To investigate the prevalence of clinically relevant multiple system atrophy (MSA) and Lewy body disease (LBD) pathologies in a large frontotemporal lobar degeneration (FTLD) cohort to determine if concomitant pathologies underlie the heterogeneity of clinical features. Coexisting LBD in FTLD comprises a small proportion of cases but has implications for clinical and neuropathologic diagnoses and the identification of biomarkers.
The location and number of brain stem serotonin-synthesizing neurons were analyzed in 11 patients with Alzheimer's disease (AD) and 5 age-matched controls using immunohistochemical techniques. In addition, the number of neuritic plaques and neurofibrillary tangles in the cortex and brain stem raphe was evaluated, as was the number of Nissl-stained raphe neurons. AD patients could be classified into two groups based on their raphe pathology; patients with such pathology (AD+) and those without (AD-). The number of large raphe neurons correlated significantly with the number of serotonin-synthesizing neurons in control material, indicating that all large neurons were serotonergic. This relationship was not apparent in AD+ patients, in whom the number of serotonin-synthesizing neurons correlated with the number of neurofibrillary tangles in the raphe of these patients. This indicates that in AD+ patients the serotonin-synthesizing neurons were selectively affected. There was no correlation between raphe and cortical pathology or raphe pathology and patient sex, age, mini-mental score or depression score, even when such scores were weighted for the interval between testing and death. There was a trend for the raphe pathology to correlate with the age of onset and duration of dementia and the Blessed dementia score in AD+ patients. Most AD+ patients with severe raphe lesions had clinical dementia only, while AD- patients had additional clinical features. The raphe lesions were more dramatic in AD+ patients with a rapid progression of symptoms.
To investigate the degree of cortical inflammation in dementia with Lewy bodies (DLB) compared with Alzheimer disease (AD) and control brains. Inflammation appears related to the tau neuritic plaques of AD. Despite similar clinical presentations, therapeutic anti-inflammatory strategies are not likely to be effective for pure DLB. Arch Neurol. 2000.
To investigate the role of anti-inflammatory medications in alleviating the pathological features of Alzheimer disease. Long-term anti-inflammatory medications in patients with Alzheimer disease enhanced cognitive performance but did not alleviate the progression of the pathological changes. Arch Neurol. 2000.
Abnormal neurofilament protein distribution and phosphorylation contributes to the cytoskeletal pathology of Alzheimer's disease. Anatomical studies suggest that cortical neurons immunoreactive for nonphosphorylated 200-kDa neurofilament are most vulnerable. We repeated these studies in formalin-fixed temporal lobe tissue from five Alzheimer's disease cases with tissue volume loss compared to five controls without tissue loss. Immunohistochemistry for nonphosphorylated and phosphorylated forms of the neurofilament protein was counterstained for Nissl substance and immuno-positive and -negative pyramidal neurons quantified using areal fraction counts. Compared with controls, cases with Alzheimer's disease had similar numbers of neurons expressing the nonphosphorylated neurofilament protein, suggesting these neurons are largely spared by the disease process. In Alzheimer's disease there was a significant increase in neurons containing phosphorylated neurofilament and tau proteins and a decrease in neurons devoid of neurofilament protein. Our results challenge the theory that neurons containing 200 kDa neurofilament are selectively vulnerable in Alzheimer's disease.
Six cases with a clinical corticobasal syndrome (progressive asymmetric apraxia and parkinsonism unresponsive to levodopa) and tau pathology were selected from 97 brain donors with parkinsonism. Postmortem volumetric measures of regional brain atrophy (compared with age/sex-matched controls) were correlated with clinical features and the degree of underlying cortical and subcortical histopathology. At death, no significant asymmetry of pathology was detected. All cases had prominent bilateral atrophy of the precentral gyrus (reduced by 22-54%) with other cortical regions variably affected. Subcortical atrophy was less severe and variable. Two cases demonstrated widespread atrophy of basal ganglia structures (44-60% atrophy of the internal globus pallidus) and substantial subcortical pathology consistent with a diagnosis of progressive supranuclear palsy (PSP). The remaining four cases had typical pathology of corticobasal degeneration. In all cases, neuronal loss and gliosis corresponded with subcortical atrophy, while the density of cortical swollen neurons correlated with cortical volume loss. Atrophy of the internal globus pallidus was associated with postural instability, while widespread basal ganglia histopathology was found in cases with gaze palsy. This study confirms the involvement of the precentral gyrus in the corticobasal syndrome and highlights the variable underlying pathology in these patients.
