Lewy Bodies In Substantia Nigra Research Articles

Substantia Nigra Pathology, Contact Sports Play, and Parkinsonism in Chronic Traumatic Encephalopathy

Parkinsonism is associated with traumatic brain injury and chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impact (RHI) exposure, but the neuropathologic substrates that underlie parkinsonism in individuals with CTE are yet to be defined. To evaluate the frequency of parkinsonism in individuals with CTE and the association of RHI and neuropathologic substrates with parkinsonism in these individuals. This cross-sectional study included brain donors with neuropathologically diagnosed CTE without other significant neurodegenerative disease and with information on parkinsonism from the Understanding Neurologic Injury and Traumatic Encephalopathy brain bank between July 2015 and May 2022. Years of contact sports participation as a proxy for RHI. The main outcomes were frequency of parkinsonism in individuals with CTE and associations between (1) RHI with substantia nigra (SN) Lewy bodies (LBs) and neurofibrillary tangles (NFTs); (2) LBs, NFTs, and arteriolosclerosis with SN neuronal loss; and (3) SN neuronal loss, LBs, NFTs, and arteriolosclerosis with parkinsonism, tested by age-adjusted logistic regressions. Of 481 male brain donors with neuropathologically diagnosed CTE, parkinsonism occurred frequently in individuals with CTE (119 [24.7%]; 362 [75.3%] did not have parkinsonism). Participants with parkinsonism had a higher mean (SD) age at death (71.5 [13.0] years) than participants without parkinsonism (54.1 [19.3] years) (P < .001) and higher rates of dementia (104 [87.4%] vs 105 [29.0%]), visual hallucinations (45 [37.8%] vs 51 [14.1%]), and probable rapid eye movement sleep behavior disorder (52 [43.7%] vs 58 [16.0%]) (P < .001 for all). Participants with parkinsonism had a more severe CTE stage (eg, stage IV: 35 [29.4%] vs 39 [10.8%]) and nigral pathology than those without parkinsonism (NFTs: 50 of 117 [42.7%] vs 103 of 344 [29.9%]; P = .01; neuronal loss: 61 of 117 [52.1%] vs 59 of 344 [17.1%]; P < .001; and LBs: 28 of 116 [24.1%] vs 20 of 342 [5.8%]; P < .001). Years of contact sports participation were associated with SN NFTs (adjusted odds ratio [AOR], 1.04; 95% CI, 1.00-1.07; P = .03) and neuronal loss (AOR, 1.05; 95% CI, 1.01-1.08; P = .02). Nigral neuronal loss (AOR, 2.61; 95% CI, 1.52-4.47; P < .001) and LBs (AOR, 2.29; 95% CI, 1.15-4.57; P = .02) were associated with parkinsonism. However, SN neuronal loss was associated with SN LBs (AOR, 4.48; 95% CI, 2.25-8.92; P < .001), SN NFTs (AOR, 2.51; 95% CI, 1.52-4.15; P < .001), and arteriolosclerosis (AOR, 2.27; 95% CI, 1.33-3.85; P = .002). In American football players, regression analysis demonstrated that SN NFTs and neuronal loss mediated the association between years of play and parkinsonism in the context of CTE (β, 0.012; 95% CI, 0.001-0.038). In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation were associated with SN tau pathology and neuronal loss, and these pathologies were associated with parkinsonism. Repetitive head impacts may incite neuropathologic processes that lead to symptoms of parkinsonism in individuals with CTE.

Comparative Analysis of MPTP Neurotoxicity in Mice with a Constitutive Knockout of the α-Synuclein Gene

Aggregated forms of α-synuclein are core components of pathohistological inclusions known as Lewy bodies in substantia nigra (SN) neurons of patients with Parkinson's disease (PD). The role of α-synuclein in selective loss of SN dopaminergic neurons (DNs) in PD is studied in mice knocked out in the α-synuclein gene. The new mouse strain delta flox KO with a constitutive knockout of the α-synuclein gene models the end point of in vivo deletion of the α-synuclein gene in mice with a conditional knockout and has no foreign sequence in the modified genomic locus, thus differing from all other α-synuclein knockout mouse strains. The effect of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is used to model PD, was compared between delta flox KO mice and mice of the well-known α-synuclein knockout strain AbKO. Subchronic MPTP administration, which models early PD, was found to reduce the dopamine content and to change the ratio of dopamine metabolites in the striatum to the same levels in delta flox KO, АbKO, and wild-type mice. Overt locomotor defects were not observed after MPTP treatment, but gait testing in a CatWalk XT (Noldus) system revealed identical gait deviations in mice of the two strains and control wild-type mice. Based on the findings, a similar mechanism of neurotoxic damage to DNs was assumed for delta flox KO and AbKO mice.

