Lateralisation in Parkinson disease.

Asymmetry of dopaminergic neurodegeneration and subsequent lateralisation of motor symptoms are distinctive features of Parkinson's disease compared to other forms of neurodegenerative or symptomatic parkinsonism. Even 200 years after the first description of the disease, the underlying causes for this striking clinicopathological feature are not yet fully understood. There is increasing evidence that lateralisation of disease is due to a complex interplay of hereditary and environmental factors that are reflected not only in the concept of dominant hemispheres and handedness but also in specific susceptibilities of neuronal subpopulations within the substantia nigra. As a consequence, not only the obvious lateralisation of motor symptoms occurs but also patterns of associated non-motor signs are defined, which include cognitive functions, sleep behaviour or olfaction. Better understanding of the mechanisms contributing to lateralisation of neurodegeneration and the resulting patterns of clinical phenotypes based on bilateral post-mortem brain analyses and clinical studies focusing on right/left hemispheric symptom origin will help to develop more targeted therapeutic approaches, taking into account subtypes of PD as a heterogeneous disorder.

Magnetic resonance imaging of fixed post mortem brains reliably reflects subcortical vascular pathology of frontal, parietal and occipital white matter.

AIMS: Subcortical vascular pathology of the white and deep grey matter (WM and DGM) is associated with cognitive impairment. Routine neuropathological assessment of subcortical vascular pathology is based on semiquantitative scoring of characteristic lesions in a limited number of histological slides from selected WM and DGM areas. Clinically, WM and DGM lesions are visualized as hyper-intensities on magnetic resonance imaging (MRI). The aim of this study was to evaluate the feasibility of MRI on fixed post mortem brain hemispheres to complement routine neuropathological assessment of subcortical vascular pathology. METHODS: We assessed subcortical vascular pathology in 40 post mortem brain hemispheres from demented (n = 26) and nondemented (n = 14) individuals (mean age 83.2 ± 14.8 years; 62.5% female) using (i) routine histological assessment; (ii) extensive histological assessment of the entire hemisphere at 7-mm intervals; and (iii) full T2-weighted MRI performed on fixed post mortem brain hemispheres. RESULTS: In both WM and DGM routine histological scores for subcortical vascular pathology were significantly lower (P < 0.01) than the corresponding scores obtained by extensive histological assessment. In contrast, no significant differences were seen between scores obtained by MRI and extensive histological assessment in frontal, parietal and occipital lobes while MRI scores were significantly lower in the temporal WM and DGM (P < 0.01). CONCLUSIONS: The results of our study indicate that routine histological assessment underrates subcortical vascular pathology and we conclude that MRI could be used in addition to complement neuropathological post mortem assessment of subcortical vascular pathology of the WM.

Correlations between cortical and subcortical tau pathology.

AIM: Recent studies indicate that tau pathology in Alzheimer's disease (AD) does not initially manifest in the cerebral cortex but in selected subcortical nuclei, in particular the locus ceruleus (LC). In this study we correlate both olfactory and brainstem tau pathology with neuritic Braak stages. METHODS: We examined 239 unselected autopsy cases (57.3% female, 42.7% male; aged 55-102, mean 82.8 ± 9.7 SD years; AD, 44.8%; non-demented controls, 31.8%; Parkinson's disease, 5.0%; dementia with Lewy bodies, 2.5%; AD+Lewy body disease, 15.9%). Neuropathological examination according to standardized methods included immunohistochemistry and semiquantitative assessment of tau lesions in LC, substantia nigra (SN), dorsal motor nucleus of nervus vagus (dmX), and olfactory bulb (OB). RESULTS: In Braak stage 0, tau pathology (usually very sparse pretangle material) was seen in the OB in 52.9% and in the SN/LC in 44%. The prevalence of OB and subcortical tau pathology increased with increasing Braak stages and reached 100% in OB, SN and LC and 95.2% in dmX in Braak stage VI, respectively. The severity of tau pathology in OB and subcortical nuclei significantly (P < 0.001) correlated with Braak stages and these correlations remained statistically significant when controlling for concomitant α-synuclein pathology in the respective regions. CONCLUSIONS: Our finding of an increase in both prevalence and severity of OB, LC, SN and dmX tau pathology in AD with increasing Braak stages suggests that these regions become increasingly involved during AD progression rather than representing sites initially affected by AD-associated tau pathology.

