Orthostatic hypotension as a risk factor for longitudinal deterioration of cognitive function in the elderly.

BACKGROUND AND PURPOSE: Orthostatic hypotension is frequent with aging with a prevalence of 20%-30% in people aged 65 or older and is considered to increase the risk for coronary events, strokes and dementia. Our objective was to characterize the association of orthostatic hypotension and cognitive function longitudinally over 6 years in a large cohort of the elderly aged over 50 years. METHODS: In all, 495 participants were assessed longitudinally with the Schellong test and comprehensive cognitive testing using the extended CERAD neuropsychological test battery at baseline and after 6 years. In a subgroup of 92 participants, cerebral magnetic resonance imaging was evaluated for white matter changes using a modified version of the Fazekas score. RESULTS: The prevalence of orthostatic hypotension increases with aging reaching up to 30% in participants aged >70 years. Participants with orthostatic hypotension presented with a higher vascular burden index (1.03 vs. 0.69, P ≤ 0.001), tended to have a higher prevalence of cerebral white matter hyperintensities (91.7% vs. 68.8%, P = 0.091) and showed a faster deterioration in executive and memory function (Trail Making Test B 95 vs. 87 s, P ≤ 0.001; word list learning sum -0.53 vs. 0.38, P = 0.002) compared to participants without orthostatic hypotension. CONCLUSION: Orthostatic hypotension seems to be associated with cognitive decline longitudinally.

Progression of prodromal motor and non-motor symptoms in the premotor phase study - 2-year follow-up data.

BACKGROUND AND PURPOSE: The neuropathological process starts years before the diagnosis of Parkinson's disease (PD). Assessment of prodromal features in healthy individuals may help to define those with high risk for future PD. Our aim was to evaluate the presence and progression of prodromal markers in individuals with low risk [healthy controls (HC), n = 14] and high risk for PD (HR-PD, n = 34) and early PD (n = 14) patients. METHODS: Several risk or prodromal markers were combined to define HR-PD. Other prodromal markers were followed in 6-month intervals for 2 years. As recommended by the Movement Disorder Society Task Force, likelihood ratios (LRs) of markers, motor scores and PD probability scores were calculated and compared. RESULTS: The baseline LR for non-motor prodromal markers was significantly higher in PD and HR-PD compared to HC. Within 2 years, changes in these LRs did not significantly differ between the groups. Motor worsening was significant only in the PD group (50% of the patients) against HR-PD (15%) and HC (7%). Change in the non-motor prodromal LR did not significantly correlate with motor worsening, but higher baseline non-motor LRs were associated with Unified Parkinson's Disease Rating Scale III values at 2 years of follow-up. CONCLUSIONS: Our study shows that the frequency of non-motor prodromal markers is higher in the HR-PD group but does not increase within 2 years. The progression of motor and non-motor markers seems to be independent, but higher baseline non-motor burden is associated with the motor status after 2 years. Moreover, our data argue for a high impact of motor markers in the risk estimation for future PD.

Inflammatory profile discriminates clinical subtypes in LRRK2-associated Parkinson's disease.

BACKGROUND AND PURPOSE: The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2 ) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes. METHODS: An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor. RESULTS: Patients classified as diffuse/malignant presented with the highest levels of the pro-inflammatory proteins interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 1-ß (MIP-1-ß) paralleled by high levels of the neurotrophic protein brain-derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis. CONCLUSIONS: Inflammation seems to be associated with the presence of a specific clinical subtype in PDLRRK2 that is characterized by a broad and more severely affected spectrum of motor and non-motor symptoms. The pro-inflammatory metabolites IL-8, MCP-1 and MIP-1-ß as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PDLRRK2 and predict progression.

[Diagnostics of clinical and prodromal idiopathic Parkinson's disease : New criteria]. / Diagnostik des klinischen und prodromalen idiopathischen Parkinson-Syndroms : Neue Kriterien.

BACKGROUND: Recently, the Movement Disorder Society (MDS) published an adaptation of the previous United Kingdom Brain Bank Society (UKBBS) criteria for the diagnosis of idiopathic Parkinson's disease (iPD). OBJECTIVES: This article presents the changes in the current clinical diagnostic criteria for IPD. Furthermore, the new MDS criteria for prodromal iPD are discussed. RESULTS: The recently introduced MDS criteria for the clinical diagnosis of iPD include useful novel features (e.g. postural instability is no longer listed as a cardinal symptom, familiar history of iPD and intake of neuroleptics at the first visit no longer lead to exclusion of the diagnosis) and red flags do not lead to exclusion of the diagnosis; however, they must be counterbalanced by the presence of supportive criteria for iPD. The criteria for identification of persons in the prodromal stage are currently established only for scientific investigations. CONCLUSION: The new MDS criteria for the diagnostics of iPD should help to improve the sensitivity and specificity.

