Association of Plasma Aß40 Peptides, But Not Aß42, with Coronary Artery Disease and Diabetes Mellitus.

BACKGROUND/OBJECTIVE: Plasma levels of amyloid-beta (Aß) 1-40 peptide have been proposed to be associated with cardiovascular mortality in patients with coronary artery disease (CAD). Therefore, we aimed to investigate the association of plasma Aß levels with CAD, cardiovascular risk factors (CVRF), and APOE genotype in non-demented elderly individuals. METHODS: Plasma Aß1 - 40 and Aß1 - 42 levels of 526 individuals (mean age of 63.0±7.3 years) were quantified with the INNO-BIA plasma Aß forms assay based on multiplextrademark technique. APOE genotype was determined with an established protocol. Presence of CAD and CVRFs were ascertained using a questionnaire and/or medical records. RESULTS: Plasma Aß1 - 40 levels were significantly higher in individuals with CAD (p = 0.043) and, independently, in individuals with diabetes mellitus (DM) type 2 (p = 0.001) while accounting for age- and gender-effects. Plasma Aß1 - 42 levels were higher in APOEɛ4 carriers (p = 0.004), but were neither relevantly associated with CAD nor with any CVRF. Plasma Aß1 - 40 showed no association with APOE genotype. DISCUSSION: Our findings argue for an association of circulating plasma Aß1 - 40 peptides with incident CAD and DM. Further investigations are needed to entangle the role of Aß1 - 40 role in the pathophysiology of cardiovascular disease independent of its known role in Alzheimer's disease.

Clinical characteristics related to worsening of motor function assessed by the Unified Parkinson's Disease Rating Scale in the elderly population.

There is evidence that nigrostriatal pathology may at least partly underlie mild Parkinsonian signs. We evaluated whether an increase in the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) could be predicted by the presence of risk and prodromal markers for neurodegenerative diseases in elderly individuals without those diseases. Therefore, we analyzed the UPDRS-III score and various risk and prodromal markers known to antecede neurodegenerative diseases in a population-based cohort comprising 807 individuals free of neurodegenerative diseases at baseline. After 5 years, eight persons (1.0 %) were diagnosed with Parkinson's Disease (PD). Of those, seven (87.5 %) had motor worsening ≥3 points on the UPDRS-III from baseline to follow-up, one had two points increase. Of the 788 people without PD, 568 (72.1 %) showed no increase in the UPDRS-III scale, 220 (27.9 %) had ≥1 point increase and out of these 104 (13.2 %) had an increase of ≥3 points in the UPDRS-III score after 5 years. We identified an age >60 years (relative risk, RR = 1.7; confidence interval, CI 1.3-2.1) and the occurrence of ≥2 risk factors (RR = 1.5; CI 1.2-1.9) as possible predictors of motor progression. After 5 years, individuals with an increase in the UPDRS-III score had more often a one-sided reduced arm swing (p < 0.001) and identified less odors in the Sniffin' sticks test (p < 0.041) than persons with stable motor performance. Our data support the assumption that progression of Parkinsonian signs assessed by the UPDRS-III parallels the development of prodromal markers for neurodegenerative diseases in the elderly population.

Reasons for mild parkinsonian signs - which constellation may indicate neurodegeneration?

INTRODUCTION: Mild parkinsonian signs (MPS) are common in the elderly population. Several factors including physical decline and comorbidities in addition to neurodegeneration may be possible sources for MPS. The objective was to examine whether MPS are associated with a history of orthopedic disturbances, vascular diseases or prodromal markers for neurodegeneration. METHODS: The TREND study is a prospective longitudinal cohort study in individuals >50 years with biennial assessments designed to identify prodromal markers for neurodegeneration. In this substudy, 1091 elderly individuals were evaluated for a possible association of MPS with prodromal markers for neurodegeneration, orthopedic disturbances, vascular diseases, as well as cerebral abnormalities. These factors were assessed by self-administered questionnaires, with a structured health interview, a neurological examination and by transcranial sonography. RESULTS: 82 participants showed MPS. They were found to have more often hyposmia and RBD, had a higher autonomic dysfunction score and they more frequently showed hyperechogenicity of the substantia nigra compared to controls. Neither orthopedic disturbances nor vascular diseases were significantly associated with the prevalence of MPS. CONCLUSION: MPS might be a sign of early neurodegeneration rather than caused by other motor influencing diseases.