Review: sporadic cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) may result from focal to widespread amyloid-ß protein (Aß) deposition within leptomeningeal and intracortical cerebral blood vessels. In addition, pericapillary Aß refers to Aß depositions in the glia limitans and adjacent neuropil, whereas in capillary CAA Aß depositions are present in the capillary wall. CAA may cause lobar intracerebral haemorrhages and microbleeds. Hypoperfusion and reduced vascular autoregulation due to CAA might cause infarcts and white matter lesions. CAA thus causes vascular lesions that potentially lead to (vascular) dementia and may further contribute to dementia by impeding the clearance of solutes out of the brain and transport of nutrients across the blood brain barrier. Severe CAA is an independent risk factor for cognitive decline. The clinical diagnosis of CAA is based on the assessment of associated cerebrovascular lesions. In addition, perivascular spaces in the white matter and reduced concentrations of both Aß(40) and Aß(42) in cerebrospinal fluid may prove to be suggestive for CAA. Transgenic mouse models that overexpress human Aß precursor protein show parenchymal Aß and CAA, thus corroborating the current concept of CAA pathogenesis: neuronal Aß enters the perivascular drainage pathway and may accumulate in vessel walls due to increased amounts and/or decreased clearance of Aß, respectively. We suggest that pericapillary Aß represents early impairment of the perivascular drainage pathway while capillary CAA is associated with decreased transendothelial clearance of Aß. CAA plays an important role in the multimorbid condition of the ageing brain but its contribution to neurodegeneration remains to be elucidated.

[Consensus statement "Dementia 2010" of the Austrian Alzheimer Society]. / Konsensusstatement "Demenz 2010" der Osterreichischen Alzheimer Gesellschaft.

The Austrian Alzheimer Society developed evidence-based guidelines based on a systematic literature search and criteria-guided assessment with subsequent transparent determination of grades of clinical recommendation. The authors evaluated currently available therapeutic approaches for the most common forms of dementia and focused on diagnosis and pharmacological intervention, taking into consideration the situation in Austria. The purpose of these guidelines is the rational and cost-effective use of diagnostic and therapeutic measures in dementing illnesses. Users are physicians and all other providers of care for patients with dementia in Austria.

Chromogranin peptides in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which primarily affects motor neurons. Eight cases of ALS and seven control cases were studied with semiquantitative immunocytochemistry for chromogranin A, chromogranin B and secretogranin II that are soluble constituents of large dense core vesicles, synaptophysin as a membrane protein of small synaptic vesicles and superoxide dismutase 1. Among the chromogranin peptides, the number and staining intensity of motor neurons was highest for chromogranin A. In ALS, the staining intensity for chromogranin peptides and synaptophysin was significantly lower in the ventral horn of ALS patients due to a loss in immunoreactive motor neurons, varicose fibers and varicosities. For all chromogranins, the remaining motor neurons displayed a characteristic staining pattern consisting of an intracellular accumulation of immunoreactivity with a high staining intensity. Confocal microscopy of motor neurons revealed that superoxide dismutase 1-immunopositive intracellular aggregates also contained chromogranin A, chromogranin B and secretogranin II. These findings indicate that there is a loss of small and large dense core vesicles in presynaptic terminals. The intracellular co-occurrence of superoxide dismutase 1 and chromogranins may suggest a functional interaction between these proteins. This study should prompt further experiments to elucidate the role of chromogranins in ALS patients.

Bimodal distribution of dopamine receptor densities in brains of schizophrenics.

