Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer's disease.

AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.

Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type.

AIMS: The aim of this study was to identify early foci of α-synuclein (α-syn pathology) accumulation, subsequent progression and neurodegeneration in multiple system atrophy of the cerebellar type (MSA-C). METHODS: We analysed 70-µm-thick sections of 10 cases with MSA-C and 24 normal controls. RESULTS: MSA-C cases with the lowest burden of pathology showed α-syn glial cytoplasmic inclusions (GCIs) in the cerebellum as well as in medullary and pontine cerebellar projections. Cerebellar pathology was highly selective and severely involved subcortical white matter, whereas deep white matter and granular layer were only mildly affected and the molecular layer was spared. Loss of Purkinje cells increased with disease duration and was associated with neuronal and axonal abnormalities. Neocortex, basal ganglia and spinal cord became consecutively involved with the increasing burden of α-syn pathology, followed by hippocampus, amygdala, and, finally, the visual cortex. GCIs were associated with myelinated axons, and the severity of GCIs correlated with demyelination. CONCLUSIONS: Our findings indicate that cerebellar subcortical white matter and cerebellar brainstem projections are likely the earliest foci of α-syn pathology in MSA-C, followed by involvement of more widespread regions of the central nervous system and neurodegeneration with disease progression.

TDP-43 pathology occurs infrequently in multiple system atrophy.

AIMS AND METHODS: The α-synucleinopathy multiple system atrophy (MSA) and diseases defined by pathological 43-kDa transactive response DNA-binding protein (TDP-43) or fused in sarcoma (FUS) aggregates such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration show overlapping clinico-pathological features. Consequently, we examined MSA for evidence of TDP-43 or FUS pathology utilizing immunohistochemical studies in autopsy material from 29 MSA patients. RESULTS: TDP-43 pathology was generally rare, and there were no FUS lesions. The TDP-43 lesions were located predominantly in medio-temporal lobe and subcortical brain areas and were comprised mainly of dystrophic processes and perivascular (and subpial) lesions. CONCLUSIONS: The multisystem clinical symptoms and signs of MSA, and in particular the neurobehavioural/cognitive and pyramidal features, appear not to result from concomitant TDP-43 or FUS pathology, but rather from widespread white matter α-synuclein positive glial cytoplasmic inclusions and neurodegeneration in keeping with a primary α-synuclein-mediated oligodendrogliopathy. The gliodegenerative disease MSA evidently results from different pathogenetic mechanisms than neurodegenerative diseases linked to pathological TDP-43.

Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions.

Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress has been implicated in the pathogenesis of some of these disorders. Using antibodies to specific nitrated tyrosine residues in alpha-synuclein, we demonstrate extensive and widespread accumulations of nitrated alpha-synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated alpha-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selective and specific nitration of alpha-synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies.

Neurofibrillary tangles in progressive supranuclear palsy contain the same tau epitopes identified in Alzheimer's disease PHFtau.

Neurofibrillary tangle (NFT)-rich brain samples from patients with progressive supranuclear palsy (PSP) or Alzheimer's disease (AD) were probed with a large panel of anti-tau antibodies to compare the species of tau present in PSP and AD NFTs by immunohistochemistry and Western blot methods. These antibodies have been shown to recognize phosphate-independent or -dependent epitopes that extend from the amino to the carboxy terminal domains of normal brain tau and the abnormal tau in the paired helical filaments (PHFs) of AD NFTs (PHFtau). The immunohistochemical studies showed that all of the tau epitopes detected in brainstem PSP NFTs also were found in hippocampal AD NFTs and vice versa. While Western blots demonstrated 2 PHFtau-like immunobands in PSP brainstem, a triplet of PHFtau proteins were seen in the AD and PSP hippocampus. Despite differences in the distribution, ultrastructure and immunoblot profile of NFTs in PSP and AD, the same constellation of tau epitopes is present in the abnormal tau proteins in PSP and AD NFTs. Thus, the generation of abnormal tau proteins in PSP (PSPtau) and AD (PHFtau) may have similar adverse biological consequences in both diseases.

Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy.