Mild parkinsonian signs in the elderly--is there an association with PD? Crossectional findings in 992 individuals.

BACKGROUND: Mild parkinsonian signs (MPS) are common in the elderly population, and have been associated with vascular diseases, mild cognitive impairment and dementia; however their relation to Parkinson's disease (PD) is unclear. Hypothesizing that individuals with MPS may reflect a pre-stage of PD, i.e. a stage in which the nigrostriatal system is already affected although to a milder degree than at the time of PD diagnosis, aim of this study was to evaluate the similarities between MPS and PD. METHODS: The TREND study is a prospective cross-sectional cohort study in individuals >50 years with biennial assessments designed to identify markers for an earlier diagnosis of Parkinson's and Alzheimer's disease. For this substudy 992 individuals were included for analyses (892 controls, 73 MPS individuals, 27 PD patients). Parameters defining risk of PD (sex, age, positive family history), prodromal markers (hyposmia, REM sleep behavior disorder, depression and autonomic failure) as well as quantitative fine motor, axial motor and cognitive parameters were compared between the three cohorts. RESULTS: As expected, PD patients differed from controls with regard to 12 of 15 of the assessed parameters. MPS individuals differed significantly from controls in 12 of the PD-associated parameters, but differed from PD only in 5 parameters. CONCLUSION: This study shows that individuals with MPS share many prodromal and clinical markers of PD with PD patients, implying that either a common dynamic process or similar constitutional factors occur in MPS individuals and PD patients.

Risk factors and prodromal markers and the development of Parkinson's disease.

Identification of risk factors and prodromal markers for Parkinson's disease (PD) and the understanding of the point in time of first occurrence is essential for the early detection of incident PD. In this three-center longitudinal, observational study, we evaluated the specific risk for PD associated with single or combinations of risk factors and prodromal markers. In addition, we evaluated which risk factors and prodromal markers emerge at which time before the diagnosis of PD. Of the 1,847 at-baseline PD-free individuals ≥ 50 years, 1,260 underwent the 5-year follow-up assessment. There were 21 cases of incident PD during the study period. Enlarged hyperechogenic substantia nigra was the most frequent baseline sign in individuals developing PD after 3 years (80.0 %) and 5 years (85.7 %) compared to healthy controls (17.5 %) followed by the occurrence of mild parkinsonian signs and hyposmia. Evaluation of the signs at the first follow-up assessment showed that individuals developing PD after two additional years showed the same pattern of signs as individuals who developed PD 3 years after baseline assessment.

Enlarged hyperechogenic substantia nigra as a risk marker for Parkinson's disease.

BACKGROUND: SN hyperechogenicity (SN+), determined by transcranial sonography, has been proposed as a risk factor for Parkinson's disease (PD). Recently, we reported a 17.4-fold increased risk for PD in individuals with SN+ older than 50 years within 3 years. METHODS: This is the second follow-up of a prospective, longitudinal, three-center observational study after 5 years. Of the initial 1,847 at baseline PD-free participants 50 years or older, 1,271 underwent the 5-year reassessment. RESULTS: Within 5 years, 21 individuals developed incident PD. Participants with SN+ at baseline had a more than 20.6 times increased risk to develop PD in this time span than those without this echo feature. CONCLUSION: We thus confirm our finding of the 3-year follow-up examination in a longer observation time and higher number of individuals with incident PD and suggest SN+ as an important risk marker for PD.