The dopamine hypothesis of schizophrenia was examined by measuring the density of dopamine receptors in the postmortem brains of 81 control subjects and 59 schizophrenics from four different countries. The densities of dopamine receptors in the tissues from the schizophrenic patients had a bimodal distribution in the caudate nucleus, putamen, and nucleus accumbens. One mode occurred 25 percent above the control density, and a second mode occurred at a density 2.3 times that of the control density for all three regions. Although almost all the patients had been medicated with neuroleptics, the two modes had the same dissociation constant for the labeled ligand used, suggesting that the neuroleptic doses were similar for the two populations of schizophrenics. The results thus provide direct evidence for two distinct categories of schizophrenia.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Sporadic cerebral amyloid angiopathy is not a frequent cause of spontaneous brain hemorrhage.

The retrospective study of a consecutive autopsy series of 1100 elderly subjects (mean age 78.3 +/- 6.8 SD years), revealed sporadic cerebral amyloid angiopathy (CAA) in 50.0% and in 95.7% of autopsy-confirmed cases of Alzheimer disease (AD). Apolipoprotein (APOE) epsilon 3/4 and epsilon 4/4 were significantly more frequent in AD than in controls, and were associated with more severe degrees of CAA. Spontaneous (non-traumatic) intracerebral hemorrhages (ICH) (excluding microbleeds and hemorrhagic infarctions) were seen in 5.4% and only in 3.3% of AD cases. CAA was found in 50.6% of brains without and in 42.4% with ICH, the latter showing a significantly higher frequency of severe degrees of CAA. ICH was related to CAA in 42.4%, whilst no such relation was seen in 57.6%. Patients with CAA were older, showed a higher frequency of clinical dementia and pathologically confirmed AD, but signs of hypertension (history and/or autopsy) occurred in 40%, compared with 80% in those with non-CAA-related ICHs. CAA-related ICH more frequently involved in cerebral lobes or hemispheres, whilst non-CAA-related ones were more often located in the basal ganglia and brainstem. The data of a lower prevalence of CAA in cases with than without ICH and of ICH with and without CAA do not support the concept that CAA represents the most important risk factor for ICH in the aged, probably because of other risk factors including hypertension.

Neuropathological evaluation of mixed dementia.

Mixed dementia (MD) refers to a combination of definite Alzheimer disease (AD) and vascular encephalopathy, but the distinction between both disorders is controversial. For the diagnosis of MD the clinical/neuroimaging criteria of possible AD plus cerebrovascular disease (CVD) as separate entities are used, but causal relations between vascular brain lesions and dementia are unclear. We proposed the combination of autopsy-proven AD with multiple vascular or ischemic lesions with about 30-50 ml of infarcted/damaged brain tissue. The population-based prevalence of MD is unknown. In retrospective and prospective autopsy studies, it ranges from 2 to 58% with reasonable means of 6-12%. In a consecutive autopsy series of 1500 demented elderly subjects, 830 of which with clinically probable AD, in Vienna, Austria, 41.5 to 52.0% showed "pure" AD, 7% atypical AD, 16-20% AD plus cerebrovascular lesions, and 9% AD plus Lewy body pathology; MD was diagnosed in 4.6 and 2.4%, and "pure" vascular dementia (VaD) in 11 and 2.0%, respectively, while 16.3/6.1% were other dementing disorders, and 1% showed no specific pathology. Like the MRC-CFAS and other studies, this indicates frequent coexistence of AD with multiple cerebrovascular lesions in cognitively impaired patients. In both AD and VaD, vascular lesions frequently involved subcortical regions (basal ganglia, thalamus, hippocampus, and white matter) or were multiple microinfarcts, whereas in MD, large/hemispheral infarcts and multiple microinfarcts were more frequent, suggesting different pathogenic mechanisms. In early/mild AD, critically located small vascular lesions may induce/promote cognitive decline, but in full-blown AD they appear of minor importance. Discussion of the major pathogenic factors inducing AD, VaD and MD suggests synergistic relations between these disorders. However, currently available morphological criteria for AD and VaD are of limited value for the diagnosis of MD and generally accepted and validated histopathological criteria for the diagnosis of VaD and MD are currently not available. Therefore, more distinct and critically evaluated clinico-pathological criteria are warranted.