The cortical neurons thought to be selectively affected in dementia with Lewy bodies (DLB) are those containing nonphosphorylated 200-kDa neurofilament (NF) protein. As these neurons are largely spared in Alzheimer's disease (AD), DLB and AD may impact on different cortical neuronal populations. The present study quantifies the NF-containing neurons in frontal and temporal cortex of 8 AD, 8 DLB, and 8 control cases. Formalin-fixed paraffin-embedded tissue was immunohistochemically stained with antibodies against nonphosphorylated and phosphorylated NF. Immunoreactive neurons were quantified by areal fraction analysis and corrected for cortical volume. As expected, nonphosphorylated and phosphorylated NF accumulated in the pathological hallmarks of AD and DLB. However, rather than a decrease in NF-containing neurons, a doubling of this population was observed in DLB, compared with AD and controls. This increased number of cortical NF-containing neurons reveal novel widespread cortical changes, beyond those explained by Lewy body formation, that are specific for DLB.
The most frequently mutated gene resulting in dominantly inherited Alzheimer's disease is presenilin-1. We have used antibodies against advanced glycation endproducts (AGE) in brain tissue sections of four patients with three different presenilin I mutations. Accumulation of intracellular AGE was observed in 75-95% of pyramidal neurons in patients with presenilin-1 mutations, far exceeding the percentage of presenilin-1-, tau- or ubiquitin-positive neurons. This high level of AGE-modified proteins in vulnerable neurons is most likely explained by higher levels of their precursors (reactive (di)carbonyl products) or a slower turnover of the participating proteins. These conditions of carbonyl stress may contribute to increased neuronal dysfunction and vulnerability leading to the early disease onset.
This article reviews the current knowledge on alpha-synuclein and its cellular locations in studies using human brain tissue. Alterations in the conformation and distribution of alpha-synuclein are examined in Parkinson's disease and the relationship between clinical symptoms and pathology explored. alpha-Synuclein as a molecular chaperone has several isoforms and is known to have different environment-dependent conformations. Processing methods for studying human brain tissue significantly impact on the conformational type of alpha-synuclein analysed, and antibody species used for the in situ detection of alpha-synuclein give variable results depending on the epitope visualised. Human studies show that alpha-synuclein is not isolated to neurons, but is also found in glia, making the interpretation of studies using brain tissue homogenates less clearly related to neurons. These methodological issues impact significantly on our understanding of the form, location, and therefore function of alpha-synuclein in normal human brain tissue. There are less methodological issues regarding highly aggregated alpha-synuclein found in the major hallmark of Parkinson's disease, the Lewy body. However, it remains unclear whether these alpha-synuclein inclusions are harmful to host neurons or provide protection. Several correlations exist between the clinical symptoms of Parkinson's disease and the distribution of Lewy pathology, the strongest being the association between limbic and cortical Lewy bodies and well-formed visual hallucinations. Further correlation studies in prospectively-followed patients and, perhaps more importantly, controls are required in order to determine normal versus pathologic alpha-synuclein and how to detect such differences in clinical situations.
Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid beta peptide (Abeta) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid beta peptide starting after the alternative beta-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.
Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause autosomal dominant familial Alzheimer's disease (AD). PSEN1 and PSEN2 are essential components of the gamma-secretase complex, which cleaves APP to affect Abeta processing. Disruptions in Abeta processing have been hypothesised to be the major cause of AD (the amyloid cascade hypothesis). These genetic cases exhibit all the classic hallmark pathologies of AD including neuritic plaques, neurofibrillary tangles (NFT), tissue atrophy, neuronal loss and inflammation, often in significantly enhanced quantities. In particular, these cases have average greater hippocampal atrophy and NFT, more significant cortical Abeta42 plaque deposition and more substantial inflammation. Enhanced cerebral Abeta40 angiopathy is a feature of many cases, but particularly those with APP mutations where it can be the dominant pathology. Additional frontotemporal neuronal loss in association with increased tau pathology appears unique to PSEN mutations, with mutations in exons 8 and 9 having enlarged cotton wool plaques throughout their cortex. The mechanisms driving these pathological differences in AD are discussed.
The recent knowledge that 10 years after transplantation surviving human fetal neurons adopt the histopathology of Parkinson's disease suggests that Lewy body formation takes a decade to achieve. To determine whether similar histopathology occurs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-primate models over a similar timeframe, the brains of two adult monkeys made parkinsonian in their youth with intermittent injections of MPTP were studied. Despite substantial nigral degeneration and increased alpha-synuclein immunoreactivity within surviving neurons, there was no evidence of Lewy body formation. This suggests that MPTP-induced oxidative stress and inflammation per se are not sufficient for Lewy body formation, or Lewy bodies are human specific.
