Enfermedad de Pick: un análisis clínico acerca de su etiología / Pick's disease: a clinical analysis regarding its etiology

Antecedentes: El curso clínico de la enfermedad de Pick (EP) es similar a la enfermedad de Alzheimer (EA). Casos clínicos: Presentamos el curso clínico y los hallazgos tomográficos en 3 pacientes (dos casos esporádicos y un caso familiar) con diagnóstico de EP. Resultados: El curso de esta enfermedad estuvo caracterizado por: 1) cambios de conducta y personalidad, 2) deterioro progresivo de la memoria reciente, 3) disturbios sexuales y/o aumento del apetito, 4) disfunción cortical superior, 5) empeoramiento motor, sensitivo y esfinteriano, y 6) deterioro de la postura, marcha y postración. Los estudios tomográficos demostraron aterosclerosis en las carótidas supraclínoideas y sus ramas, así como atrofia moderada o severa en los lóbulos prefrontales y temporales anteriores. Conclusiones: Estos hallazgos sugieren que la EP es también causada por isquemia progresiva en el territorio intraparenquimal de las arterias perforantes anteriores, coroideas anteriores y lentículo-estriadas, debido a placas ateroscleróticas localizadas en las bocas de estas ramas arteriales.

Background: The clinical course of Pick´s disease (PD) is similar to that of Alzheimer´s disease (AD). Clinical cases: We present the clinical course and CT-scan findings in 3 patients (two sporadic cases and one familial case) diagnosed with PD. Results: The course of this disease was characterized by the following: 1) behavioral and personality changes; 2) progressive impairment of recent memory; 3) sex disturbances and/or appetite incr ease; 4) upper cortex dysfunction; 5) motor, sensorial and sphincter control worsening, and 6) posture and gait impairment, as well as prostration. Brain tomography studies demonstrated atherosclerosis at the supraclinoid segment of carotid arteries and its branches, and also moderate or severe atrophy in both prefrontal and anterior temporal lobes. Conclusions: These findings suggest that PD is also caused by progressive ischemia in the intra-par enchymal territory of the anterior perforating, anterior choroidal, and lenticulostriate arteries; due to atherosclerotic plaques located at the origin of these arterial branches.

Impaired action knowledge in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system, but recent work also shows more widespread cognitive impairment. This study examined performance on measures requiring knowledge of actions, and related performance to MRI cortical atrophy in ALS. METHODS: A total of 34 patients with ALS performed measures requiring word-description matching and associativity judgments with actions and objects. Voxel-based morphometry was used to relate these measures to cortical atrophy using high resolution structural MRI. RESULTS: Patients with ALS were significantly more impaired on measures requiring knowledge of actions than measures requiring knowledge of objects. Difficulty on measures requiring action knowledge correlated with cortical atrophy in motor cortex, implicating degraded knowledge of action features represented in motor cortex of patients with ALS. Performance on measures requiring object knowledge did not correlate with motor cortex atrophy. Several areas correlated with difficulty for both actions and objects, implicating these brain areas in components of semantic memory that are not dedicated to a specific category of knowledge. CONCLUSION: Patients with amyotrophic lateral sclerosis are impaired on measures involving action knowledge, and this appears to be due to at least two sources of impairment: degradation of knowledge about action features represented in motor cortex and impairment on multicategory cognitive components contributing more generally to semantic memory.

Carotid atherosclerosis is associated with brain atrophy in Japanese elders.

BACKGROUND: The relation between atherosclerosis and brain atrophy remains unclear in patients with risk factors for cardiovascular diseases. OBJECTIVE: This study was performed to clarify the relation between brain atrophy and carotid atherosclerosis. METHODS: A total of 142 patients (78 women and 64 men, mean age 74 years) with no neurologic disturbances were studied. Brain atrophy was evaluated on the basis of the brain atrophy index (BAI, BAI = brain parenchyma/intracranial space A 100%), calculated by means of digitized computed tomographic scans obtained at the level of the basal ganglia. Carotid atherosclerosis was evaluated on the basis of the plaque score (PS), defined as the sum of all plaque heights in both carotid arteries, intima-media thickness (IMT), and vessel diameter (VD) of the common carotid artery as assessed by ultrasonography. RESULTS: Age negatively correlated with BAI in both men (r = -0.587, p < 0.001) and women (r = -0.724, p < 0.001). PS of the carotid artery also negatively correlated with BAI in men (r = -0.502, p < 0.001) as well as women (r = -0.480, p < 0.001). VD and IMT of the right carotid artery negatively correlated with BAI in women (VD; -0.256, p < 0.05, IMT; -0.216, p < 0.05) but not in men. Other characteristics were unrelated to BAI. Multiple regression analysis showed that age and PS were independent predictors of brain atrophy in both sexes. The percentage of variance of BAI values explained by this model in women (51.9%) was much greater than that in men (35.5%). CONCLUSION: Carotid atherosclerosis may be a useful morphological index of brain atrophy.