Morphological substrates of parkinsonism with and without dementia: a retrospective clinico-pathological study.

A retrospective study of a 50-year autopsy series of 900 patients with the clinical diagnosis of parkinsonism (31.2% with dementia) revealed pure Lewy body disease (LBD) in 84.9%, but only 44.7% with idiopathic Parkinson disease (PD); 16% were associated with cerebrovascular lesions, 14.8% with Alzheimer pathology; 8.9% were classified dementia with Lewy bodies (DLB), 9.4% showed other degenerative disorders, and 5.6% other/ secondary parkinsonian syndromes. The frequency of LBD during different periods was fairly stable, with increase of DLB and PD plus Alzheimer changes, but decrease of associated cerebrovascular lesions during the last decades. Using variable clinical diagnostic criteria not only by specified neurologists, the misdiagnosis rate ranged from 11.5 to 23% and was similar to that in most previous clinico-pathological studies. The majority of cases with false clinical diagnosis of PD had a final pathological diagnosis of DLB with or without Alzheimer lesions. A postmortem series of 330 elderly patients clinically diagnosed as parkinsonism with (37.6%) and without dementia showed that IPD, Braak stages 3-5 were rarely associated with cognitive impairment, which was frequently seen in IPD with associated Alzheimer pathology (35.5%), DLB (33.9%), and in Alzheimer disease (AD) or mixed dementia (17%), whereas it almost never was associated with minor cerebrovascular lesions. Clinico-pathological studies in DBL, demented and nondemented PD, and AD cases showed a negative relation between cognitive impairment and Alzheimer changes, suggesting that these either alone or in combination with cortical Lewy body pathologies are major causes of cognitive dysfunction. Further prospective clinico-pathological studies are needed to validate the currently used clinical criteria for PD, to increase the diagnostic accuracy until effective biomarkers are available, and to clarify the impact of structural and functional changes on cognitive function in parkinsonism as an ultimate goal of early disease detection and effective treatment.

The morphological basis of mental dysfunction in Parkinson's disease.

Mental dysfunction including dementia in Parkinson's disease (PD), the incidence of which averages 20-40%, is suggested to have six-fold lifetime risk compared to age-matched controls. It is caused by a variety of functional and pathological lesions ranging from damage to subcortical-cortical networks to cortical and limbic Lewy body and neuritic Alzheimer pathologies, the relationship and impact of which are still under discussion. Based on two consecutive autopsy series of PD, with prevalence of cognitive impairment of 33% to 35.7%, its essential morphological changes and their impact on the natural history (survival) are discussed. Whereas cortical Lewy body stages 5 and 6 without additional pathologies only rarely were associated with dementia, around 20% of demented PD cases were classified as dementia with Lewy bodies (DLB) with variable degrees of Alzheimer (AD) pathology, and around one third showed severe neuritic AD lesions which occurred in PD patients with later disease onset and significantly shorter survival. Frequent close relations in the severity between alpha-synuclein and tau-pathologies suggest synergistic reaction and common underlying pathogenesis of both lesions. Clinico-pathological studies in PD showed a significantly negative relation between cognitive impairment and neuritic AD lesions somewhat different from that in AD, suggesting that neuritic AD pathology, either alone or in combination with cortical and limbic Lewy bodies, are major causes of mental and cognitive dysfunction in PD.

Antioxidant capacity in postmortem brain tissues of Parkinson's and Alzheimer's diseases.