The reactive changes in different types of astrocytes were analyzed in parkinsonian syndromes in order to identify common reactions and their relationship to disease severity. Immunohistochemistry was used on formalin-fixed, paraffin-embedded sections from the putamen, pons, and substantia nigra from 13 Parkinson disease (PD), 29 multiple-system atrophy (MSA), 34 progressive supranuclear palsy (PSP), 10 corticobasal degeneration(CBD), and 13 control cases. Classic reactive astrocytes were observed in MSA, PSP, and CBD, but not PD cases; the extent of reactivity correlated with indices of neurodegeneration and disease stage. Approximately 40% to 45% of subcortical astrocytes in PD and PSP accumulated alpha-synuclein and phospho-tau, respectively; subcortical astrocytes in MSA and CBD cases did not accumulate these proteins. Protoplasmic astrocytes were identified from fibrous astrocytes by their expression of parkin coregulated gene and apolipoprotein D, and accumulated abnormal proteins in PD, PSP, and CBD, but not MSA. The increased reactivity of parkin coregulated gene-immunoreactive protoplasmic astrocytes correlated with parkin expression in PSP and CBD. Nonreactive protoplasmic astrocytes were observed in PD and MSA cases; in PD, they accumulated alpha-synuclein, suggesting that the attenuated response might be due to an increase in the level of alpha-synuclein. These heterogeneous astroglial responses in PD, MSA, PSP, and CBD indicate distinct underlying pathogenic mechanisms in each disorder.
To identify the progression of pathology over the entire course of Parkinson's disease, we longitudinally followed a clinical cohort to autopsy and identified three clinicopathological phenotypes that progress at different rates. Typical Parkinson's disease has an initial rapid loss of midbrain dopamine neurons with a slow progression of Lewy body infiltration into the brain (over decades). Dementia intervenes late when Lewy bodies invade the neocortex. Older onset patients (> 70 years old) dement earlier and have much shorter disease durations. Paradoxically, they have far more alpha-synuclein-containing Lewy bodies throughout the brain, and many also have additional age-related plaque pathology. In contrast, dementia with Lewy bodies has the shortest disease course, with substantive amounts of Lewy bodies and Alzheimer-type pathologies infiltrating the brain. These data suggest that two age-related factors influence pathological progression in Parkinson's disease–the age at symptom onset and the degree and type of age-related Alzheimer-type pathology.
ATP-binding cassette transporter A1 (ABCA1) reduces amyloid-beta burden in transgenic mouse models of Alzheimer's disease (AD). Associations between ABCA1 polymorphisms and AD risk are also established. Little is known regarding the regulation of ABCA1 expression in the brain and how this may be affected by AD. In the present study we assessed ABCA1 mRNA and protein expression in the hippocampus of AD cases compared to controls. ABCA1 was clearly expressed in hippocampal neurons and expression was increased two- to three-fold in AD cases. The increased hippocampal ABCA1 expression was associated with increased APOE and PUMA gene expression, implying an association with neuronal stress. Consistent with this, treatment of SK-N-SH neurons with amyloid-beta peptide resulted in a 48% loss in survival and a significant upregulation of ABCA1, APOE, and PUMA gene expression. Studies in young (2 month) and old (12 month) transgenic mice expressing a familial AD form of human amyloid-beta protein precursor and presenilin-1 revealed a significant age-dependent upregulation of hippocampal Abca1 compared to wild-type control mice. However, hippocampal Apoe and Puma gene expression were not correlated with increased Abca1 expression in mice. Our data indicate that ABCA1 is upregulated in AD hippocampal neurons potentially via an amyloid-beta-mediated pathway.