Parkinsonism Versus Concomitant Parkinson's Disease in Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is characterized by the presence of ubiquitin-positive inclusions in neurons and astrocytes and by cerebellar tremor and ataxia. Parkinsonism has been reported in FXTAS, but most patients lack the characteristic rest tremor and severe rigidity seen in idiopathic Parkinson's disease (PD). To describe the frequency of concomitant PD in FXTAS. We reviewed the medical record of 40 deceased patients diagnosed with FXTAS and performed a pathology analysis to confirm both FXTAS and PD. Clinical histories indicated that 5 FXTAS patients were diagnosed with idiopathic PD and 2 with atypical parkinsonian syndrome. After pathological examination, we found that 7 patients in the PD clinical diagnosis group had dopaminergic neuronal loss; however, only 2 of 7 presented Lewy bodies (LBs) in the substantia nigra. Therefore, a total of 5% of the 40 cohort patients met the pathologic criteria for the concomitant diagnosis of FXTAS and PD. In addition, 2 patients not clinically diagnosed with PD also had nigral neuronal loss with LBs in substantia nigra. In total 10% of these 40 patients had LBs. This report expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS and the concept that the parkinsonism found in FXTAS is sometimes indistinguishable from PD. We propose that FMR1 should be recognized as one of the exceptional genetic causes of parkinsonism with presynaptic dopaminergic loss and LBs.

Glucose levels during life and neuropathologic findings at autopsy among people never treated for diabetes

We evaluated associations between glucose and dementia-related neuropathologic findings among people without diabetes treatment history to elucidate mechanisms of glucose's potential effect on dementia. We used glucose and hemoglobin A1c values to characterize glucose exposures over 5 years before death (primary) and age bands from 55–59 through 80–84 (secondary). Autopsy evaluations included Braak stage for neurofibrillary tangles, Consortium to Establish a Registry for Alzheimer's Disease grade for neuritic plaques, macroscopic infarcts including lacunar infarcts, Lewy bodies, cerebral microinfarcts, and hippocampal sclerosis. Of 529 who came to autopsy, we included 430 with no history of diabetes treatment. We found no associations between glucose levels and Braak stage or Consortium to Establish a Registry for Alzheimer's Disease grade. There was a suggestion of a relationship between glucose and hippocampal sclerosis, although this was inconsistent across analyses. There was higher risk of Lewy bodies in substantia nigra and locus ceruleus with higher glucose levels in age band analyses. We did not find interactions between glucose levels, neuropathologic findings, and dementia. The mechanism by which glucose may impact dementia risk is still unknown.

Clinicopathological characteristics of freezing of gait in autopsy-confirmed Parkinson's disease.

Twenty-five percent to sixty percent of Parkinson's disease (PD) patients reportedly have freezing of gait, leading to impaired mobility, falls, and decreased quality of life. Several factors have been associated with gait freezing in PD patients. We analyze for these factors in autopsy-proven PD patients. We performed a chart review of 58 patients with pathologically confirmed PD based on substantia nigra Lewy bodies. Freezing of gait was defined as a score of 1 or more on Item 14 of the Unified Parkinson's Disease Rating Scale or if documented on examination. Serial office notes and scales were used to determine onset and progression of motor and non-motor symptoms. Patients had been followed up for an average of 20 visits over 9 y. The mean onset of gait freezing was 9.3 y from initial motor symptoms. Patients with earlier gait freezing more commonly had initial gait difficulties and developed postural instability, dyskinesias, memory impairment, hallucinations, and vivid dreams earlier during the disease course. Early onset of hallucinations was correlated with more rapid progression of gait freezing. Maximal equivalent levodopa dose was not correlated with earlier onset or progression of gait freezing. Progressive and more severe gait freezing trended toward higher-severity Lewy body disease on postmortem examination. Early onset and rapid progression of freezing of gait in this cohort were correlated with early cognitive impairment and hallucinations that are potential clinical hallmarks of cortical Lewy bodies. The gradual worsening and severity of gait freezing correlated with the density of cortical Lewy body-containing neurons.

