María Jesús Rey

Neuropathology and Pathogenesis of Encephalitis following Amyloid β Immunization in Alzheimer's Disease

Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop β‐amyloid deposition resembling plaques in Alzheimers disease (AD), results in a decrease of amyloid burden when compared with non treated transgenic animals im‐munization with amyloid β peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of menigoencephalitis following immunization with amyloid‐β peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation‐ with amyliod deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense(collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Aβ42and Aβ40, in addition to severe small cerebral blood Reduced amyloid burden was accompanied by low amyloid‐associated oxidative stress responses (reduced superoxide dismutase‐1:SOD‐1 expression) and by local inhibition of the stress‐activated protein kinase/c‐Jun N‐terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau in neurofibrillary tangles and β‐amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28α/β inductor, and of LMP7, LMP2 and MECL1 subunits of the immunopro‐teasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells.Immunoproteasome subunit expression was accompanied by local presentation of MHC class molecules. Release of antigenic peptides derived from β‐amyloid processing may enhance T‐cell inflammatory responses accounting for the meningoencephalitis following amyloid‐β peptide immunization

Multiple organ involvement by alpha‐synuclein pathology in Lewy body disorders

Lewy body (LB) diseases are characterized by alpha‐synuclein (AS) aggregates in the central nervous system (CNS). Involvement of the peripheral autonomic nervous system (pANS) is increasingly recognized, although less studied. The aim of this study was to systematically analyze the distribution and severity of AS pathology in the CNS and pANS. Detailed postmortem histopathological study of brain and peripheral tissues from 28 brain bank donors (10 with Parkinsons disease [PD], 5 with dementia with LB [DLB], and 13 with non‐LB diseases including atypical parkinsonism and non‐LB dementia). AS aggregates were found in the pANS of all 15 LB disease cases (PD, DLB) in stellate and sympathetic ganglia (100%), vagus nerve (86.7%), gastrointestinal tract (86.7%), adrenal gland and/or surrounding fat (53.3%), heart (100%), and genitourinary tract (13.3%), as well as in 1 case of incidental Lewy body disease (iLBD). A craniocaudal gradient of AS burden in sympathetic chain and gastrointestinal tract was observed. DLB cases showed higher amounts of CNS AS aggregates than PD cases, but this was not the case in the pANS. No pANS AS aggregates were detected in Alzheimers disease (AD) cases with or without CNS AS aggregates. All pathologically confirmed LB disease cases including 1 case of iLBD had AS aggregates in the pANS with a craniocaudal gradient of pathology burden in sympathetic chain and gastrointestinal tract. AS was not detected in the pANS of any AD case. These findings may help in the search of peripheral AS aggregates in vivo for the early diagnosis of PD.

G2019S LRRK2 mutation causing Parkinson’s disease without Lewy bodies

The G2019S leucine-rich repeat kinase 2 gene (LRRK2) mutation has been identified in a significant proportion of familial and sporadic cases of Parkinson’s disease (PD). Until now, information on the neuropathological changes associated with the G2019S LRRK2 mutation has been sparse. We report a 77-year-old patient who presented with a 14 year history of PD but, unexpectedly, histopathological examination disclosed mild neuronal loss in the substantia nigra without α-synuclein, tau or ubiquitin cytoplasmic inclusions. A G2019S LRRK2 mutation was eventually detected. The present case confirms that clinical PD caused by G2019S mutations can be associated with non-specific nigral degeneration without Lewy bodies.

Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation

I. Ferrer, P. Pastor, M. J. Rey, E. Muñoz, B. Puig, E. Pastor, R. Oliva and E. Tolosa (2003) Neuropathology and Applied Neurobiology 29, 23–34 
Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation

Rapidly progressive diffuse Lewy body disease

Lewy body syndromes (mainly Parkinsons disease and dementia with Lewy bodies) share many clinical features and usually have a slowly progressive course. Some patients may show rapid symptoms progression.

Clinicopathological and genetic correlates of frontotemporal lobar degeneration and corticobasal degeneration

ObjectiveTo correlate clinical diagnosis and genetic features with different pathological substrates in patients with frontotemporal lobar degeneration (FTLD) and corticobasal degeneration (CBD).Methods32 cases with pathological proven FTLD or CBD were selected. Patients were classified clinically as frontotemporal dementia (FTD), progressive nonfluent aphasia (PNFA), semantic dementia (SD), CBD or FLTD with motor neuron disease (FLTDMND). Coding exons 1 and 9–13 of MAPT and exons 0–12 of the PGRN gene were screened by direct sequencing. Regarding the neuropathological findings, cases were classified as tau-positive, ubiquitinpositive tau-negative (FTLD-U), neuronal intermediate filaments inclusions disease (NIFID), dementia lacking distinctive histology (DLDH) or CBD.Results17 patients were clinically diagnosed with FTD. Ten showed tau pathology, 3 FTLD-U, 1 NIFID and 3 DLDH. All patients clinically classified as FTLD-MND (6 patients) or SD (3 patients) were FTLD-U. Tau-positive pathology was the substrate of the three patients with PNFA. All three patients classified clinically as CBD presented neuropathologic features of CBD. The three individuals with familial history of early onset FTD and tau-positive pathology carried the P301L mutation in the MAPT gene. One out of 3 cases with FTLD-U and intranuclear inclusions carried a mutation in the PGRN gene.ConclusionsWe found that pathology underlying sporadic FTD is heterogeneous and not predictable. MAPT mutations and clinical diagnosis of PNFA and CBD were associated with tau-positive pathology. The presence of signs of lower MND and SD correlated with FTLD-U.A genetic study of MAPT is only recommended when familial history of early onset DFT is present.