Although alpha-synuclein (alpha-syn) has been implicated as a major component of the abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA), it is uncertain if GCIs are homogenous and contain full-length alpha-syn. Since this has implications for hypotheses about the pathogenesis of GCIs, we used a novel panel of antibodies to defined regions throughout alpha-syn in immunohistochemical epitope mapping studies of GCIs in MSA brains. Although the immunostaining profile of GCIs with these antibodies was similar for all MSA brains, there were significant differences in the immunoreactivity of the alpha-syn epitopes detected in GCIs. Notably, carboxy-terminal alpha-syn epitopes were immunodominant in GCIs, but the entire panel of antibodies immunostained cortical Lewy bodies (LBs) in dementia with LBs brain with similar intensity. While the distribution of alpha-syn labeled GCIs paralleled that previously reported using silver stains, antibodies to carboxy-terminal alpha-syn epitopes revealed a previously undescribed burden of GCIs in the MSA hippocampal formation. Finally, Western blots demonstrated detergent insoluble monomeric and high-molecular weight alpha-syn species in GCI rich MSA cerebellar white matter. Collectively, these data indicate that alpha-syn is a prominent component of GCIs in MSA, and that GCIs and LBs may result from cell type specific conformational or post-translational permutations in alpha-syn.

Reliability of regional cerebral blood flow activation to cognitive tasks in elderly normal subjects.

The assessment of cerebral blood flow (CBF) using noninvasive 133Xe techniques provides an indirect measurement of cortical metabolic activity. The utility of this method in longitudinal clinical studies depends on the stability and reproducibility of resting and activated flow measures. We evaluated CBF in a sample of 16 elderly normal subjects (aged 54-73 years) at rest and during task performance in two sessions separated by an average of 9 weeks. Resting global CBF was lower in the second session, a finding consistent with the known effects of habituation previously reported. Regionally specific activated CBF did not change with repeated measurements. The results provide evidence that the 133Xe technique is reliable and of potential utility in evaluating the effect of the natural course of brain disease, as well as the effects of therapeutic interventions on brain activity.

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.

The epidemiology of Parkinson's disease. A case-control study of young-onset and old-onset patients.

While the cause of Parkinson's disease (PD) remains unknown, recent evidence suggests that certain external factors, ie, environmental agents, may act as neurotoxins, initiating the chain of oxidative reactions that ultimately destroy neurons in the substantia nigra. Young-onset PD might result from greater exposure to a putative neurotoxin. This hypothesis has rekindled interest in the epidemiology of PD. We therefore conducted a detailed analysis of various environmental exposures and early life experiences in 80 patients with old-onset PD (at an age older than 60 years), 69 young-onset patients (younger than 40 years), and 149 age- and sex-matched control subjects. Contrary to previous reports, we were unable to implicate well water or exposure to herbicides, pesticides, or industrial toxins as significant PD risk factors. A residential history of rural living was reported by more patient cases than control subjects and was marginally significant. On the other hand, at least one episode of head trauma "severe enough to cause vertigo, dizziness, blurred or double vision, seizures or convulsions, transient memory loss, personality changes, or paralysis" occurred significantly more often prior to disease onset in patients with both young-onset and old-onset PD than in control subjects (odds ratio = 2.7). When adjusted for head trauma and rural living, smoking was inversely associated with PD, as has been previously reported (odds ratio = 0.5). There were no significant differences in early life experiences or environmental exposures between young-onset and old-onset patients. We suggest that the risk of developing PD is influenced by a variety of factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurologic complications of coronary artery bypass grafting: case-control study.

In a retrospective case-control study, we identified 18 patients who had neurologic symptoms associated with coronary artery bypass grafting, or 1.3% of all patients who had this operation. Cerebral infarction and anoxic encephalopathy accounted for almost all the complications. The overall mortality was 33%, higher among those with an intraoperative compared with a postoperative deficit. Prior cerebrovascular risk factors as well as intraoperative hypotension were no more prevalent in patients with complications than in age-matched controls who had the same operation.

Sentence comprehension and praxis deficits in Parkinson's disease.