Association of Parkinson disease risk loci with mild parkinsonian signs in older persons.

Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored. To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons. Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies. The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson's Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss. Parkinson disease risk alleles in the MAPT (rs2942168; P = .0006) and CCDC62 (rs12817488; P = .004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson's Disease Rating Scale subscores, MAPT (P = .0002) and CCDC62 (P = .003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P = .005) and gait impairment, SNCA (rs356220; P = .04) and rigidity, and GAK (rs1564282; P = .03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P = .03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies. In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.

The co-occurrence of Alzheimer's disease and Huntington's disease: a neuropathological study of 15 elderly Huntington's disease subjects.

Dementia is a common feature in both Huntington's disease (HD) and Alzheimer's disease (AD), as well as in the general elderly population. Few studies have examined elderly HD patients with dementia for neuropathologic evidence of both HD and AD. We present neuropathological findings in a retrospective case series of 15 elderly HD patients (ages 60-91 years), 11 of whom had prominent clinical dementia. Post-mortem brain tissue was examined and stained for evidence of both HD and AD including Vonsattel grading and Htt-repeat expansion, Bielskowsky, tau, β amyloid, and TDP43 immunostaining. Mean age at death was 76.8 years, mean disease duration was 18.6 years, and mean CAG repeat expansion was 42. Evidence of AD in addition to HD pathology was present in 9 of 11 (82%) patients with prominent dementia, suggesting that AD may be more commonly co-occurring with HD than previously appreciated. Two patients had only HD as the basis of dementia and four patients did not have prominent dementia. One patient with marked parkinsonian features was not L-dopa responsive and had no substantia nigra Lewy bodies at autopsy. Our study suggests that AD may frequently contribute to cognitive decline in elderly HD patients which complicates the assessment and management of such individuals. Further study is needed to determine if there is a higher incidence of AD in persons with HD compared to the general population. In addition, our series includes one HD patient whose clinical features masqueraded as Parkinson's disease but was not responsive to levodopa therapy.

14-3-3 protein is a component of Lewy bodies in Parkinson’s disease—Mutation analysis and association studies of 14-3-3 eta

Mutations in α-synuclein have been identified in some rare families with autosomal dominant Parkinson’s disease (PD). The synuclein gene family shares physical and functional homology with 14-3-3 proteins and binds to 14-3-3 proteins and to its ligands. We therefore investigated whether 14-3-3 proteins are also involved in the pathogenesis of PD. Here we demonstrate that 14-3-3 proteins are colocalized with Lewy bodies in PD. We investigated the 14-3-3 eta ( YWHAH) gene by mutation analysis and association studies as it maps to human chromosome 22q12.1–q13.1, a region which has been recently implicated in PD and carried out immunohistochemical studies of Lewy bodies with two different 14-3-3 eta antibodies. In 358 sporadic and familial PD patients, disease causing mutations were not identified. Furthermore, association studies with intragenic polymorphisms do not provide evidence for an involvement of 14-3-3 eta in the pathogenesis of PD. In accordance with these findings, there was no staining of substantia nigra Lewy bodies with antibodies specific for the 14-3-3 eta subunit.

Anosmia in dementia is associated with Lewy bodies rather than Alzheimer's pathology

OBJECTIVESTo assess olfactory function of patients with dementia. Odour detection ability is impaired in clinical Parkinson's disease. Evidence of impaired detection in patients with clinically diagnosed Alzheimer's disease is inconsistent....

Lewy body and Alzheimer pathology in a family with the amyloid-beta precursor protein APP717 gene mutation.