[Helpful instrumental examinations in idiopathic Parkinson's disease]. / Hilfreiche Zusatzuntersuchungen beim idiopathischen Parkinson-Syndrom.

BACKGROUND: The clinical diagnosis of idiopathic Parkinson's disease (iPD) can be challenging. In these cases, additional diagnostic methods are available that can help to improve diagnostic accuracy. OBJECTIVES, MATERIAL AND METHODS: This article provides an overview of currently available and promising novel ancillary methods for the early and differential diagnosis of iPD. RESULTS: Imaging tools, such as 1.5 Tesla magnetic resonance imaging (MRI) and computed tomography (CT) are mainly used for the differentiation between iPD and symptomatic parkinsonian syndromes (PS). High-resolution diffusion tensor imaging and iron and neuromelanin-sensitive high-field MRI sequences can become important in the future, particularly for earlier diagnosis. Transcranial B­mode sonography of the substantia nigra and basal ganglia is established for early and differential diagnostics, especially in the combination of diagnostic markers but necessitates an adequately trained investigator and the use of validated digital image analysis instruments. DATScan can discriminate iPD from essential tremor, medication-induced parkinsonism and psychogenic movement disorder but not iPD from atypical PS. For the latter differential diagnosis, fluorodeoxyglucose positron emission tomography and myocardial metaiodobenzylguanidine scintigraphy can be helpful. Olfactory testing should preferably be used in combination with other diagnostic tests. Genetic, biochemical and histopathological tests are currently not recommended for routine use. Novel sensor-based techniques have a high potential to support clinical diagnosis of iPD but have not yet reached a developmental stage that is sufficient for clinical use. Novel sensor-based techniques have high potential to support clinical diagnosis of iPD, but have not yet reached a development stage that is sufficient for clinical use. CONCLUSION: Ancillary diagnostic methods can support the early and differential diagnosis of iPD.

GBA-associated parkinsonism and dementia: beyond α-synucleinopathies?

BACKGROUND AND PURPOSE: To date the role of GBA mutations beyond α-synucleinopathies in the parkinsonism-dementia spectrum is still unclear. The aim of the study was to screen for GBA mutations in progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), primary progressive aphasia (PPA) and the behavioural variant of frontotemporal dementia (bvFTD). METHODS: In all, 303 patients with a clinical diagnosis of PSP (n = 157), CBS (n = 39), PPA (n = 35) and bvFTD (n = 72) and 587 neurologically healthy controls were screened for the most common GBA mutations. RESULTS: GBA mutations were detected in one healthy control and four patients with a clinical diagnosis of PSP (n = 1), probable CBS (n = 2) and PPA (n = 1, with concomitant C9orf72 expansion). Overall the prevalence of GBA mutations was low in non-α-synucleinopathies but significantly higher in the CBS subgroup compared to controls. CONCLUSION: Although numbers are small, our findings indicate that the clinical phenotype of GBA-associated neurodegenerative disease is more heterogeneous than previously assumed, including phenotypes not usually associated with underlying α-synucleinopathies. This may be of relevance, once causal therapeutic strategies for GBA-associated neurodegenerative disease are developed.

Substantia nigra hyperechogenicity is related to decline in verbal memory in healthy elderly adults.

BACKGROUND AND PURPOSE: Deficits in cognition have been reported in Parkinson's disease (PD) already in the early and even in the pre-motor stages. Whilst substantia nigra hyperechogenicity measured by transcranial B-mode sonography (TCS) represents a strong PD marker and is associated with an increased risk for PD in still healthy individuals, its association with cognitive performance in prodromal PD stages is not well established. METHODS: Two different cohorts of healthy elderly individuals were assessed by TCS and two different neuropsychological test batteries covering executive functions, verbal memory, language, visuo-constructional function and attention. Cognitive performance was compared between individuals with hyperechogenicity (SN+) and without hyperechogenicity (SN-). RESULTS: In both cohorts, SN+ individuals performed significantly worse than the SN- group in tests assessing verbal memory (word list delayed recall P = 0.05, logical memory II P < 0.017). Significant differences in Mini-Mental State Examination score (cohort 1, P = 0.02) and executive function tests (cohort 2, Stroop Color-Word Reading, P = 0.004) could only be shown in one of the two cohorts. No between-group effects were found in other cognitive tests and domains. CONCLUSIONS: These results indicate that individuals with the PD risk marker SN+ perform worse in verbal memory compared to SN- independent of the assessment battery. Memory performance should be assessed in detail in individuals at risk for PD.