Oxidative stress has been associated with damage and progressive cell death that occurs in neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). The aim of this study was to investigate the antioxidant capacity in postmortem motor cortex (MC), nucleus caudatus (NC), gyrus temporalis (GT) and substantia nigra (SN) from controls (C) and patients with PD and AD. The initial samples consisted of 68 subjects of PD, AD and C. Brains were matched for age, sex and postmortem time. Brain tissue was homogenized in a phosphate buffer pH 7.3 and separated with two-step centrifugation at 15,000rpm for 30 min and 15,000 rpm for 10 min at 4 degrees C. Antioxidant capacity in the supernatants was measured using the oxygen radical absorbance assay (ORAC). The results showed that in the SN of parkinsonian's brain the balance between production of free radicals and the neutralization by a complex antioxidant system is disturbed. No changes in the antioxidant capacity of postmortem MC and NC of parkinsonian's brain in comparison with C were found. In the SN of parkinsonian's brain, antioxidant capacity seems to be lower in comparison with C (p < 0.05). Antioxidant capacity against peroxyl radical showed that MC of AD patients was lower than in the MC of C (p < 0.005). In NC of AD patients the antioxidant capacity against hydroxyl radical was increased in comparison with C (p < 0.04). No changes in the antioxidant capacity were found in brain tissues of AD in comparison with C, when CuSO4 was used as a free radical generator.

Olfactory tau pathology in Alzheimer disease and mild cognitive impairment.

OBJECTIVE: To examine the occurrence of tau pathology in the olfactory system in aged subjects and its relation to the severity of Alzheimer disease (AD) pathology. MATERIAL AND METHODS: 273 autopsy cases (167 female, 106 male, aged 61-102, mean 83.2+/-4.5 SD years) underwent a standard neuropathological assessment with immuno-histochemical study of tau and Abeta amyloid in the olfactory bulb and nerve, and diagnosis of AD using established consensus criteria including Braak staging of neuritic AD pathology. RESULTS: All cases of definite AD (Braak stages 5 and 6, n = 96) showed large numbers of neuropil threads and neurofibrillary tangles, with amyloid deposits in 50%, and neuritic plaques only in two cases. Braak stage 4 (n = 73) was associated with tau pathology in the olfactory system in 90.4 and amyloid deposits in 9%, Braak stage 3 (n = 56) with mainly mild to moderate olfactory tau lesions in 44.6 and Abeta deposits in 9%. Braak stage 2 (n = 22) showed olfactory tau pathology in 36.4% without amyloid deposits, whereas Braak stages 0 and 1 (n = 25) were all negative. Olfactory tau pathology showed highly significant correlation with neuritic Braak staging in the brain, while both scores showed significant but low correlation with age. CONCLUSIONS: These data confirm previous studies demonstrating considerable tau pathology in the olfactory system in all definite AD cases, in more than 2/3 of limbic AD and in more than 1/3 of elderly individuals with or without mild cognitive impairment associated with Braak stage 2. Clinical dementia correlated with both Braak and olfactory tau scores, indicating that both are associated with a high risk of cognitive decline.

Dopamine, 6-hydroxydopamine, iron, and dioxygen--their mutual interactions and possible implication in the development of Parkinson's disease.

The reactions of dopamine (1-amino-2-(3,4-dihydroxyphenyl)-ethane, DA), 5-hydroxydopamine (5-OHDA), and 6-hydroxydopamine (6-OHDA), with molecular oxygen-with and without the addition of catalytic amounts of iron(III) and other metal ions-have been studied and the implication of these results with respect to the chemistry involved in the progress of Parkinson's disease is discussed. In the presence of O2 DA reacts spontaneously without the necessity of metal-ion catalysis under the production of stoichiometric amounts of H2O2, to form initially pink dopaminochrome, which is not stable and reacts further (without the consumption of dioxygen) to form the insoluble polymeric material known as 'melanine'. DA reacts with iron(III) yielding an intermediate 1:1 complex, which decomposes releasing Fe(II) and the semiquinone, which reacts further under involvement of both Fe(III) and dioxygen. 6-OHDA reacts without showing the necessity of such an intermediate, and it is shown to be able to release iron as Fe(II) from ferritine. On the other hand, it is shown (in vitro) that Fe(II) reacts in a Fenton type reaction with DA and the present H2O2 producing 5-OHDA and especially 6-OHDA. Based on these mutual interacting reactions a mechanism for the initiation and progress of Parkinson's disease is suggested. The catalytic effects of some other transition-metal ions are presented and an explanation for the peculiarly toxic effects of manganese(II) is put forward. Finally, a possible reason for the effect that nicotine has in the mitigation of Parkinson's disease is discussed.

