Neuropathological lesions in the very old: results from a large Brazilian autopsy study.

OBJECTIVE: To compare neuropathological correlates of cognitive impairment between very old and younger individuals from a Brazilian clinicopathological study. METHODS: We assessed the frequency of neuropathological lesions and their association with cognitive impairment (Clinical Dementia Rating scale ≥0.5) in the 80 or over age group compared to younger participants, using logistic regression models adjusted for sex, race and education. RESULTS: Except for infarcts and siderocalcinosis, all neuropathological lesions were more common in the 80 or over age group (n = 412) compared to 50-79 year olds (n = 677). Very old participants had more than twice the likelihood of having ≥2 neuropathological diagnoses than younger participants (OR = 2.66, 95% CI = 2.03-3.50). Neurofibrillary tangles, infarcts and hyaline arteriolosclerosis were associated with cognitive impairment in the two age groups. Siderocalcinosis was associated with cognitive impairment in the younger participants only, while Lewy body disease was associated with cognitive impairment in the very old only. In addition, we found that the association of infarcts and multiple pathologies with cognitive impairment was attenuated in very old adults (Infarcts: P for interaction = 0.04; and multiple pathologies: P = 0.05). However, the predictive value for the aggregate model with all neuropathological lesions showed similar discrimination in both age groups [Area under Receiver Operating Characteristic curve (AUROC) = 0.778 in younger participants and AUROC = 0.765 in the very old]. CONCLUSION AND RELEVANCE: Despite a higher frequency of neuropathological findings in the very old group, as found in studies with high-income populations, we found attenuation of the effect of infarcts rather than neurofibrillary tangles and plaques as reported previously.

The center of olfactory bulb-seeded α-synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice.

At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α-synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α-synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α-synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex-one of the earliest and most frequently affected brain regions in Lewy body disorders-in 3-month-old female and male mice and in 11-month-old male mice. After 6 months, we observed that α-synucleinopathy did not expand significantly beyond the limbic connectome in the 9-month-old male and female mice or in the 17-month-old male mice. However, the 9-month-old male mice had developed greater α-synucleinopathy, smell impairment and cell loss than age-matched females. By 10.5 months post-infusion, fibril treatment hastened mortality in the 21.5-month-old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post-infusion, this was not attributable to true cell death. Furthermore, mesencephalic α-synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson's disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α-synucleinopathy.

Propagation of alpha-synuclein pathology from the olfactory bulb: possible role in the pathogenesis of dementia with Lewy bodies.

Olfactory limbic structures, like the amygdala, the entorhinal, and the piriform cortices, are closely involved in cognitive processes. Thus, besides olfactory dysfunctions, it is conceivable that the compromise of these structures can lead to cognitive impairment. The olfactory bulb is affected by alpha-synuclein pathology in almost all cases of both Parkinson's disease and dementia with Lewy bodies. The clinical distinction between these disorders relies on the timing in the appearance of dementia in relationship to motor symptoms. Typically, it occurs late in the course of Parkinson's disease, and within the first year in dementia with Lewy bodies. The close anatomical proximity of the olfactory bulb with limbic regions, together with the early occurrence of cognitive impairment that is observed in dementia with Lewy bodies, raise the question whether the propagation of alpha-synuclein pathology in this condition might originate in the olfactory bulb, spreading from there to other limbic structures, and thereby reaching the associative neocortex. This review will describe the anatomical basis of the olfactory system and discuss the evidence of potential spreading pathways from the olfactory bulb that could support the presence of early dementia in the setting of Lewy body disorders.