Mutations in the amyloid precursor protein (APP) gene cause one form of early onset familial Alzheimer's disease (AD). One such family has been studied genetically and neuropathologically and represents the basis of the present report. Four siblings with the APP717 Val to Ile mutation, aged 59, 65, 61 and 64 years, apolipoprotein E (APOE) genotyped 2,4 (first three) and 2,3 respectively, had severe AD, Braak stage VI with frequent neurofibrillary tangles in the primary visual cortex, Brodmann area 17. The first one also met McKeith criteria for the limbic stage of dementia with Lewy bodies but did not have substantia nigra Lewy bodies. The second two met McKeith criteria for the neocortical stage of dementia with Lewy bodies and both had substantia nigra Lewy bodies. The fourth had AD but no Lewy bodies. A cousin without the APP717 mutation who was APOE 3, 4, developed dementia at age 60 and died at age 75. She had severe cerebrovascular atherosclerosis, less severe AD, Braak stage V, with sparing of area 17. She also had Lewy bodies in the substantia nigra and in the cortex and met McKeith criteria for neocortical stage of dementia with Lewy bodies. Extrapyramidal features were present in all five. Lewy bodies have been described in 53% of reported autopsies on individuals with the APP717 Val to Ile mutation coincident with dementia and AD neuropathologic changes. These observations suggest an association between the chromosome 21 APP mutation and Lewy body formation, possibly mediated by other environmental or genetic factors.

Clinical and quantitative pathologic correlates of dementia with Lewy bodies.

To examine the distribution of cortical Lewy bodies (LB) and their contribution to the clinical syndrome in dementia with LB (DLB) and to address their relationship to the pathologic markers of AD and PD. We studied 25 cases meeting neuropathologic criteria for DLB: 13 cases without AD (Braak stage I or II) and 12 cases with concomitant AD changes (Braak stages III to V). Age at onset, disease duration, and clinical symptoms were reviewed for each case. We quantified the regional distribution of LB in substantia nigra, paralimbic areas (cingulate gyrus, insula, entorhinal cortex, and hippocampus), and neocortex (frontal and occipital association areas) using anti-alpha-synuclein immunostaining. We compared the LB pathology between groups of patients with different symptoms at onset or with specific clinical phenotypes. There were no significant differences in clinical symptoms or LB density between cases with or without concomitant AD. LB density showed a consistent gradient as follows: substantia nigra > entorhinal cortex > cingulate gyrus > insula > frontal cortex > hippocampus > occipital cortex. LB density in substantia nigra and neocortex was not significantly different in cases that started with parkinsonism compared with those that started with dementia. There were no significant differences in LB density in any region among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls, or parkinsonism. Duration of the disease correlated with a global LB burden for each case (p = 0.02) but did not correlate with LB density in any individual area. Paralimbic and neocortical LB density were highly correlated with each other (p<0.0001), but neither of these correlated well with the number of LB in substantia nigra. LB density did not correlate with Braak stage or frequency of neuritic plaques. There is a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, and neocortical structures that is similar for DLB cases with or without concomitant AD. Paralimbic and neocortical LB do not correlate with LB in substantia nigra, suggesting that DLB should not be considered just a severe form of PD. LB density correlates weakly with clinical symptoms and disease duration.

Clinical parkinsonism in dementia patients with substantia nigra Lewy bodies.

In a retrospective clinicopathological study, we examined the substantia nigra (SN) of 48 dementia patients with SN Lewy bodies (LBs) to determine if the severity of degeneration correlated with either the occurrence of signs of parkinsonism at dementia presentation or with the frequency of treatment for parkinsonism during the disease course. The SN specimens were graded for microscopic degeneration using a semi-quantitative five-tiered scale. Whereas no correlation was found between the grade of degeneration and occurrence of signs at presentation (r = -0.16, p = 0.18), with 16 of 38 patients having had signs reported, a more severe grade was statistically correlated with an increased frequency of treatment during the course (r = 0.41, p = 0.004), with ten of 41 patients having been treated for parkinsonism. Contrary to our expectations, we found that fewer than half of the patients with the two most severe grades of degeneration presented with signs of parkinsonism or were ever treated for parkinsonism.

Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease.