[Wearable Technique for the Assessment of Parkinson Symptoms: What's the Future?]. / Tragbare und aktiv vom Parkinson-Patienten genutzte Technologie im häuslichen Umfeld: Was bringt die Zukunft?

Parkinson's disease (PD) is a multisystem disorder with a plethora of symptoms affecting the quality of life of patients in the home environment. Due to the rapid development of wearable technique in the health and fitness sector, an increasing number of such wearable devices are available to complement diagnostic strategies of PD symptoms not only in the clinical but also in the home environment. This development has clear advantages over clinical evaluation, as the latter is relatively subjective, time-consuming and costly, and provides only a snapshot of the condition. First results about the use of such technology for the assessment of PD symptoms (including bradykinesia, dyskinesia, tremor, daily activity and sleep behavior) in the home environment are promising. They suggest that these techniques can provide complementary information about the symptoms of PD patients, and have the potential to be included in future diagnostic workup concepts of routine care in PD. The use of such technique provides also the opportunity to more actively include patients into medical decision-making processes.

[Successful aging: what can neurology and geriatrics contribute?]. / Gelingendes Altern: Was können Neurologie und Geriatrie beitragen?

The relative proportion of elderly persons in Western societies is rapidly growing, leading to an increasing frequency of age-related neurological diseases (e.g. dementia) and functional impairments (e.g. immobility). This article argues that this development should prompt a new focus in medical care. The key questions should not only be how can we improve treatment of age-related disorders but also how can we prevent age-related disorders in the first place or at least substantially delay their onset? These questions touch on an even more profound question: how can successful aging be accomplished? That is, which factors and processes characterize successful aging both on a system and on a molecular level? Thus, the crucial societal, scientific and medical challenges for Western societies are to develop and implement measures of primary prevention of dysfunctional aging. The disease-centered framework which currently determines most clinical thinking, scientific research and third party funding has to be supplemented by a novel framework of successful aging. This article defines dysfunctional aging as a convergent downstream result of multiple interacting system processes. Each of these detrimental system processes must be targeted by specific measures of geriatric primary prevention. This, in turn, implies that geriatrics does not start in the elderly or with the onset of particular geriatric disorders. Instead, it starts in the daily practice of neurology and other medical disciplines taking care of persons aged 20-40 years who are largely healthy and in the middle of their professional and personal career. Or, in a nutshell, geriatrics starts right in the middle of medical care.

[Sarcopenia and frailty in neurology]. / Sarkopenie und Frailty in der Neurologie.

Sarcopenia and frailty are common geriatric syndromes and are associated with adverse health outcome and impaired health-related quality of life. Co-occurrences of these two syndromes with age-related neurological diseases are potentially high but not well investigated. Moreover, it is not well understood how these syndromes interact with neurological diseases, such as Parkinson's disease, Alzheimer's disease and stroke. This article introduces the currently most accepted concepts of sarcopenia and frailty, discusses the potential relevance of the syndromes for geriatric patients and presents examples of studies that investigated potential interactions between these geriatric and neurological syndromes and conditions. First results indicate that (i) the co-occurrence of these geriatric syndromes and age-related neurological diseases is high, (ii) sarcopenia and frailty can influence the clinical state of neurological diseases to a relevant extent and (iii) at least some common causes and pathophysiological processes confer the geriatric and neurological conditions. In conclusion, profound knowledge about the interaction of sarcopenia, frailty and age-associated neurological conditions is currently not available. Such knowledge would have an enormous potential for improved therapy of these neurological conditions.

Prodromal features for Parkinson's disease--baseline data from the TREND study.