Actualización en enfermedad con cuerpos de Lewy / Update in Lewy body disease

La enfermedad con cuerpos de Lewy incluye 2 entidades que podrían ser consideradas variantes clínicas de una misma patología: la demencia con cuerpos de Lewy y la demencia en enfermedad de Parkinson. Con la finalidad de describir correctamente lo que sucede en la evolución de la enfermedad se divide el cuadro en etapa prodrómica y de demencia propiamente dicha. La primera está clínicamente representada por aquel período en el cual, si bien el paciente exhibe algunos signos y síntomas propios de la enfermedad, no reúne criterios de demencia. A pesar de ser difícil de definir y por carecerse todavía de contundentes datos clínicos y biomarcadores, se caracteriza principalmente por deterioro leve selectivo en función atencional ­ visuoespacial, trastorno del sueño REM y disautonomía‒. La segunda etapa está claramente caracterizada en los criterios de consenso del año 2005. Recientemente hemos publicado la validación de un instrumento llamado ALBA Screening Instrument, que permite diagnosticar con alta sensibilidad y especificidad la enfermedad aun en etapas tempranas y diferenciarla de otras patologías semejantes. La tomografía por emisión de positrones (PET) para transportador de dopamina es el procedimiento de referencia (gold standard) del diagnóstico. El tratamiento sintomático con anticolinesterásicos y neurolépticos atípicos favorece una buena evolución de la enfermedad y es fundamental tener en cuenta evitar medicamentos que pueden dañar gravemente a los pacientes como los anticolinérgicos y antipsicóticos típicos. Los avances en el diagnóstico y la difusión del impacto de esta enfermedad en la población contribuirán a generar mayores esfuerzos de investigación para hallar un tratamiento eficaz, preventivo o curativo o de ambas características. (AU)

Lewy body disease includes 2 entities that could be considered clinical variants of the same pathology: Dementia with Lewy bodies and Parkinson's disease Dementia. Two stages of the disease are described in this review, a prodromal stage and one of explicit dementia. The first one is clinically represented by that period in which, the patient exhibits some typical features of the disease, but not dementia criteria. Despite being difficult to define the prodromal stage and that strong clinical data and biomarkers are still lacking, there is evidence to characterize it mainly by mild selective impairment in attention and visuo-spatial function, REM sleep disorder and dysautonomia. The second stage is clearly characterized in the known consensus criteria of 2005. We have recently published the validation of an instrument called ALBA Screening Instrument which showed a high sensitivity and specificity for diagnosis of the disease even in the early stages. It´s useful to differentiate the disease from other similar pathologies. Positron Emission Tomography for dopamine transporter is the gold standard of diagnosis in life. Symptomatic treatment with anticholinesterases and atypical neuroleptics help patients in their evolution of the disease. Anticholinergics and typical antipsychotics are agents to avoid in the treatmen of the disease because can severely damage patients. Future advances in the diagnosis and dissemination of the knowledge of the disease will contribute to generate greater research efforts to find an effective preventive and / or curative treatment. (AU)

Pathological correlates of gastrointestinal dysfunction in Parkinson's disease.

Gastrointestinal dysfunction is a prominent manifestation of Parkinson's disease (PD). Gastrointestinal symptoms in PD include reduced salivation, dysphagia, impaired gastric emptying, constipation, and defecatory dysfunction. Constipation may precede the development of somatic motor symptoms of PD for several years. Neuropathological studies show early accumulation of abnormal alpha-synuclein (α-SYN) containing inclusions (Lewy neurites) in the enteric nervous system (ENS) and dorsal motor nucleus of the vagus (DMV) both in PD and in incidental Lewy body disease (ILBD). These findings provided the basis for the hypothesis that α-SYN pathology progresses in a centripetal, prion-like fashion, from the ENS to the DMV and then to more rostral areas of the central nervous system. Colonic biopsies may show accumulation α-SYN immunoreactive Lewy neurites in the submucosal plexus of PD patients. Salivary gland involvement is prominent in PD and α-SYN pathology can be detected both at autopsy and in minor salivary gland biopsies.

[Diagnostic value of cardiac 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy in Lewy body disorders]. / Valor diagnóstico de la gammagrafía cardíaca con 123I-metaiodobenzilguanidina en las enfermedades con cuerpos de Lewy.