Genetic cross-interaction between apoe and prnp in sporadic alzheimer's and creutzfeldt-jakob diseases

Alzheimers disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD.

Presynaptic parkinsonism in multiple system atrophy mimicking Parkinson's disease: A clinicopathological case study

We describe the clinicopathological findings in a patient aged 63 years at death who, at age 55 years, developed levodopa‐responsive parkinsonism with no atypical features. A diagnosis of idiopathic Parkinsons disease (PD) was made. During the clinical course, fluctuations and dyskinesias appeared. Eight years after onset, he was successfully treated with subthalamic nucleus stimulation but died 3 weeks postoperatively from pulmonary embolus. Brain autopsy showed marked neuronal loss and gliosis in the substantia nigra and locus coeruleus, and, to a much lesser extent, in the basis pontis, inferior olivary nuclei, and cerebellar cortex. Striatum was normal. There were numerous oligodendroglial and neuronal cytoplasmic inclusions and neuropil threads, the highest density being localized in the pons and cerebellar white matter. No Lewy bodies were observed. We conclude that nigral, presynaptic parkinsonism may occur in multiple system atrophy, which even in the long run can be indistinguishable from PD. Putaminal preservation accounts for good response to both levodopa therapy and subthalamic nucleus stimulation.

Screening for the LRRK2 G2019S and codon-1441 mutations in a pathological series of parkinsonian syndromes and frontotemporal lobar degeneration

BACKGROUND The neuropathology associated with LRRK2 mutations is heterogeneous but Lewy body (LB) type pathology is the most common substrate encountered. While the prevalence of LRRK2 mutations has been extensively studied in Parkinsons disease (PD), limited information is available on the frequency of LRRK2 mutations in dementia with Lewy bodies (DLB) and in other pathological conditions associated with these mutations, such as non-specific nigral degeneration without LB, tau-immunopositive neurofibrillary tangle pathology, and ubiquitin-positive neuronal inclusions resembling those observed in a subtype of frontotemporal lobar degeneration (FTLD-U). OBJECTIVE To further investigate the neuropathology associated with LRRK2 mutations. METHODS We have screened for the LRRK2 G2019S and codon-1441 (R1441G/C/H) mutations in 110 cases from a Spanish Brain Bank, which include: 66 synucleinopathies (33 PD, 25 DLB and 8 multiple system atrophy cases), 29 tauopathies (21 progressive supranuclear palsy, 3 corticobasal degeneration and 5 tau-positive FTLD cases), 3 cases of non-specific nigral degeneration and 12 tau-negative FTLD (9 FTLD-U and 3 dementia lacking distinctive histology cases). RESULTS The G2019S mutation was found in two cases: One case had a clinical and pathological diagnosis of PD and the other suffered from typical PD and on neuropathological examination had non-specific nigral degeneration without LB. A synonymous variant (R1441R; c.4323C>T) was detected in another PD case. CONCLUSIONS In this brain bank-based series, LRRK2 G2019S mutation occurred in patients with parkinsonism associated with either typical brainstem LB pathology or non-specific nigral degeneration. LRRK2 mutations were not encountered in other neurodegenerative disorders associated with synuclein and tau deposition.

Clinical and Pathological Heterogeneity of Neuronal Intermediate Filament Inclusion Disease

OBJECTIVE To report new cases of neuronal intermediate filament inclusion disease (NIFID). DESIGN Case report. PATIENTS Pathologically proved NIFID was found in 2 patients from the Universitat de Barcelona-Hospital Clínic Brain Bank. The findings of a neuropathological examination in both patients revealed intracellular inclusions that were detected with hematoxylin-eosin and stained positive for antineurofilament and alpha-internexin antibodies, variably for ubiquitin, and negatively for tau, alpha-synuclein, and TAR-DNA binding protein 43. INTERVENTIONS Medical records were retrospectively reviewed. RESULTS The first patient developed progressive behavioral changes characterized by apathy and indifference at the age of 37 years, and frontotemporal dementia was diagnosed. The second patient developed progressive tremor and mild speech disturbances at the age of 70 years. Her neurological examination results showed mild dysarthria, hypomimia, a mild rigid-akinetic left-predominant parkinsonism, and bilateral rest and postural tremor. The clinical impression was atypical parkinsonism. No response was obtained with levodopa, and the disease progressed rapidly, with falls and frontal-subcortical cognitive impairment. CONCLUSIONS Late-onset presentation may be the clinical debut of NIFID. These 2 cases confirm the clinical and pathological heterogeneity of NIFID and suggest its inclusion in the differential diagnosis of several neurodegenerative disorders, including frontotemporal dementia and atypical parkinsonism.