We undertook this study to investigate the neuropathologic relationships among Alzheimer disease (AD), idiopathic Parkinson disease (PD), and the Lewy body variant of AD (AD/LBV). We retrieved 30 autopsy cases in which Lewy bodies (LB) had been identified in the substantia nigra (SN) in routine hematoxylin-eosin-stained sections. Twenty-two of the cases had a primary clinical diagnosis of dementia and neuropathologic changes of AD; 12 of these demented patients also had clinical parkinsonism. Eight cases had clinical and neuropathologic evidence of PD with minimal or no AD neuropathology, though 6 had clinical dementia. Controls consisted of 6 cases of AD without SN LB by hematoxylin-eosin, and 5 neurologically normal aged controls. Paraffin sections of SN, superior temporal gyrus, and cingulate gyrus from each case were immunostained with rabbit anti-ubiquitin antiserum, randomized, and analyzed individually by light microscopy, and the density of LB-like profiles in each section were graded. None of 5 nondemented aged controls showed any neocortical LB, even though 2 had significant numbers of incidental SN LB by ubiquitin immunostaining. Of 6 AD cases without SN LB by hematoxylin-eosin, 3 had rare SN LB on ubiquitin stain, 1 of which showed rare neocortical Lewy-like profiles. Seven of 8 PD cases showed neocortical LB, including the 6 with dementia. Twenty-one of 22 AD cases with SN LB showed ubiquitin-immunoreactive Lewy-like bodies in the neocortex that were statistically significantly greater in number than in either pure PD or pure AD cases. The frequent occurrence of LB in the neocortex in PD alone suggests that AD/LBV likely represents mixed AD/PD. However, AD neuropathology may favor or promote the formation of neocortical LB in patients who go on to develop mixed AD/PD pathology.

Detection of Lewy bodies in Trisomy 21 (Down's syndrome).

The presence of cortical senile plaques and neurofibrillary tangles sufficient to warrant a neuropathological diagnosis of Alzheimer's disease is well established in middle-aged individuals with Trisomy 21 (Down's syndrome). In contrast a relationship between Down's syndrome and Lewy bodies, one of the major neuropathological features of Parkinson's disease, has not been previously reported. In a clinico-neuropathological survey of 23 cases of Down's Syndrome, two patients, aged 50 and 56 years respectively, were found to have Lewy body formation in the substantia nigra in addition to cortical Alzheimer-type pathology. Neither case showed significant substantia nigra neuron loss although locus coeruleus loss was present in both. Since substantia nigra Lewy bodies are a characteristic neurohistological feature of idiopathic Parkinson's disease, their occurrence in cases of Down's syndrome with evidence of Alzheimer-type pathology supports an aetiopathological connection between Parkinson's disease, Alzheimer's disease, and Down's syndrome; and suggests that common pathogenic mechanisms may underlie aspects of neuronal degeneration in these three disorders, some of which may relate to aberrant chromosome 21 expression.

Lewy bodies contain beta-amyloid precursor proteins of Alzheimer's disease

To assess the contribution of Alzheimer's disease amyloid proteins to cortical and substantia nigra Lewy bodies (LBs), regions of postmortem brain rich in intraneuronal LBs were examined immunohistochemically. Antibodies to epitopes in domains outside the amyloidogenic beta-amyloid peptide (BAP) in BAP precursor proteins (BAPPs) as well as to the BAP itself were used as probes. These studies showed that only BAPP epitopes outside the BAP were present in substantia nigral and cortical LBs. Thus, non-amyloidogenic domains of BAPPs may be associated with intraneuronal inclusions comprised of neurofilament proteins.

Epitopes located in spatially separate domains of each neurofilament subunit are present in parkinson's disease lewy bodies

Subcortical Lewy bodies are the pathological hallmark of idiopathic Parkinson's disease. This study sought to determine the extent to which each neurofilament subunit [low (NF-L), mid (NF-M), or high (NF-H)] was present in Lewy bodies by using light, confocal, and electron microscopy. A battery of 37 antineurofilament antibodies, characterized as to subunit specificity, epitope domain, and phosphorylation status, was employed to probe substantia nigra Lewy bodies from 15 Parkinson's disease cases. All 37 antibodies labelled Lewy bodies. The epitopes recognized by these antibodies included those in the NF-L rod and tail domains; the NF-M head, rod, and tail domains, as well as epitopes within, and flanking, the multiphosphorylation repeat site; and the NF-H rod domain and multiphosphorylation repeat sites. With these probes, nearly the entire length of each subunit could be demonstrated in Lewy bodies. However, the staining pattern of the Lewy bodies suggested that the tail domains of NF-M and NF-H were present in the periphery of the Lewy body core and in the Lewy body corona, but they appeared to be altered or missing in the center of the Lewy body core. In contrast, the head domain of NF-M, the tail domain of NF-L, and the rod domains of all three subunits are present throughout the Lewy body. These results strongly suggest that the entire extent of each neurofilament subunit is found in Lewy bodies but that the neurofilament subunits may be altered during the processing of these filaments into Lewy bodies.