INTRODUCTION: Lewy body disorders such as Parkinson's disease (PD) and Lewy body dementia (LBD) are associated with cardiac sympathetic denervation, which can be visualized on 123I-MIBG scintigraphy. Our objectives were to study the diagnostic value of this technique in Lewy body disorders and its relationship with PD clinical variables. PATIENTS AND METHODS: We studied 90 patients: 51 with PD, 19 with LBD, 9 with multiple system atrophy (MSA) and 11 controls. Scintigraphy images were qualitatively evaluated and early and delayed heart-to-mediastinum ratios (HMR) were calculated. The main confounding factors (ischemic heart disease, diabetes, hypertension and drugs) were controlled by multivariate linear regression analysis. We investigated correlations between scintigraphy variables and PD variables. RESULTS: The delayed HMR, which showed better discriminative ability was 2.03 +/- 0.32 in controls, 1.37 +/- 0.30 in PD (p<0.001 vs controls), 1.47+/-0.45 in LBD (p=0.001 vs controls) and 1.69+/-0.28 in MSA (p=0.02 vs controls; p=0.004 vs PD). This ratio was influenced by PD/LBD diagnosis (beta= -0.638; p<0.001) and to a lesser degree, by ischemic heart disease (beta= -0.244; p=0.028). Optimal cut-off value between PD/LBD and controls was 1.71 (83% sensitivity and 82% specificity). Within the PD group, those with a family history of PD/LB showed higher delayed HMR values (1.65+/-0.34 vs 1.30+/-0.24 without history; p<0.001) and proportion with normal scintigraphy (56% vs 5%; p=0.001). CONCLUSIONS: Cardiac 123I-MIBG scintigraphy is useful in the diagnosis of Lewy body disorders, although its value in PD is conditioned by having a family history of PD.

Demencia con cuerpos de Lewy: presentación de 1 caso / Dementia with Lewy bodies: a case report

Se ha planteado que la demencia constituye la cuarta causa básica de muerte en países del primer mundo. La demencia con cuerpos de Lewy (DCL) constituye la segunda causa de demencia en estudios necrópsicos actuales, superada solo por la enfermedad de Alzheimer. Se reportó el primer caso cubano de demencia con cuerpos de Lewy, una paciente femenina de 89 años de edad, de la raza blanca, con diagnóstico clínico de demencia, que falleció luego de 5 años de deterioro progresivo. En el estudio neuropatológico se evidenció con la técnica de hematoxilina / eosina la presencia de cuerpos de Lewy al nivel de la sustancia negra, locus cerúleo y corteza transentorrinal, la patología neurofibrilar valorada con la técnica de Bielschowsky se correspondió con un estadio II de Braak. Se identificó además cambio espongiforme focal al nivel del hipocampo. Se hizo el diagnóstico de DCL variedad a predominio del tallo cerebral. Se revisó la literatura y los principales diagnósticos diferenciales(AU)

Demencia con cuerpos de Lewy: presentación de 1 caso / Dementia with Lewy bodies: a case report

Se ha planteado que la demencia constituye la cuarta causa básica de muerte en países del primer mundo. La demencia con cuerpos de Lewy (DCL) constituye la segunda causa de demencia en estudios necrópsicos actuales, superada solo por la enfermedad de Alzheimer. Se reportó el primer caso cubano de demencia con cuerpos de Lewy, una paciente femenina de 89 años de edad, de la raza blanca, con diagnóstico clínico de demencia, que falleció luego de 5 años de deterioro progresivo. En el estudio neuropatológico se evidenció con la técnica de hematoxilina / eosina la presencia de cuerpos de Lewy al nivel de la sustancia negra, locus cerúleo y corteza transentorrinal, la patología neurofibrilar valorada con la técnica de Bielschowsky se correspondió con un estadio II de Braak. Se identificó además cambio espongiforme focal al nivel del hipocampo. Se hizo el diagnóstico de DCL variedad a predominio del tallo cerebral. Se revisó la literatura y los principales diagnósticos diferenciales

[Dementia with Lewy bodies. A description of a case with a genetic variant]. / Demencia con cuerpos de Lewy. Presentación de un caso con variante genética.