Cognitive profiles in Parkinson's disease and their relation to dementia: a data-driven approach.

Parkinson's disease is characterized by a substantial cognitive heterogeneity, which is apparent in different profiles and levels of severity. To date, a distinct clinical profile for patients with a potential risk of developing dementia still has to be identified. We introduce a data-driven approach to detect different cognitive profiles and stages. Comprehensive neuropsychological data sets from a cohort of 121 Parkinson's disease patients with and without dementia were explored by a factor analysis to characterize different cognitive domains. Based on the factor scores that represent individual performance in each domain, hierarchical cluster analyses determined whether subgroups of Parkinson's disease patients show varying cognitive profiles. A six-factor solution accounting for 65.2% of total variance fitted best to our data and revealed high internal consistencies (Cronbach's alpha coefficients >0.6). The cluster analyses suggested two independent patient clusters with different cognitive profiles. They differed only in severity of cognitive impairment and self-reported limitation of activities of daily living function but not in motor performance, disease duration, or dopaminergic medication. Based on a data-driven approach, divers cognitive profiles were identified, which separated early and more advanced stages of cognitive impairment in Parkinson's disease without dementia. Importantly, these profiles were independent of motor progression.

Lowered serum amyloid-ß1-42 autoantibodies in individuals with lifetime depression.

Reduced levels of naturally occurring autoantibodies against amyloid-ß (Aß) have been described in Alzheimer's disease (AD). Lifetime depression doubles the risk of AD, thus these autoantibodies may also be reduced in this group. We measured serum IgG autoantibody titers against Aß1-42, S100b and α-synuclein in 214 individuals with depression and 419 controls. Titers against Aß1-42 were lower in individuals with lifetime depression (5544.6 ± 389.3) compared to controls (7208.7 ± 482.4; p = 0.048). Titers against S100b and α-synuclein were comparable between the cohorts. These data suggest an AD-like impairment of the humoral immune response in a relevant proportion of individuals with depression.

Poor trail making test performance is directly associated with altered dual task prioritization in the elderly--baseline results from the TREND study.

BACKGROUND: Deterioration of executive functions in the elderly has been associated with impairments in walking performance. This may be caused by limited cognitive flexibility and working memory, but could also be caused by altered prioritization of simultaneously performed tasks. To disentangle these options we investigated the associations between Trail Making Test performance--which specifically measures cognitive flexibility and working memory--and dual task costs, a measure of prioritization. METHODOLOGY AND PRINCIPAL FINDINGS: Out of the TREND study (Tuebinger evaluation of Risk factors for Early detection of Neurodegenerative Disorders), 686 neurodegeneratively healthy, non-demented elderly aged 50 to 80 years were classified according to their Trail Making Test performance (delta TMT; TMT-B minus TMT-A). The subjects performed 20 m walks with habitual and maximum speed. Dual tasking performance was tested with walking at maximum speed, in combination with checking boxes on a clipboard, and subtracting serial 7 s at maximum speeds. As expected, the poor TMT group performed worse when subtracting serial 7 s under single and dual task conditions, and they walked more slowly when simultaneously subtracting serial 7 s, compared to the good TMT performers. In the walking when subtracting serial 7 s condition but not in the other 3 conditions, dual task costs were higher in the poor TMT performers (median 20%; range -6 to 58%) compared to the good performers (17%; -16 to 43%; p<0.001). To the contrary, the proportion of the poor TMT performance group that made calculation errors under the dual tasking situation was lower than under the single task situation, but higher in the good TMT performance group (poor performers, -1.6%; good performers, +3%; p = 0.035). CONCLUSION: Under most challenging conditions, the elderly with poor TMT performance prioritize the cognitive task at the expense of walking velocity. This indicates that poor cognitive flexibility and working memory are directly associated with altered prioritization.

