Abstract Traditionally, the clinical picture of progressive supranuclear palsy (PSP) was defined by early postural instability with falls, supranuclear vertical gaze palsy, symmetric akinesia and ...rigidity, frontal and subcortical dementia, and pseudobulbar palsy, leading to death after a mean disease duration of approximately six years. A definite diagnosis of PSP depends on neuropathological confirmation. In recent years, clinico-pathological studies have drawn attention to various “atypical” clinical manifestations of PSP. In these, a clinical diagnosis of PSP is delayed or never accomplished. Comprehensive understanding of the natural history of PSP is required to permit an early and accurate diagnosis. Based on current evidence, this review provides an update on the clinical spectrum of PSP.
To date, the diagnoses of Parkinson syndromes are based on clinical examination. Therefore, these specific diagnoses are made, when the neuropathological process is already advanced. However, disease ...modification or neuroprotection, is considered to be most effective before marked neurodegeneration has occurred. In recent years, early clinical or prodromal stages of Parkinson syndromes came into focus. Moreover, subtypes of distinct diseases will allow predictions of the individual course of the diseases more precisely. Thereby, patients will be enrolled into clinical trials with more specific disease entities and endpoints. Furthermore, novel fluid and imaging biomarkers that allow biochemical diagnoses are under development. These will lead to earlier diagnoses and earlier therapy in the future as consequence. Furthermore, therapeutic approaches will take the underlying neuropathological process of neurodegenerative Parkinson syndromes more specific into account. Specifically, future therapies will target the aggregation of aggregation-prone proteins such as alpha-synuclein and tau, the degradation of pathological aggregates, and the spreading of pathological protein aggregates throughout the brain. Many of these approaches are already in (pre)clinical development. In addition, anti-inflammatory approaches are in development. Furthermore, drug-repurposing is a feasible approach to shorten the developmental process of new drugs.
New classification of tauopathies Höglinger, G.U.; Respondek, G.; Kovacs, G.G.
Revue neurologique,
November 2018, 2018-Nov, 2018-11-00, 20181101, Letnik:
174, Številka:
9
Journal Article
Recenzirano
Tauopathies are a group of neurodegenerative diseases characterized by pathological intracellular deposits of the protein tau. Isoform composition, morphology and anatomical distribution of cellular ...tau-immunoreactivities are defining distinct tauopathies as molecular pathological disease entities. The clinical spectrum of tauopathies includes syndromes with primary motor symptoms and with primary cognitive dysfunction. The traditional syndrome-based classification is currently being complemented by a molecular-pathological classification. While the syndrome-based classification is helpful to select symptomatic therapies, and to generate clinical working hypotheses about underlying etiologies, the molecular-pathological classification is most important for the development and application of molecularly tailored disease-modifying therapies.
Highlights • Striatal TH+ neurons correlated positively with AIMs and striatal ΔFosB expression. • Striatal serotonergic innervation was increased in dyskinetic mice. • Striatal TH+ cells and ...serotonergic terminals may cooperatively synthesize dopamine. • The lateral striatum represents a key region of neuronal plasticity in LID. • AIM subtypes correlated with the distribution of TH+ neurons in striatal subregions.
Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the ...brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior.
We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively.
•Adult neurogenesis in hippocampus and olfactory bulb is reduced after 6-OHDA lesion.•l-DOPA and PPX increase adult neurogenesis in the olfactory bulb of all animals.•l-DOPA and PPX normalize adult neurogenesis in the hippocampus after 6-OHDA lesion.•PPX and l-DOPA show a differential effect on depression- and anxiety-like behavior.
To study
gray matter (GM) volumes of the nucleus basalis of Meynert (nbM) in different parkinsonian syndromes and assess their relationship with clinical variables.
T1-weighted magnetic resonance ...images from patients with progressive supranuclear palsy (PSP,
= 43), multiple system atrophy (MSA,
= 23), Parkinson's disease (PD,
= 26), and healthy controls (HC,
= 29) were included. T1-weighted images were analyzed using a voxel-based morphometry approach implemented in the VBM8 toolbox, and nbM volumes were extracted from the spatially normalized GM images using a cyto-architectonically-defined nbM mask in stereotactic standard space. NbM volumes were compared between groups, while controlling for intracranial volume. Further, within each group correlation analyses between nbM volumes and the Mini Mental Status Examination (MMSE), Hoehn and Yahr stage, PSP Rating Scale, Unified Parkinson's Disease Rating Scale part III and Frontal Assessment Battery scores were performed.
Significantly lower nbM volumes in patients with PSP and PD compared to HC or patients with MSA were found. No significant correlations between MMSE and nbM volumes were detected in any of the subgroups. No significant correlations were found between clinical scores and nbM volumes in PSP or other groups.
nbM volumes were reduced both in PD and PSP but not in MSA. The lack of significant correlations between nbM and cognitive measures suggests that other factors, such as frontal atrophy, may play a more important role than subcortical cholinergic atrophy in PSP patients. These results may indicate that other drug-targets are needed to improve cognitive function in PSP patients.