Oxidative stress related markers in the "VITA" and the centenarian projects.

Oxidative stress seems to play an important role in the pathophysiology of Alzheimer's disease (AD). At present there are no easily accessible biochemical markers for AD. We performed activity assays for platelet MAO-B and erythrocyte Cu/Zn-SOD as well as Western blotting for these two proteins. Moreover, we assessed plasma lactoferrin and performed RFLP-analysis for the MAO-B-intron-13-polymorphism in patients from the Vienna-Transdanube Aging (VITA) and from the so called centenarian project. The first one, VITA, is a community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. The centenarian project investigates chronic care in-old patients suffering from AD. In both sexes platelet MAO-B activity increased significantly in the AD group, and Cu/Zn-SOD activity decreased, but the latter effect was significant only in females. No significant difference was found regarding plasma lactoferrin. No correlation was found between MAO-Bi13 and MAO-B platelet activity or allele MAO-Bi13 and disease frequency. These results point to the possibility that a combination of MAO-B and SOD activity levels might be useful tools for an early diagnosis of AD.

The neuropathologic basis of different clinical subgroups of Parkinson's disease.

Clinical and neuropathologic data in 45 patients with Parkinson's disease (PD) were compared. Twenty-seven patients suffered from marked akinesia and rigidity (AR-type) and 18 patients from predominant resting tremor (T-type). Dementia, depression, and psychosis occurred in 26, 18, and 18 patients, respectively. Neuronal counts were performed in defined areas of the medial and lateral substantia nigra (SNM, SNL), locus ceruleus (LC), and dorsal raphe nucleus (DRN). The AR-type (compared with the T-type) showed higher neuronal loss of LC, SNL, SNM, and more severe gliosis, extraneuronal melanin deposits, and neuroaxonal dystrophy in substantia nigra. Demented PD patients showed more intense cortical Alzheimer lesions and higher neuronal depletion in the SNM, whereas PD subjects with moderate or marked dementia differed from mildly or not demented ones only in the higher degree of cortical Alzheimer lesions. More severe neuronal cell loss of DRN was observed in PD patients with depression. Occurrence of psychosis was not associated with any pathologic feature. Our findings indicate that some major clinical features of PD are related to distinct neuropathologic lesions.

Alzheimer disease: DNA fragmentation indicates increased neuronal vulnerability, but not apoptosis.

Although nerve cell loss is prominent in certain brain regions in Alzheimer disease (AD), it is currently unresolved how these cells die. Recent studies unanimously agree that there are more neurons displaying DNA fragmentation in AD compared with normal controls. However, controversy remains as to whether cell death is mediated by apoptosis or necrosis. We addressed this question by comparing AD lesions with those from cases with pontosubicular neuron necrosis (PSNN), a human pathological condition with unequivocal neuronal apoptosis, with regard to cell and nuclear morphology, immunohistochemistry, and in situ tailing. Immunohistochemistry was performed for an array of proteins with presumptive roles in the apoptotic process or the protection thereof, i.e. a recently described apoptosis-specific protein (ASP), the transcription factor c-Jun, Bcl-2, and various stress proteins: alpha B-Crystallin, heat shock protein (HSP) 27, HSP 65, HSP 70, HSP 90, and ubiquitin. Apoptotic neurons in PSNN displayed chromatin condensation, nuclear fragmentation, and cytoplasmic condensation. They were labeled with the in situ tailing technique and stained for the ASP. Despite the large numbers of cells with DNA fragmentation identified in the hippocampus of AD brains, only exceptional cells displayed the morphological characteristics of apoptosis or labeled for the ASP. We suggest that the increased rate of neuronal DNA fragmentation in AD patients indicates a higher susceptibility of the cells to metabolic disturbances compared with normal controls. The large number of cells with DNA fragmentation most likely reflects metabolic disturbances in the premortem period, and cell destruction is mediated through necrosis rather than apoptosis.