BACKGROUND AND PURPOSE: A number of non-motor features are known to precede motor manifestations of Parkinson's disease (PD). They are supposed to already represent the prodromal neurodegenerative state in those who later develop PD and are thus called prodromal markers. In this study, three prodromal markers, depression, rapid eye movement behaviour disorder (RBD) and hyposmia, were selected and were related to other prodromal features in elderly individuals without PD. METHODS: From the Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration (TREND) study, 698 healthy individuals aged 50-80 years reporting one or more of the selected prodromal markers (SPMs), but without neurodegenerative disorders, were evaluated and classified according to the status of prodromal markers. Other prodromal PD-related features were assessed with a 23-item questionnaire and compared between participants with and without the three SPMs. RESULTS: Individuals with the SPMs for PD endorsed more of the additional possible prodromal features of PD than those without; of 23 possible prodromal features, the median number identified amongst participants with no SPMs was two, compared with four with one marker, five with two and seven with three (P < 0.001). Regarding individual SPMs, participants with depression and RBD endorsed five of 23 markers, compared with three for those with hyposmia (P = 0.001). There was no significant increase in the number of prodromal features amongst those with two SPMs compared with those with only one marker. CONCLUSIONS: Individuals with the SPMs for PD report a higher prevalence of other prodromal PD symptoms. This may indicate that these markers can identify individuals at risk for PD.

Technical and clinical view on ambulatory assessment in Parkinson's disease.

With the progress of technologies of recent years, methods have become available that use wearable sensors and ambulatory systems to measure aspects of--particular axial--motor function. As Parkinson's disease (PD) can be considered a model disorder for motor impairment, a significant number of studies have already been performed with these patients using such techniques. In general, motion sensors such as accelerometers and gyroscopes are used, in combination with lightweight electronics that do not interfere with normal human motion. A fundamental advantage in comparison with usual clinical assessment is that these sensors allow a more quantitative, objective, and reliable evaluation of symptoms; they have also significant advantages compared to in-lab technologies (e.g., optoelectronic motion capture) as they allow long-term monitoring under real-life conditions. In addition, based on recent findings particularly from studies using functional imaging, we learned that non-motor symptoms, specifically cognitive aspects, may be at least indirectly assessable. It is hypothesized that ambulatory quantitative assessment strategies will allow users, clinicians, and scientists in the future to gain more quantitative, unobtrusive, and everyday relevant data out of their clinical evaluation and can also be designed as pervasive (everywhere) and intensive (anytime) tools for ambulatory assessment and even rehabilitation of motor and (partly) non-motor symptoms in PD.

The PRIPS study: screening battery for subjects at risk for Parkinson's disease.

BACKGROUND AND PURPOSE: Screening batteries to narrow down a target-at-risk population are essential for trials testing neuroprotective compounds aiming to delay or prevent onset of Parkinson's disease (PD). METHODS: The PRIPS study focuses on early detection of incident PD in 1847 at baseline PD-free subjects, and assessed age, male gender, positive family history, hyposmia, subtle motor impairment and enlarged substantia nigra hyperechogenicity (SN+). RESULTS: After 3 years follow-up 11 subjects had developed PD. In this analysis of the secondary outcome parameters, sensitivity and specificity of baseline markers for incident PD were calculated in 1352 subjects with complete datasets (10 PD patients). The best approach for prediction of incident PD comprised three steps: (i) prescreening for age, (ii) primary screening for positive family history and/or hyposmia, and (iii) secondary screening for SN+. CONCLUSION: With this approach, one out of 16 positively screened participants developed PD compared to one out of 135 in the original cohort. This corresponds to a sensitivity of 80.0%, a specificity of 90.6% and a positive predictive value of 6.1%. These values are higher than for any single screening instrument but still too low for a feasible and cost-effective screening strategy which might require longer follow-up intervals and application of additional instruments.

Differentiation of progressive supranuclear palsy: clinical, imaging and laboratory tools.

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian syndrome comprising two main clinical subtypes: Richardson's syndrome (RS), characterized by prominent postural instability, supranuclear vertical gaze palsy and frontal dysfunction; and PSP-parkinsonism (PSP-P) which is characterized by an asymmetric onset, tremor and moderate initial therapeutic response to levodopa. The early clinical features of PSP-P are often difficult to discern from idiopathic Parkinson's disease (PD), and other atypical parkinsonian disorders, including multiple system atrophy (MSA) and corticobasal syndrome (CBS). In addition, rare PSP subtypes may be overlooked or misdiagnosed if there are atypical features present. The differentiation between atypical parkinsonian disorders and PD is important because the prognoses are different, and there are different responses to therapy. Structural and functional imaging, although currently of limited diagnostic value for individual use in early disease, may contribute valuable information in the differential diagnosis of PSP. A growing body of evidence shows the importance of CSF biomarkers in distinguishing between atypical parkinsonian disorders particularly early in their course when disease-modifying therapies are becoming available. However, specific diagnostic CSF biomarkers have yet to be identified. In the absence of reliable disease-specific markers, we provide an update of the recent literature on the assessment of clinical symptoms, pathology, neuroimaging and biofluid markers that might help to distinguish between these overlapping conditions early in the course of the disease.

