Neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTD), Lewy body disease (LBD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) have ...in common that protein aggregates represent pathological hallmark lesions. Amyloid β-protein, τ-protein, α-synuclein, and TDP-43 are the most frequently aggregated proteins in these disorders. Although they are assumed to form disease-characteristic aggregates, such as amyloid plaques and neurofibrillary tangles in AD or Lewy bodies in LBD/PD, they are not restricted to these clinical presentations. They also occur in non-diseased individuals and can co-exist in the same brain without or with a clinical picture of a distinct dementing or movement disorder. In this review, we discuss the co-existence of these pathologies and potential additive effects in the human brain as well as related functional findings on cross-seeding and molecular interactions between these aggregates/proteins. We conclude that there is evidence for interactions at the molecular level as well as for additive effects on brain damage by multiple pathologies occurring in different functionally important neurons. Based upon this information, we hypothesize a cascade of events that may explain general mechanisms in the development of neurodegenerative disorders: (1) distinct lesions are a prerequisite for the development of a distinct disease (e.g., primary age-related tauopathy for AD), (2) disease-specific pathogenic events further trigger the development of a specific disease (e.g., Aβ aggregation in AD that exaggerate further Aβ and AD-related τ pathology), (3) the symptomatic disease manifests, and (4) neurodegenerative co-pathologies may be either purely coincidental or (more likely) have influence on the disease development and/or its clinical presentation.
Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Parkinson’s disease and other synucleinopathies, Alzheimer’s disease (AD), and mild cognitive ...impairment heralding its progression to dementia. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb/tract, primary olfactory cortices, and their secondary targets. Olfactory dysfunction is related to deposition of pathological proteins, α-synuclein, hyperphosphorylated tau protein, and neurofilament protein in these areas, featured by neurofibrillary tangles, Lewy bodies and neurites inducing a complex cascade of molecular processes including oxidative damage, neuroinflammation, and cytosolic disruption of cellular processes leading to cell death. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with severe anosmia. Recent studies of olfactory dysfunction have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Here, we summarize the current knowledge on neuropathological and pathophysiological changes of the olfactory system in the most frequent neurodegenerative diseases, in particular AD and synucleinopathies. We also present neuropathological findings in the olfactory bulb and tract in a large autopsy cohort (
n
= 536, 57.8 % female, mean age 81.3 years). The severity of olfactory bulb HPτ, Aβ, and αSyn pathology correlated and increased significantly (
P
< 0.001) with increasing neuritic Braak stages, Thal Aβ phases, and cerebral Lewy body pathology, respectively. Hence, further studies are warranted to investigate the potential role of olfactory biopsies (possibly restricted to the olfactory epithelium) in the diagnostic process of neurodegenerative diseases in particular in clinical drug trials to identify subjects showing early, preclinical stages of neurodegeneration and to stratify clinically impaired cohorts according to the underlying cerebral neuropathology.
Cerebral amyloid angiopathy (CAA) was observed for the first time nearly 100 years ago and systematically described in 1938. It is a common finding in elderly individuals, defined by beta-amyloid ...peptide (Abeta) depositions in cerebral blood vessels, and associated with Alzheimer's disease (AD). A variety of genetic mutations cause hereditary forms of CAA; in this review, however, only the sporadic variant of CAA is considered. In CAA, Abeta depositions primarily occur in the abluminal portion of the tunica media, and with increasing severity all layers of the blood vessel wall are infiltrated and an additional spread of Abeta into the surrounding neuropil may be seen (i.e., dyshoric changes). CAA is most pronounced in the occipital lobe and its distribution is usually patchy. The relationship between CAA and AD is poorly understood; however, low positive correlations between the severity of both CAA and AD pathology have been observed. CAA is a frequent cause of (warfarin-associated) intracerebral hemorrhage, and the diagnosis of probable CAA-related hemorrhage can be made during life with high accuracy. Both APOE-epsilon4 and APOE-epsilon2 are risk factors for CAA, while only APOE-epsilon2 increases the risk for hemorrhage in CAA. Although the role of CAA as an independent risk factor for cognitive decline is unclear, severe CAA is likely to lower the threshold for clinically overt dementia in neurodegenerative diseases. As for the origin of Abeta in CAA, it may be both produced by smooth muscle cells (vessel wall) and derived from neurons in the course of perivascular drainage.
Olfaction and Aging: A Mini-Review Attems, Johannes; Walker, Lauren; Jellinger, Kurt A
Gerontology (Basel),
01/2015, Letnik:
61, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Decreased olfactory function is very common in the older population, being present in >50% of individuals aged between 65 and 80 years and in 62-80% of those >80 years of age. Smell dysfunction ...significantly influences physical well-being, quality of life, nutritional status as well as everyday safety and is associated with increased mortality. Multiple factors contribute to age-related olfactory sensory loss, including nasal engorgement, cumulative damage of the olfactory epithelium from environmental insults, a reduction in mucosal metabolizing enzymes, sensory loss of receptor cells to odorants, and changes in neurotransmitter and neuromodulator systems. In addition, structural and functional abnormalities of the olfactory epithelium, olfactory bulb, central olfactory cortex, and basic olfactory circuitry, which are related to the neuronal expression of aberrant proteins in these areas, may result in olfactory sensory impairment in aging and neurodegenerative diseases. Impaired odour identification is associated with a decrease in cognitive abilities and memory decline. A reduction in the sense of smell is considered to potentially represent an early and important warning of neurodegenerative disorders, particularly of Parkinson's disease and Alzheimer's disease, and, in mild cognitive impairment, olfactory impairment may herald progression to dementia. Further investigations of the potential role of olfactory dysfunction in the early diagnosis and treatment of neurodegenerative diseases are warranted.
Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB ...is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson's disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as disease progresses, there has been controversy about the separation of DLB from PD dementia (PDD) and consensus reports have put forward guidelines to assist clinicians in the identification and management of both syndromes. Here, we present basic concepts and definitions, based on our current understanding, that should guide the community to address open questions that will, hopefully, lead us towards improved diagnosis and novel therapeutic strategies for DLB and other synucleinopathies.
Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease ...(PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.
Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by ...McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP;
i.e.
, Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (
i.e.
, “absent” vs. “present”) and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (
n
= 202) and NBTR (
n
= 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff’s
α
≈ 0.6), while both Braak and Beach systems had lower (Krippendorff’s
α
≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (
p
< 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (
p
= 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.
The supplementary motor area (SMA) is frequently involved by brain tumours (particularly WHO grade II gliomas). Surgery in this area can be followed by the 'SMA syndrome', characterised by ...contralateral akinesia and mutism. Knowledge of the connections of the SMA can provide new insights on the genesis of the SMA syndrome, and a better understanding of the challenges related to operating in this region.
White matter connections of the SMA were studied with both postmortem dissection and advance diffusion imaging tractography. Postmortem dissections were performed according to the Klingler technique. 12 specimens were fixed in 10% formalin and frozen at -15°C for 2 weeks. After thawing, dissection was performed with blunt dissectors. For diffusion tractography, high-resolution diffusion imaging datasets from 10 adult healthy controls from the Human Connectome Project database were used. Whole brain tractography was performed using a spherical deconvolution approach.
Five main connections were identified in both postmortem dissections and tractography reconstructions: (1) U-fibres running in the precentral sulcus, connecting the precentral gyrus and the SMA; (2) U-fibres running in the cingulate sulcus, connecting the SMA with the cingulate gyrus; (3) frontal 'aslant' fascicle, directly connecting the SMA with the pars opercularis of the inferior frontal gyrus; (4) medial fibres connecting the SMA with the striatum; and (5) SMA callosal fibres. Good concordance was observed between postmortem dissections and diffusion tractography.
The SMA shows a wide range of white matter connections with motor, language and lymbic areas. Features of the SMA syndrome (akinesia and mutism) can be better understood on the basis of these findings.
With Alzheimer's disease (AD) exhibiting reduced ability of neural stem cell renewal, we hypothesized that de novo mutations controlling embryonic development, in the form of brain somatic mutations ...instigate the disease. A leading gene presenting heterozygous dominant de novo autism-intellectual disabilities (ID) causing mutations is activity-dependent neuroprotective protein (ADNP), with intact ADNP protecting against AD-tauopathy. We discovered a genomic autism ADNP mutation (c.2188C>T) in postmortem AD olfactory bulbs and hippocampi. RNA-Seq of olfactory bulbs also identified a novel ADNP hotspot mutation, c.2187_2188insA. Altogether, 665 mutations in 596 genes with 441 mutations in AD patients (389 genes, 38% AD-exclusive mutations) and 104 genes presenting disease-causing mutations (OMIM) were discovered. OMIM AD mutated genes converged on cytoskeletal mechanisms, autism and ID causing mutations (about 40% each). The number and average frequencies of AD-related mutations per subject were higher in AD subjects compared to controls. RNA-seq datamining (hippocampus, dorsolateral prefrontal cortex, fusiform gyrus and superior frontal gyrus-583 subjects) yielded similar results. Overlapping all tested brain areas identified unique and shared mutations, with ADNP singled out as a gene associated with autism/ID/AD and presenting several unique aging/AD mutations. The large fusiform gyrus library (117 subjects) with high sequencing coverage correlated the c.2187_2188insA ADNP mutation frequency to Braak stage (tauopathy) and showed more ADNP mutations in AD specimens. In cell cultures, the ADNP-derived snippet NAP inhibited mutated-ADNP-microtubule (MT) toxicity and enhanced Tau-MT association. We propose a paradigm-shifting concept in the perception of AD whereby accumulating mosaic somatic mutations promote brain pathology.
Primary pathologies including amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) develop many years before the onset of dementia symptoms in Alzheimer's disease (AD). Age-related small vessel ...disease (SVD) is common in elderly subjects and may contribute to the clinical syndrome of AD. Each type of pathology shows a specific spatio-temporal sequence of spreading in the brain. Here, we review neuropathological and neuroimaging findings (PET tracers of Aβ and NFT, MRI markers of SVD) to assess whether staging of these primary pathologies is useful to predict clinical symptoms in AD. On the basis of neuropathological data, early stages of Aβ plaque and NFT pathology distribution occur in preclinical AD, but advanced stages with spreading into further brain regions are associated with dementia symptoms. Amyloid PET presumably detects Aβ in advanced neuropathological Aβ stages, and increased global amyloid PET uptake is associated with clinical worsening in non-demented subjects. Tau PET may provide additional predictive value by detecting NFT in the allocortex. There is weak evidence that SVD is related to amyloid or NFT pathology. Global volume of MRI-assessed white matter hyperintensities (WMH) contribute in addition to biomarker levels of Aβ to predict cognitive decline. Regional differences of the effect of WMH on cognition have been demonstrated but are not yet established as a biomarker in AD. In conclusion, biomarkers for amyloid and tau pathology allow a distinction between early and advanced stages of AD, but a subgroup of pathologically identified preclinical AD cases is not identified by the currently available biomarkers.
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