Enlarged substantia nigra hyperechogenicity and risk for Parkinson disease: a 37-month 3-center study of 1847 older persons.

OBJECTIVE: To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population. DESIGN: Longitudinal 3-center observational study with 37 months of prospective follow-up. SETTING: Individuals 50 years or older without evidence of PD or any other neurodegenerative disease. PARTICIPANTS: Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment. MAIN OUTCOME MEASURE: Incidence of new-onset PD in relation to baseline transcranial sonography status. RESULTS: There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants. CONCLUSIONS: In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.

Influence of different cut-off values on the diagnosis of mild cognitive impairment in Parkinson's disease.

Comparable to Alzheimer's disease, mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with an increased risk for dementia. However different definitions of PD-MCI may have varying predictive accuracy for dementia. In a cohort of 101 nondemented Parkinson patients who underwent neuropsychological testing, the frequency of PD-MCI subjects and PD-MCI subtypes (i.e., amnestic/nonamnestic) was determined by use of varying healthy population-based cut-off values. We also investigated the association between defined PD-MCI groups and ADL scales. Varying cut-off values for the definition of PD-MCI were found to affect frequency of PD-MCI subjects (9.9%-92.1%) and, maybe more important, lead to a "shift" of proportion of detected PD-MCI subtypes especially within the amnestic single-domain subtype. Models using a strict cut-off value were significantly associated with lower ADL scores. Thus, the use of defined cut-off values for the definition of PD-MCI is highly relevant for comparison purposes. Strict cut-off values may have a higher predictive value for dementia.

The patients' perception of prodromal symptoms before the initial diagnosis of Parkinson's disease.

BACKGROUND: Before the occurrence of motor symptoms permits the clinical diagnosis of Parkinson's disease (PD), about or even more than 50% of the dopaminergic neurons of the substantia nigra have degenerated. This time be called the prodromal phase of PD. OBJECTIVE: To evaluate the time span from onset of first prodromal symptoms to the initial diagnosis of PD as well as the order of symptom occurrence. METHODS: Retrospective study of 93 consecutively interviewed PD patients without dementia and 93 sex and age matched controls free of neurodegenerative disorders. A standardized in-house telephone worksheet assessing 19 nonmotor and six early motor signs was used. RESULTS: A total of 98.8% of all patients interviewed reported to have experienced prodromal symptoms prior to receiving the initial diagnosis of PD. Patients noticed an average of 7.6 different symptoms during this time interval. The mean time span between the recalled onset of any one symptom and PD diagnosis was 10.2 years. In both groups, the course of prodromal sign onset was associated with early neuropathological disease stages proposed by Braak. OUTLOOK: These retrospectively gathered data confirm the existence of a long prodromal phase for PD that is consistent with neuropathological staging. A standardized questionnaire assessing such early symptoms may be helpful in identifying subjects at high risk for PD while they are still in the prodromal phase of the disorder.

Reduced but not oxidized cerebrospinal fluid glutathione levels are lowered in Lewy body diseases.

Reduced (GSH(R)) but not oxidized glutathione (GSSG) has been shown to be dramatically altered in the substantia nigra (SN) of Lewy body disease (LBD) patients post mortem; but up to now, there is no convincing evidence that these changes can be monitored in vivo. We investigated GSH(R) and GSSG in rapidly processed cerebrospinal fluid (CSF) and plasma samples of 80 LBD and 35 control subjects and detected reduced CSF GSH(R) levels in LBD subjects. The reduction was negatively associated with age but not with disease-associated parameters. Plasma GSH(R), CSF GSSG, and plasma GSSG levels did not significantly differ between the groups. Our findings confirm the results from neuropathologic studies, which demonstrated an alteration of the glutathione system in LBD. We hypothesize that alterations of the glutathione system occur in a very early stage of the disease or may even represent a risk marker for LBD.

Pre-motor signs of PD are related to SN hyperechogenicity assessed by TCS in an elderly population.