Co-occurrence of parkinsonism and dementia in clinical practice: relevant differential diagnoses.

Co-occurrence of parkinsonism and dementia is commonly observed in the aging population. This narrative review gives an overview of disorders regularly presenting with these symptoms, e.g., idiopathic Parkinson disease with dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration syndrome, vascular cognitive impairment, drug-induced parkinsonism, and normal-pressure hydrocephalus. Both a thoroughly performed medical history and a comprehensive clinical examination can narrow down relevant differential diagnoses. Characteristic clinical and neuropsychological features are highlighted, including cognitive screening strategies. Neurophysiological and neuropathological aspects of the disorders are briefly discussed to give a better understanding of treatment options.

[Gait changes as an early indicator of dementia]. / Gangveränderungen als Frühindikator einer Demenz.

Gait disorders are more common in dementia than in the context of the physiological aging process. Prevalence of dementia-associated gait disturbances depends on the type of dementia and the severity of cognitive impairment. While in vascular dementia gait abnormalities are often clinically apparent at early disease stages, Alzheimer's disease patients usually have stable gait until late disease stages. With up-to-date ''brain-imaging" methods, it has been demonstrated that people suffering from dementia are more dependent on cortical activity in order to maintain gait stability in complex situations. When dysfunction of the frontal or temporal lobes occurs, allocation of these resources may no longer be sufficient. Dual-task paradigms are useful to test such resources. It has been shown in early Alzheimer's disease patients that, if the demand of attention exceeds available capacities, quantitative gait changes occur. Relevant parameters seem to be, e.g., walking speed and stride-time variability. Quantitative assessment of gait dysfunction in dementia may, thus, have the potential to serve as a trait marker.

Improvement of balance after audio-biofeedback. A 6-week intervention study in patients with progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease with no sufficient treatment options to date. The most devastating symptom is the loss of balance with consecutive falls. Based on the observation that postural control improved in patients with vestibular dysfunction after audio-biofeedback training, we tested the effects of this training in PSP patients. Eight PSP patients were included into an uncontrolled 6-week intervention trial. The focus of the training was the improvement of posture and dynamic balance by using audio-biofeedback. The device was well accepted. No adverse events occurred. A significant improvement in the Berg Balance Scale was observed (T2 vs. T1, p=0.016), which remained significant at the 4-week follow-up (T3 vs. T1, p=0.008). Significant improvement of the Parkinson's disease questionnaire was demonstrated. No significant changes were found in the Timed Up-and-Go Test, the Five Chair Rise Test, and in specific clinical scales. To our knowledge, the present study is the first to demonstrate that audio-biofeedback training with PSP patients is associated with improvements of balance and psychosocial aspects.

Microcalcification after excitotoxicity is enhanced in transgenic mice expressing parvalbumin in all neurones, may commence in neuronal mitochondria and undergoes structural modifications over time.

AIMS: Parenchymal microcalcification in the brain coincides with neurodegenerative diseases, but is also frequently found in neurologically normal individuals. The origin and role of this process are still under debate. Parvalbumin (PV) is a protein acting as a Ca(2+) buffer and Ca(2+) shuttle towards intracellular Ca(2+) sinks, like mitochondria and the endoplasmic reticulum. Constitutively, it is present in a subset of inhibitory neurones. In transgenic mice expressing pan-neuronal PV, the mitochondrial volume is reduced. We tested whether elevated levels of intraneuronal [Ca(2+)] and reduced mitochondrial volume in the neurone interfere with the generation of parenchymal microcalcification. METHODS: The striatum of wild type and transgenic mice was injected with the glutamate receptor agonist ibotenic acid (IBO), which is known to induce not only excitotoxic neurodegeneration, but also parenchymal calcification. Sections were studied by light and electron microscopy at various time points after IBO application. RESULTS: Morphometric analysis 2, 4 and 20 weeks after IBO application revealed microcalcification in transgenic and wild type mice; the calcification process, however, was enhanced and accelerated in the transgenic animals. Ultrastructural analyses suggest neuronal mitochondria as the nucleators of the deposits which consist of hydroxyapatite. The time-dependent changes in size and surface structure of the deposits indicate the presence of biological mechanisms in the brain promoting regression of bioapatites. CONCLUSIONS: The overload of intraneuronal [Ca(2+)] in combination with impaired mitochondrial function activates neuronal microcalcification. It is hypothesized that this process is an alternative/adaptive mechanism of the neurone to reduce further brain damage.