INTRODUCTION: Dementia with Lewy bodies represents the third cause of dementia in the clinicopathological series reported to date. CASE REPORT: A 79-year-old white female with a 3-year history of symptoms of dementia, Parkinsonism and visual hallucinations; the symptoms were difficult to control with medication and there was a family history of similar clinical pictures of dementia in the paternal grandfather, an aunt on the father's side and six siblings. A genetic study was not possible. The study thus involves a patient with relatives that may have had the pure or mixed variant of these dementias, without the DNA study for determining the e4 allele of the gene for apolipoprotein E that has been found most frequently in dementia due to Alzheimer.

Nightmares without atonia as an early symptom of diffuse Lewy bodies disease

A male 70 years old patient with diffuse or ''pure'' Lewy body disease is described. The diagnosis was made based on clinical features of nightmares with no atonia, attention deficits with fluctuation in cognitive function, incapacity to find his way around the neighbourhood and other formerly familiar environments and mild neuropsychiatric symptoms. Neuropsychological assessment showed memory deficits, visuospatial and visuo-constructive disturbances. He had neither parkinsonism nor recurrent visual hallucinations typically well formed and detailled. Neuroimaging (computed tomography and magnetic resonance spectroscopy) showed mild diffuse cortical atrophy, mostly on the left temporal lobe and a decrease of N-acetil-aspartate levels. A cholinesterase inhibitor was prescribed to this patient during 6 months with clinically relevant behavioral effect. Diagnosis confirmation was made by post-mortem neuropathological findings. Macroscopical features were mild atrophy on the frontal, parietal and temporal lobes, notedly on the frontal lobes. Microscopically, there was neuronal loss and diffuse classic Lewy bodies. Brainstem (substantia nigra, raphe nucleus, locus coeruleus, pedunculopontine nucleus), limbic cortex, and neocortex (frontal, parietal and temporal) were the areas of predilection for Lewy bodies. Hematoxylin-eosin and Bielschowsky staining did not show neuronal swelling (balooned cell), argyrophilic inclusion (Pick's bodies), neurofibrillary tangles nor senile plaques. Immunohistochemical staining for anti-tau, anti-beta-amyloid, and anti-prion protein were negative. Antiubiquitine reaction was positive for Lewy body in the cerebral cortex and brainstem

Nightmares without atonia as an early symptom of diffuse Lewy bodies disease.

A male 70 years old patient with diffuse or "pure" Lewy body disease is described. The diagnosis was made based on clinical features of nightmares with no atonia, attention deficits with fluctuation in cognitive function, incapacity to find his way around the neighbourhood and other formerly familiar environments and mild neuropsychiatric symptoms. Neuropsychological assessment showed memory deficits, visuospatial and visuo-constructive disturbances. He had neither parkinsonism nor recurrent visual hallucinations typically well formed and detailed. Neuroimaging (computed tomography and magnetic resonance spectroscopy) showed mild diffuse cortical atrophy, mostly on the left temporal lobe and a decrease of N-acetyl-aspartate levels. A cholinesterase inhibitor was prescribed to this patient during 6 months with clinically relevant behavioral effect. Diagnosis confirmation was made by post-mortem neuropathological findings. Macroscopical features were mild atrophy on the frontal, parietal and temporal lobes, notedly on the frontal lobes. Microscopically, there was neuronal loss and diffuse classic Lewy bodies. Brainstem (substantia nigra, raphe nucleus, locus coeruleus, pedunculopontine nucleus), limbic cortex, and neocortex (frontal, parietal and temporal) were the areas of predilection for Lewy bodies. Hematoxylin-eosin and Bielschowsky staining did not show neuronal swelling (ballooned cell), argyrophilic inclusion (Pick's bodies), neurofibrillary tangles nor senile plaques. Immunohistochemical staining for anti-tau, anti-beta-amyloid, and anti-prion protein were negative. Antiubiquitine reaction was positive for Lewy body in the cerebral cortex and brainstem.