The Niemann-Pick type C1 (NPC1) protein mediates the trafficking of cholesterol from lysosomes to other organelles. Mutations in the NPC1 gene lead to the retention of cholesterol and other lipids in the lysosomal compartment, and such defects are the basis of NPC disease. Several parallels exist between NPC disease and Alzheimer's disease (AD), including altered cholesterol homeostasis, changes in the lysosomal system, neurofibrillary tangles, and increased amyloid-beta generation. How the expression of NPC1 in the human brain is affected in AD has not been investigated so far. In the present study, we measured NPC1 mRNA and protein expression in three distinct regions of the human brain, and we revealed that NPC1 expression is upregulated at both mRNA and protein levels in the hippocampus and frontal cortex of AD patients compared to control individuals. In the cerebellum, a brain region that is relatively spared in AD, no difference in NPC1 expression was detected. Similarly, murine NPC1 mRNA levels were increased in the hippocampus of 12-month-old transgenic mice expressing a familial AD form of human amyloid-beta precursor protein (APP) and presenilin-1 (APP/PS1tg) compared to 12-month-old wild type mice, whereas no change in NPC1 was detected in mouse cerebellum. Immunohistochemical analysis of human hippocampus indicated that NPC1 expression was strongest in neurons. However, in vitro studies revealed that NPC1 expression was not induced by transfecting SK-N-SH neurons with human APP or by treating them with oligomeric amyloid-beta peptide. Total cholesterol levels were reduced in hippocampus from AD patients compared to control individuals, and it is therefore possible that the increased expression of NPC1 is linked to perturbed cholesterol homeostasis in AD.
Braak's proposal that, in patients with Parkinson's disease, Lewy bodies and neurites progressively invade the brain through regions connected to autonomic and olfactory centers remains contentious. Confounding factors include the lack of an in vivo marker to examine the progression of Lewy pathology, the retrospective nature or absence of clinical information for many cross-sectional pathological datasets, and for those with limited disease (clinically or neuropathologically), the absence of information concerning additional conditions. Despite these data limitations at this time, the brain pathology for most patients with typical Parkinson's disease can be predicted using Braak's scheme. What this tells us about the pathogenesis of Parkinson's disease will be explored in this review.
This study demonstrates a higher consistency across independent observers in the pathological subtyping of FTLD-TDP cases with the use of a pTDP43 antibody in comparison to the iTDP43 antibody, and corroborates the use of pTDP43 for pathological classification of FTLD-TDP cases.
Parkinson's disease is a progressive neurodegenerative disorder with multiple factors contributing to increasing severity of pathology in specific brain regions. The Braak hypothesis of Lewy pathology progression in Parkinson's disease proposes a systematic spread of α-synuclein that can be staged, with the later stages correlating with clinical aspects of the disease. The spread of pathology through the different stages suggests progression, a theory that has proven correct from evidence of pathology in healthy neurons grafted into the brains of patients with Parkinson's disease. Progression of pathology occurs on a number of levels, within a cell, between nearby cells, and then over longer distances throughout the brain, and evidence using prion proteins suggests two dissociable mechanisms-intracellular toxicity versus a nontoxic infectious mechanism for propagation. In Parkinson's disease, intracellular changes associated with mitochondria and lysosome dysfunction appear important for α-synuclein propagation, with high stress conditions favoring mitochondrial cell death mechanisms. Functional neurons appear necessary for propagation. Unconventional exocytosis releases α-synuclein under stress conditions, and endocytic uptake occurs in nearby cells. This cell-to-cell transmission of α-synuclein has been recapitulated in both cell culture and animal models, but the timeframe of transmission is considerably shorter than that observed in transplanted neurons. The time course of Lewy pathology formation in patients is consistent with the long time course observed in grafted neurons, and the restricted neuronal loss in Parkinson's disease is potentially important for the propagation of α-synuclein through relatively intact circuits.
The hypoglossal nucleus was recently identified as a key brain region in which the presence of TDP-43 pathology could accurately discriminate TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis (ALS). The objective of the present study was to assess the hypoglossal nucleus in behavioral variant frontotemporal dementia (bvFTD), and determine whether TDP-43 in this region is associated with clinical ALS. Twenty-nine cases with neuropathological FTLD-TDP and clinical bvFTD that had not been previously assessed for hypoglossal TDP-43 pathology were included in this study. Of these 29 cases, 41% (n=12) had a dual diagnosis of bvFTD-ALS at presentation, all 100% (n=12) of which demonstrated hypoglossal TDP-43 pathology. Of the 59% (n=17) cohort that presented with pure bvFTD, 35% (n=6) were identified with hypoglossal TDP-43 pathology. Review of the case files of all pure bvFTD cases revealed evidence of possible or probable ALS in 5 of the 6 hypoglossal-positive cases (83%) towards the end of disease, and this was absent from all cases without such pathology. In conclusion, the present study validates grading the presence of TDP-43 in the hypoglossal nucleus for the pathological identification of bvFTD cases with clinical ALS, and extends this to include the identification of cases with possible ALS at end-stage.