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.

Chitinase enzyme activity in CSF is a powerful biomarker of Alzheimer disease.

OBJECTIVE: DNA damage accumulation in brain is associated with the development of Alzheimer disease (AD), but newly identified protein markers of DNA damage have not been evaluated in the diagnosis of AD and other forms of dementia. METHODS: Here, we analyzed the level of novel biomarkers of DNA damage and telomere dysfunction (chitinase activity, N-acetyl-glucosaminidase activity, stathmin, and EF-1α) in CSF of 94 patients with AD, 41 patients with non-AD dementia, and 40 control patients without dementia. RESULTS: Enzymatic activity of chitinase (chitotriosidase activity) and stathmin protein level were significantly increased in CSF of patients with AD and non-AD dementia compared with that of no dementia control patients. As a single marker, chitinase activity was most powerful for distinguishing patients with AD from no dementia patients with an accuracy of 85.8% using a single threshold. Discrimination was even superior to clinically standard CSF markers that showed an accuracy of 78.4% (ß-amyloid) and 77.6% (tau). Combined analysis of chitinase with other markers increased the accuracy to a maximum of 91%. The biomarkers of DNA damage were also increased in CSF of patients with non-AD dementia compared with no dementia patients, and the new biomarkers improved the diagnosis of non-AD dementia as well as the discrimination of AD from non-AD dementia. CONCLUSIONS: Taken together, the findings in this study provide experimental evidence that DNA damage markers are significantly increased in AD and non-AD dementia. The biomarkers identified outperformed the standard CSF markers for diagnosing AD and non-AD dementia in the cohort investigated.

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.

Cerebral amyloid angiopathy in Lewy body disease.

While Alzheimer and Lewy body pathologies are discussed as major substrates of dementia in Parkinson's disease (PD/Lewy body disease of brainstem type), the incidence and impact of cerebral amyloid angiopathy (CAA) and its association with cognitive decline in PD and dementia with Lewy bodies (DLB) are unknown. The severity of CAA and other Alzheimer lesions were assessed in 68 cases of autopsy-confirmed PD, 32 of them with dementia (PDD), and in 20 cases of DLB. PDD patients were significantly older than those without dementia (mean age 84.5 vs 77.6 years; p < 0.01), the age of DLB patients was in between both groups (mean 80.0 years), while duration of disease was DLB < PDD < PD (mean 6.5 vs 8.5 and 14.3 years). PDD patients had a significantly higher neuritic Braak stage (mean 4.2 vs 2.4, p < 0.01), significantly higher cortical amyloid beta (Abeta) load, capillary cerebral amyloid angiopathy (CapCAA) and generalized CAA than those without dementia (mild CapCAA in 22% vs moderate to severe CapCAA in 87%; mild generalized CAA in 5.5% vs moderate to severe generalized CAA in 82%). Mean PD stage was higher in both DLB and PDD than in PD (mean 5.2 vs 4.5 and 4.0, respectively): Mean neuritic Braak stage in DLB was 3.4, severe Abeta plaque load was seen in 95%, moderate to severe CapCAA in 90% and mild to severe generalized CAA in 70%. This and other recent studies imply an association of CAA with cognitive decline in both PD/PDD and DLB, particularly in cases with concomitant AD-type pathology.

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.

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.

Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease.

Neurofibrillary tangle predominant dementia (NFTPD) is a subset of late onset dementia, clinically different from traditional "plaque and tangle" Alzheimer disease (AD): later onset, shorter duration, less severe cognitive impairment, and almost absence of ApoE epsilon4. Neuropathology reveals abundant allocortical neurofibrillary pathology with no or few isocortical tau lesions, absence of neuritic plaques, absence or scarcity of amyloid deposits, but neurofibrillary changes comprising both 3 and 4 repeat (3R and 4R) tau immunohistochemistry are not significantly different from those in classical AD. Comparing 51 autopsy cases of NFTPD with 244 classical AD subjects, the nosology of NFTPD and its differences from AD are discussed.

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.

Alzheimer 100--highlights in the history of Alzheimer research.