We evaluated the ability of nondemented patients with idiopathic Parkinson's disease (PD) to interpret various aspects of sentences and to perform learned limb and oral gestures. The patients were significantly compromised in their ability to answer simple questions about sentences such as "The eagle chased the hawk that was fast. Which bird was chased?" A discriminant analysis revealed that up to 73% of PD patients differ from control subjects in their ability to perform this task. Patients with PD were also significantly compromised in their gestural performance, and a discriminant analysis indicated that a praxis deficit may be evident in up to 64% of patients. We conclude that language and gestural processing impairments are frequent in patients with PD.

Magnetic resonance imaging in Parkinson's disease and parkinsonian syndromes.

High field strength magnetic resonance imaging (MRI) provides a noninvasive means of evaluating patients with parkinsonism. Using strict clinical criteria, we began a prospective study of patients with Parkinson's disease (PD) and parkinsonian syndromes (PS) including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and atypical parkinsonism (ATYP). We detected moderate to severe putaminal hypointensity more frequently in PS than in PD and controls, although putaminal hypointensity did not distinguish between MSA, PSP, or ATYP. Signal intensity in the lateral substantia nigra did not differ significantly among patients with PD, PS, or controls and was therefore not a useful MRI marker. Pars compacta width was significantly narrower in both PD and PS. Subcortical and periventricular hyperintense foci were more abundant in PD and PS than controls. Atrophy of the brainstem occurred only in patients with PS.

Cerebral hemodynamics in the diagnosis of normal pressure hydrocephalus.

We studied the effect of CSF drainage on cerebral blood flow (CBF) in normal pressure hydrocephalus (NPH) and non-NPH dementia using the 133Xenon inhalation technique. Dementia patients had lower CBF than matched elderly normals. Flow values for NPH and non-NPH patients did not differ before or after CSF drainage. CBF did not increase after lumbar puncture, and these measurements were not useful in predicting the outcome of ventricular shunt surgery. Postoperative CBF did not increase after successful shunting.

Olfactory function in Parkinson's disease subtypes.

Decreased olfactory function commonly occurs in idiopathic Parkinson's disease (PD), regardless of stage, treatment, or duration of disease. In the present study, we sought to determine whether different subtypes of PD, categorized according to well-defined clinical criteria, evidence different degrees of olfactory dysfunction. Significantly different scores on the University of Pennsylvania Smell Identification Test (UPSIT) were present between patients with benign PD and malignant PD (respective means [SD] = 22.51 [8.50] and 17.38 [6.29]) and between tremor-predominant PD and postural instability-gait disorder (PIGD)-predominant PD (23.43 [8.18] versus 17.35 [6.00]). No statistically significant differences in UPSIT scores were observed between young-onset and older-onset PD patients. Women outperformed men in most subtypes examined.

Epitope analysis of senile plaque components in the hippocampus of patients with Parkinson's disease.

We conducted an epitope analysis of senile plaque (SP) proteins on hippocampal SPs in patients with Parkinson's disease (PD), using a library of antibodies to proteins implicated in the genesis of hippocampal SPs in Alzheimer's disease (AD). The library included antibodies to the beta-amyloid protein (beta-AP), domains outside the beta-AP in beta-amyloid precursor proteins (beta-APPs), ubiquitin, diverse neuronal cytoskeletal proteins, and polypeptides located mainly in axon terminals. We obtained samples of hippocampus at autopsy from 14 PD patients, 10 of whom were demented. As in the AD hippocampus, the SPs detected by conventional stains in five of the 10 demented subjects contained the beta-AP and flanking domains in beta-APPs as well as epitopes in tau, neurofilament proteins, and synaptophysin. Further, with the exception of the beta-AP, epitopes in the other proteins were confined to the coronas of SPs, while clathrin light chain, microtubule-associated protein 5, and neural cell adhesion molecules were almost undetectable or absent in the neuropil occupied by SPs. The same group of antibodies rarely labeled SPs in the other five demented PD subjects or in the four nondemented PD subjects, and conventional stains for amyloid and neurofibrillary pathology revealed rare SPs in these cases. Hence, when conventional stains reveal lesions diagnostic of AD in PD patients, the molecular features of the hippocampal SPs in these patients are the same as those in SPs of the AD hippocampus.

Superficial temporal-middle cerebral artery anastomosis: effects on vascular, neurologic, and neuropsychological functions.