Much effort has been put in the identification of risk factors and pre-motor markers for Parkinson's disease (PD). In contrast to many of the pre-motor markers, SN hyperechogenicity (SN+) assessed by transcranial sonography (TCS) has been found to be conclusive for vulnerability for PD. In two centers in Germany 1204 individuals ≥50 years without the diagnosis of PD were recruited and the prevalence and relation of SN+ to a range of pre-motor markers was evaluated. SN+ was detected in 193 (16.0%) of 1204 subjects. Hyposmia (25.4%) was the most frequent sign in the cohort, followed by the occurrence of slight motor deficits. Male gender, positive family history of PD as possible risk factors and the pre-motor markers slight parkinsonian signs, one-sided reduced arm swing, and hyposmia were found to be significantly associated with SN+. The number of subjects who had more than one marker was significantly larger in the SN+ subgroup than in the non-hyperechogenic group (9.2% vs. 2.1%). Most of the discussed markers for PD seem to be unspecific with older age, but related to SN+. Co-occurrence of these markers is more probable in SN+ subjects. These findings may have implications for the design of high-risk cohorts for PD.

Early diagnosis of Parkinson's disease.

The accuracy of the clinical diagnosis of Parkinson's disease (PD) is still limited. Especially in the early stages, when cardinal symptoms are not conclusive, diagnosis can be delayed as structural neuroimaging methods such as CCT or MRI do not provide characteristic features that allow the diagnosis of this chronic neurodegenerative disorder. Functional neuroimaging using PET and SPECT techniques is helpful in patients with first signs of parkinsonism, but expensive and not broadly available. In this scenario, transcranial sonography (TCS) has proven to be helpful. Up to 90% of PD patients show hyperechogenicity of the substantia nigra (SN) on TCS. Already in the early stages of PD this echofeature is visible, allowing the differentiation of very mildly affected patients with idiopathic PD from healthy persons and from patients with atypical parkinsonism with high sensitivity and specificity. Additionally, specific ultrasound features for some forms of secondary parkinsonism can be detected by TCS, helping in the early identification, for example, of patients with Wilson's disease. Therefore, especially in the early diagnosis, TCS can be recommended as a supplementary tool to facilitate the diagnostic classification of patients with first signs of parkinsonism.

Transcranial sonography in dystonia.

The cause of idiopathic dystonia is not entirely elucidated. In the pathophysiological model of dystonia, the basal ganglia play a major role, mainly putamen, globus pallidus internus, thalamus, and cortex. However, using conventional structural neuroimaging methods, no specific alterations could be detected in this area. Using transcranial sonography (TCS) as a noninvasive, easy to perform, and side-effect-free method, it could be shown that in up to 75% of patients with cervical dystonia (CD), in a high percentage of other focal dystonias, but seldom in facial and genetically determined dystonia, hyperechogenicity of the medial part of the lentiform nuclei (LN) can be visualized in the third ventricular scanning plane. Based on these TCS findings an increased copper content of the LN could be verified in dystonia, opening new perspectives on possible pathophysiological aspects and future research. In clinical routine, this method may be used for early and differential diagnosis of primary dystonia.

Enlarged hyperechogenic substantia nigra is related to motor performance and olfaction in the elderly.