To reduce potentially inappropriate medications, the FORTA (Fit fOR The Aged) concept classifies drugs in terms of their suitability for geriatric patients with different labels, namely A ...(indispensable), B (beneficial), C (questionable), and D (avoid). The aims of our study were to assess the medication appropriateness in PD inpatients applying the FORTA list and drug-drug interaction software, further to assess the adequacy of FORTA list for patients with PD. We retrospectively collected demographic data, comorbidities, laboratory values, and the medication from the discharge letters of 123 geriatric inpatients with PD at the university hospital of Hannover Medical School. Patients suffered on average from 8.2 comorbidities. The majority of the medication was labeled A (60.6% of PD-specific and 40.9% of other medication) or B (22.3% of PD-specific and 26.9% of other medication). Administered drugs labeled with D were amantadine, clozapine, oxazepam, lorazepam, amitriptyline, and clonidine. Overall, 545 interactions were identified, thereof 11.9% severe interactions, and 1.7% contraindicated combinations. 81.3% of patients had at least one moderate or severe interaction. The FORTA list gives rational recommendations for PD-specific and other medication, especially for general practitioners. Considering the demographic characteristics and the common multimorbidity of geriatric PD patients, this study underlines the importance of awareness, education, and preventive interventions to increase drug safety.
Parkinson’s disease (PD) is a chronic progressive movement disorder with severe reduction in patients’ health-related quality of life (HR-QoL). Motor and cognitive symptoms are especially linked with ...decreased PD patients’ HR-QoL. However, the relationship of these symptoms to caregiver burden is relatively unclear. Influence of the Montreal Cognitive Assessment scale (MoCA) as a cognitive screening tool and Movement Disorders Society Unified Parkinson’s disease Rating Scale MDS-UPDRS symptoms in relation to patients’ HR-QoL and caregivers` burden was analyzed. PD patients (n = 124) completed MDS-UPDRS, MoCA, and the PD questionnaire 8 (PDQ-8) as a measure of quality of life. Caregivers (n = 78) were assessed by the PD caregiver burden inventory (PDCB). PDQ-8 and PDCB scores were regressed on MDS-UPDRS subscales and MoCA subscores. PDQ-8 correlated with attention (R2 0.1282; p<0.001) and executive (R2 0.0882; p 0.001) MoCA subscores and all parts of the MDS-UPDRS. PDCB correlated most strongly with MDS-UPDRS part III motor symptoms (R2 0.2070; p<0.001) and the MoCA attention subscore (R2 0.1815; p<0.001). While all facets of PD symptoms assessed by the MDS-UPDRS relate to PD patients’ quality of life, motor symptoms are the most relevant factor for the prediction of caregiver burden. In addition, patients’ attentional symptoms seem to affect not only them, but also their caregivers. These findings show the potential of a detailed analysis of MDS-UPDRS and MoCA performance in PD patients.
Abstract Adult hippocampal cell proliferation (HCP) has been associated with psychopathology, especially depression. However, it is controversial whether a constitutively low rate of HCP is a trait ...predisposing an individual to psychopathology or whether HCP varies with the subject's affective state. We made use of a so far neglected measure of affect, namely ultrasonic vocalizations, to gain new insights into the relationship of HCP and affect. Rats emit distinct types of ultrasonic vocalizations, which serve as situation-dependent affective signals. In appetitive situations, rats produce 50-kHz-calls, whereas 22-kHz-calls occur in aversive situations. We applied a standardized protocol of repeated tickling and assessed tickling-induced ultrasonic vocalizations as an index of the animals affect. Stereological quantifications of 5-bromo-2′-deoxyuridine (BrdU) and proliferating-cells-nuclear-antigen (PCNA) immunolabeled cells were used to estimate the rate of cell proliferation in the subventricular zone and the subgranular zone of the dentate gyrus in the hippocampus. The rate of cell proliferation was compared between the groups of tickled vs. non-tickled rats and between subgroups of tickled rats defined by the effect of tickling on ultrasonic vocalizations. Tickling induced ultrasonic vocalizations in a subject-dependent manner. HCP correlated positively with appetitive 50-kHz-calls, but negatively with aversive 22-kHz-calls in individual animals, while cell proliferation in the subventricular zone was not associated with the emission of ultrasonic vocalizations. Repeated tickling did not change HCP in all rats, but increased HCP in the subgroup of rats, which experienced this procedure as appetitive, i.e. in rats emitting high numbers of 50-kHz-calls or low numbers of 22-kHz-calls. Together, these data indicate that the effect of tickling on HCP depends on an interaction between a predisposing trait and stimulation-dependent variations of the subject's affective state.
PDF
