neopterin metabolism.

Immune activation not only accompanies inflammation in various disorders including infections, autoimmune syndromes and cancer, but it also represents a characteristic feature of ageing. Immune deviations which are most widely expressed in the elderly include increased neopterin production and tryptophan breakdown. These biochemical events result from the activation of the immune system and are preferentially triggered by pro-inflammatory stimuli, such as the Th1-type cytokine interferon-γ. They seem to play a role in the development of several age-related disorders and might be involved in the pathogenesis of common symptoms, including neurobehavioral disorders (e.g., cognitive and mood disturbances), anemia, cachexia, weight-loss but also immunodeficiency. Concentrations of the biomarkers neopterin and Kyn/Trp were found to be predictive of overall disease specific mortality in coronary artery disease, infections and various types of cancer. Immune activation and inflammation are also accompanied by high output of reactive oxygen species and thereby may lead to the development of oxidative stress and contribute to the vitamin deficiency which is often observed in the elderly. Accordingly, increases in neopterin were found to correlate with a substantial decline in key vitamins, including folate and vitamin-B6, - B12, -C, -D and -E.

Immune activation in patients with Alzheimer's disease is associated with high serum phenylalanine concentrations.

BACKGROUND: Immune activation and inflammation represent critical factors in the pathogenesis of Alzheimer's disease (AD) and are associated with increased blood concentrations of markers like neopterin and the kynurenine to tryptophan ratio (Kyn/Trp). In chronic inflammatory conditions, also increased serum phenylalanine concentrations and phenylalanine to tyrosine ratios (Phe/Tyr) were reported and could relate to neuropsychiatric symptoms. OBJECTIVE: To examine serum phenylalanine and tyrosine concentrations in patients with AD and to compare results to neopterin and Kyn/Trp levels. MATERIALS AND METHODS: Serum was collected from 43 patients with AD and concentrations of phenylalanine and tyrosine as well as neopterin, tryptophan and kynurenine were measured and Phe/Tyr and Kyn/Trp were calculated. RESULTS: A subgroup of AD patients presented with increased phenylalanine and Phe/Tyr concentrations, phenylalanine levels correlated with neopterin (rs=0.329), kynurenine (rs=0.352) and Kyn/Trp levels (rs=0.288; all p<0.05). There was no significant relationship between phenylalanine metabolism and cognitive ability test scores mini-mental state examination and clock drawing test. CONCLUSIONS: Higher serum phenylalanine concentrations related to immune activation are detectable in a subgroup of AD patients. The impaired conversion of phenylalanine may affect not only the production of tyrosine but also the biosynthesis of the neurotransmitters dopamine, norepinephrine and epinephrine. Further studies are justified in patients with AD to investigate a possible role of phenylalanine biochemistry in the development of neurovegetative and behavioral abnormalities.

Cognition, gender, and functional abilities in Alzheimer's disease: how are they related?

BACKGROUND: Few studies have investigated in detail which factors influence activities of daily (ADL) in Alzheimer's disease (AD). OBJECTIVE: To assess the influence of cognitive, gender, and other factors on ADL in patients with mild to moderate AD. METHODS: This study is part of the Prospective Registry on Dementia in Austria (PRODEM) project, a multicenter dementia research project. A cohort of 221 AD patients (130 females; means: age 76 years, disease duration 34.4 months, MMSE 22.3) was included in a cross-sectional analysis. Everyday abilities were assessed with the Disability Assessment for Dementia scale, and cognitive functions with the CERAD plus neuropsychological test battery. Two models of multiple linear regressions were performed to find factors predicting functional decline, one entering demographical and disease related factors, and a joint model combining demographical and disease variables with neuropsychological scores. RESULTS: Non-cognitive factors explained 18%, whereas the adding of neuropsychological variables explained 39% of variance. Poor figural and verbal memory, constructional abilities, old age, longer disease duration, depression, and male gender were independent risk factors for reduced ADL. Instrumental and basic ADL were predicted by similar factors, except gender (predicting only instrumental ADL) and phonological fluency (predictor of basic ADL). CONCLUSION: In addition to demographical factors, disease duration, and depression, neuropsychological variables are valuable predictors of the functional status in AD in an early disease stage.

Driving cessation and dementia: results of the prospective registry on dementia in Austria (PRODEM).

OBJECTIVE: To assess the influence of cognitive, functional and behavioral factors, co-morbidities as well as caregiver characteristics on driving cessation in dementia patients. METHODS: The study cohort consists of those 240 dementia cases of the ongoing prospective registry on dementia in Austria (PRODEM) who were former or current car-drivers (mean age 74.2 (±8.8) years, 39.6% females, 80.8% Alzheimer's disease). Reasons for driving cessation were assessed with the patients' caregivers. Standardized questionnaires were used to evaluate patient- and caregiver characteristics. Cognitive functioning was determined by Mini-Mental State Examination (MMSE), the CERAD neuropsychological test battery and Clinical Dementia Rating (CDR), activities of daily living (ADL) by the Disability Assessment for Dementia, behavior by the Neuropsychiatric Inventory (NPI) and caregiver burden by the Zarit burden scale. RESULTS: Among subjects who had ceased driving, 136 (93.8%) did so because of "Unacceptable risk" according to caregiver's judgment. Car accidents and revocation of the driving license were responsible in 8 (5.5%) and 1(0.7%) participant, respectively. Female gender (OR 5.057; 95%CI 1.803-14.180; p = 0.002), constructional abilities (OR 0.611; 95%CI 0.445-0.839; p = 0.002) and impairment in Activities of Daily Living (OR 0.941; 95%CI 0.911-0.973; p<0.001) were the only significant and independent associates of driving cessation. In multivariate analysis none of the currently proposed screening tools for assessment of fitness to drive in elderly subjects including the MMSE and CDR were significantly associated with driving cessation. CONCLUSION: The risk-estimate of caregivers, but not car accidents or revocation of the driving license determines if dementia patients cease driving. Female gender and increasing impairment in constructional abilities and ADL raise the probability for driving cessation. If any of these factors also relates to undesired traffic situations needs to be determined before recommendations for their inclusion into practice parameters for the assessment of driving abilities in the elderly can be derived from our data.