In 44 patients, we studied the effects of superficial temporal-middle cerebral artery anastomosis on cerebral blood flow (CBF), neurologic examination, and cognitive functions. At 3 months, there was significant improvement in all variables. At 9 months, CBF was no longer significantly greater, but neurologic examination and cognitive functions had further improved. Patients with TIA had significant postoperative decreases in TIA frequency and did not progress to stroke, but had no significant changes in any variable. In stroke patients, we could not separate the effects of surgery from the natural evolution of changes in CBF and examination after stroke. None of the preoperative measurements predicted postoperative clinical improvement.

A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease. Ropinirole Study Group.

OBJECTIVE: To evaluate the nonergot dopamine agonist ropinirole as an adjunct to L-dopa in a randomized, double-blind trial in PD patients with motor fluctuations. BACKGROUND: L-dopa in the treatment of PD is associated with motor fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists in the treatment of PD delays recourse to L-dopa and thus delays the possibility of adverse effect onset. METHODS: Ropinirole (n = 95) or placebo (n = 54) was added to L-dopa, and L-dopa was then reduced in a planned manner during the 6-month trial. RESULTS: A significantly greater number of ropinirole patients were able to achieve a 20% or greater reduction in both L-dopa dose and in percent time spent "off" compared with placebo (35.0% versus 13.0%; p = 0.003). The mean daily L-dopa dose was reduced significantly with ropinirole treatment (242 mg versus 51 mg; p < 0.001) as was the percent awake time spent "off" (11.7% versus 5.1%; p = 0.039). There was no difference in the percent of patients who withdrew because of adverse effects (15.8% on ropinirole versus 16.7% on placebo). CONCLUSIONS: Ropinirole permits a reduction in L-dopa dose with enhanced clinical benefit for PD patients with motor fluctuations.

Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease.

BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS: The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.

Multicenter, placebo-controlled trial of cabergoline taken once daily in the treatment of Parkinson's disease.

Cabergoline is a dopaminergic agonist relatively specific for the D2 receptor and much longer-acting than other dopamine agonists. We conducted a randomized, placebo-controlled, double-blind study of cabergoline in 188 levodopa/carbidopa-treated patients with suboptimally controlled Parkinson's disease (PD). The cabergoline patients had significantly better Activities of Daily Living (p = 0.032) and Motor Examination (p = 0.031) scores at the conclusion of the trial compared with the placebo group. The daily levodopa dose for the cabergoline patients decreased 18% compared with a 3% reduction for the placebo group (p < 0.001). The amount of time in the "on" state increased more in the cabergoline group (p = 0.022). The side-effect was similar to that seen with other dopamine agonists, and cabergoline was generally well tolerated. We conclude that cabergoline is an effective adjunct to levodopa for the treatment of PD.

Loss of dopamine D2 receptors in Alzheimer's disease with parkinsonism but not Parkinson's or Alzheimer's disease.

A significant proportion of patients with Alzheimer's disease (AD) exhibit extrapyramidal features that are referred to as parkinsonism (AD/Park) to distinguish the clinical and pathological features that differ from Parkinson's disease (PD). Previous results from this laboratory have shown that, although the presynaptic components of the dopamine (DA) system are markedly affected in AD/Park, the pathology is not similar to PD (Murray et al. 1995; Joyce et al. 1997). In the present study, we determined whether the parkinsonian symptoms in AD/Park might also reflect changes in numbers of postsynaptic DA receptors. We analyzed the binding of [125I]epidepride biding to DA D2/D3 receptors and [3H]SCH 23390 to D1 receptors by autoradiography in the striatum of six patients with PD, nine patients with AD, seven patients with AD/Park, and 14 neurologically intact control subjects. D2 receptors were reduced in the caudate and putamen of the AD/Park group (by 42 and 27% of controls, respectively) but not reduced in AD or PD. D1 receptors were elevated by 36% in the putamen of the PD group. Dopamine receptor changes are, therefore, not similar in PD, AD, and AD/Park. The elevation in D1 receptors in PD may contribute to the unwanted side effects of L-dopa treatment. The loss of D2 receptors in AD/Park, not observed in AD lacking overt parkinsonian symptomatology, may contribute to the presence of parkinsonian features and lack of responsiveness to L-dopa.