Alzheimer disease, a progressive neurodegenerative disorder of hitherto unknown etiology leading progressively to severe incapacity and death, has become the pandemic of the 21(st) century. On World Alzheimer Day, September 21, 2006, the 100(th) anniversary of the first description of the clinical and histological findings in this disorder by A. Alzheimer, was celebrated. This retrospective review of the most important events and advances in Alzheimer research presents its early history in which only clinical and histologic signs of this peculiar disease were described. Electron microscopy, quantitative morphology and modern biochemistry emerging in the second half of the 20(th) century opened a new era in dementia research with description of the ultrastructure and biochemistry of senile plaques and neurofibrillary tangles, the major disease markers of AD. Advances in the development of clinical, neuropathological, and neuroimaging criteria, modern instruments and algorithms in the diagnosis of the disorder followed, enabling long-term studies and more exact diagnosis of AD and related disorders. Landmark studies were the development of operational criteria for the post mortem diagnosis of AD based on semiquantitative assessment and developmental patterns of its major markers. Basic research gave insight into the molecular genetics and pathophysiology of AD, and, based on the biochemical findings, new pharmacological treatment options were opened. Recently, biological and other surrogate, in particular functional neuroimaging, markers allow an early detection of presymptomatic stages of AD, their risk factors and progression which, in the future, might be prevented or at least slowed by new therapeutic approaches. Since the etiology of AD is hitherto unknown, causative therapies are still not available. The paper discusses future research needs and challenges for developing new diagnostic strategies for early and accurate detection of neurodegenerative processes leading to dementia, better epidemiologic and gender data as well as more insights into the pathogenic cascade of AD and other dementing disorders which will depend on international networks and close cooperation between clinicians, neuroscientists, caregivers, public health institutions, and individual sponsors.

Prevalence and impact of cerebrovascular pathology in Alzheimer's disease and parkinsonism.

OBJECTIVE: To study the prevalence and impact of cerebrovascular lesions (CVL) in Alzheimer's disease (AD) and their effects on cognitive impairment. MATERIAL AND METHODS: In study I, the prevalence of vascular lesions in a prospective series of 244 autopsy-proved AD cases (mean age 83.1+/-8.4 years) and 230 age-matched non-demented controls was examined using immunochemistry and current morphological diagnostic criteria. In study II, in 100 consecutive autopsy cases (mean age 84.3+/-9.3 years), the incidence of general and capillary cerebral amyloid angiopathy (CAA, CapCAA) was examined. RESULTS: In study I, AD cases showed significantly more frequent CVL than age-matched controls without differences in the Braak stages, but the severity of CAA was significantly higher in AD brain with associated vascular lesions. In study II, CAA was more frequent in demented than in non-demented patients, but did neither correlate with high-grade AD pathology nor with clinical dementia, whereas CapCAA correlated with both dementia and high Braak stages; the severity of both types of CAA showed only low correlation with each other. CONCLUSIONS: The present data and other studies confirm the importance of CVL in AD and Parkinson's disease without considerable impact on cognitive impairment in progressed stages of AD, and the close association of CapCAA but not of general CAA with clinical dementia and AD pathology.

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.

A short history of neurosciences in Austria.

Based on internal medicine and psychiatry and in close connection with pathology, the neurosciences in Austria began to develop in the 18(th) century, e.g. with the description of inflammation of the central nervous system by J. P. Franck (1745-1823) and the "phrenology" by F. J. Gall (1745-1823). Under the influence of the great pathologist C. Rokitansky (1804-1878), the tripode of the Vienna neurology - L. Türck (1810-1868), as initiator, Th. v. Meynert (1833-1892) the activator, and H. Obersteiner (1847-1922) as the founder of the Vienna Neurological Institute, presented basic contributions to the morphology and pathology of the nervous system. At the end of the 19(th) and in the early 20(th) century, they were followed by important publications by S. Fred (aphasia), C. Redlich (tabes dorsalis), F. Sträussler (CNS syphilis), A. Spitzer (fiber anatomy of the brain), P. Schilder (diffuse sclerosis), R. Barany (Nobel price for physiology and medicine 1914), J. Wagner v. Jauregg (Nobel price for medicine, 1927), O. Loewi (Nobel Price for Physiology and Medicine together with Sir H. Dale, 1936), A. Schüller (histiocytosis X), C. v. Economo (encephalitis lethargica and cytoarchitectonics of the human cerebral cortex), E. Pollak (Wilson disease), E. Gamper (mesencephalic subject), J. Gerstmann (Gerstmann-Sträussler-Scheinker syndrome and Gerstmann parietal syndrome), H. Hoff with L. Schönbauer (brain tumors and surgery), and others. Major research institutions were the departments of psychiatry I and II at the University of Vienna School of Medicine (foundation 1870), unification 1911, separation into departments of neurology, psychiatry and neuropsychiatry of children and adolescents in 1971), the Obersteiner Institute in Vienna (foundation 1882, separation 1993), the university departments at Graz and Innsbruck, both founded in 1891, and other laboratories, where renouned clinicans and neuroscientists, like O. Marburg, H. Hoff, O. Pötzl, O. Kauders, F. Seitelberger, H. Tschabitscher, K. Weingarten, H. Reisner,W. Birkmayer, H. Petsche, F. Gerstenbrand, H. Bernheimer, H. W. Heiss, H. Lassmann, W. Poewe, L. Deecke, and many of their associates produced important contributions to wide areas of modern neurosciences. Important for the future are the foundation of the Institute of Brain Research at Vienna Medical University and of the Austrian Society of Neurology which will give further impact for the future progress of neuroscience research in Austria and its integration into the international science community.