Enlarged substantia nigra hyperechogenicity (SN+) assessed by transcranial sonography (TCS) may be associated with Parkinson's disease (PD) risk markers such as impaired motor performance and hyposmia. The aim of this multicenter cross-sectional study was to define the association between SN+ and these risk markers in a large population older than 50 years without the diagnosis of PD. In three centers (Tuebingen, Homburg, and Innsbruck), 1,839 individuals were examined. The echostatus of the SN was assessed by TCS, motor performance by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, and olfactory function with Sniffin' Sticks. From the 1,603 subjects included in the analysis, 16.2% were SN+, 23.0% scored above zero in the UPDRS motor section, and 28.0% were hyposmic as defined by less than 75% correctly classified Sniffin' Sticks. SN+ was associated with a UPDRS motor score above zero (OR 1.45, 95% CI 1.08-1.96) and with a lower odor identification capability (OR 1.48, 95% CI 1.12-1.96). The combination of these two features (OR 1.98, 95% CI 1.25-3.15) and UPDRS motor scores >or=3 lead to higher OR. It is concluded that SN+, impaired motor performance, and hyposmia are frequently observed in the elderly and in isolation are unspecific and of limited use to predict a subject's risk for PD. Whether the association of SN+ with both impaired motor performance and hyposmia as seen in this study predicts an increased risk for the development of PD needs to be evaluated in the follow-up investigations.

Place value of transcranial sonography in early diagnosis of Parkinson's disease.

Transcranial B-mode sonography (TCS) is a relatively new method which has been proven to be helpful in the diagnosis of Parkinson's disease (PD). Due to the underlying physical principles, supplementary information to other neuroimaging methods can be derived. Substantia nigra (SN) hyperechogenicity is the characteristic feature of idiopathic PD, which can help in the differentiation of atypical parkinsonian syndromes like multiple system atrophy or progressive supranuclear palsy. Besides, the quick 'look into the brain' can easily visualize an enlargement of the ventricular system, alterations of the basal ganglia like increased contents of calcium or trace metals, or a missing brain stem raphe, typically seen in depressive disorders, and can therefore give further diagnostic hints for symptomatic parkinsonian syndromes. Many studies indicate that SN hyperechogenicity constitutes a stable marker, irrespective of the disease stage. In a prospective study of patients with very first signs of yet unclear parkinsonism, a high predictive value of TCS for the diagnosis of PD could be proven. Moreover, there is accumulating evidence that SN hyperechogenicity could play a role in the premotor diagnosis of PD. In this review, the additional diagnostic value of TCS in the early diagnosis of PD as well as limitations of the method are being discussed.

Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: Clinical observations as a basis for power calculations and safety analysis.

Cognitive decline and dementia are present in about 50% of patients with progressive supranuclear palsy (PSP). Based on the known involvement of the cholinergic system in PSP patients, and because rivastigmine, in contrast to other cholinesterase inhibitors, inhibits both acetylcholinesterase and butyrylcholinesterase, we discuss clinical observations of five patients suffering from PSP and dementia who were all treated with rivastigmine over a period of 3 to 6 months. We found a slight improvement in specific cognitive function that may justify further controlled studies. A calculation of sample size revealed that a study on the effect of rivastigmine in PSP should include about 31 patients to detect a significant effect. In subtests, meaningful results can be obtained with even lower numbers (five patients for a verbal fluency test, and 14 patients for a logical memory task).

Cortical hypometabolism assessed by a metabolic ratio in Parkinson's disease primarily reflects cognitive deterioration-[18F]FDG-PET.

In Parkinson's disease patients with cognitive deterioration, regional cortical hypometabolism has been observed with [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET). Our aim was to develop a robust method to subsume the overall degree of metabolic deterioration in Parkinson's disease by means of a single index and to investigate which of the clinical features correlates best with hypometabolism. Twenty-two Parkinson's patients (10 demented) and seven controls underwent FDG-PET. A metabolic index (mean relative uptake in typically affected regions) was calculated for each patient and compared with scores for cognition [Minimental State Examination (MMSE)], motor performance [Unified Parkinson's Disease Rating Scale (UPDRS III)" and behavior (Neuropsychiatric Inventory). In stepwise linear regression analysis, MMSE (P < 0.001) score showed the only significant effect. Estimated sensitivity and specificity for DSM-IV diagnosis of dementia were high for the metabolic index (MI), with 91 and 100%. Taken together, the presented data indicate that cerebral hypometabolism in Parkinson's disease is primarily associated with cognitive impairment.