Saitohin, which is nested in the tau locus and confers allele-specific susceptibility to several neurodegenerative diseases, interacts with peroxiredoxin 6.

Saitohin is a gene unique to humans and their closest relatives, the function of which is not yet known. Saitohin contains a single polymorphism (Q7R), and its Q and R alleles belong to the H1 and H2 tau haplotype, respectively. The Saitohin Q allele confers susceptibility to several neurodegenerative diseases. To get a handle on Saitohin function, we used it as a bait in a yeast two-hybrid screen. By this assay and subsequent co-immunoprecipitation and glutathione S-transferase pull-down assays, we discovered and confirmed that Saitohin interacts with peroxiredoxin 6, a unique member of that family that is bifunctional and the levels of which increase in Pick disease. The strength of the interaction appeared to be allele-specific, giving the first distinction between the two forms of Saitohin.

Tau protein and neurodegeneration.

Tau protein is the major component of the intracellular filamentous deposits that define a number of neurodegenerative diseases. They include the largely sporadic Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), argyrophilic grain disease, as well as the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The identification of mutations in Tau as the cause of FTDP-17 established that dysfunction or misregulation of tau protein is sufficient to cause neurodegeneration and dementia. At an experimental level, the new understanding is leading to the development of good transgenic animal models of the tauopathies.

Severity of gliosis in Pick's disease and frontotemporal lobar degeneration: tau-positive glia differentiate these disorders.

Frontotemporal dementia is a term used to characterize diverse neuropathological conditions that can present with the same clinical phenotype. Five different neuropathologies underlie this disorder. However, consistent frontal and/or temporal neuronal loss and gliosis characterize all cases, the majority having no obvious pathological inclusions. Because neuronal loss and gliosis are consistent features across all cases, the present study aimed to determine the relationship between neuronal loss, gliosis and, for cases with abnormal tau inclusions, intracellular tau deposition. Formalin-fixed brain specimens from sporadic cases with frontotemporal dementia (eight with tau-positive Pick bodies, five with frontotemporal lobar degeneration without inclusions) were compared with those from non-diseased controls (n = 5). Brain specimens were cut into 3 mm coronal slices for evaluation and tissue samples from the superior frontal gyrus were taken for microscopic analysis. Immuno histochemistry for glia-specific proteins (astrocytic glial fibrillary acidic protein and microglial major histocompatibility complex II) and different tau epitopes was performed on 50 microm free-floating sections. Gross patterns of brain atrophy were analysed and upper and lower layer pyramidal neurons and glial cell numbers were quantified. A disease severity scheme was devised using the degree of gross macroscopic frontal and temporal atrophy to establish the relationship between the gliosis and neurodegeneration. In this small sample, the patterns of gross atrophy could be grouped reliably into four stages of severity. These stages were the same across disease groups and correlated with volume- corrected pyramidal neuron densities. In cases with Pick bodies, disease stage also correlated with duration, providing further evidence that these stages represent the progression of degeneration in this limited sample. Whereas there were, on average, many more reactive astrocytes in the cases with Pick bodies than in those with frontotemporal lobar atrophy, there was significant overlap between cases in the degree of astrocytosis. However, a large proportion of the astrocytes in Pick's disease displayed phosphorylated tau immunoreactivity, whereas no tau-positive astrocytes were found in frontotemporal lobar degeneration. The pattern and degree of microglia activation were similar in all the dementia cases analysed, with considerably more activated microglia accumulating in white matter. In this small sample, the abundance of white matter microglia at early disease stages suggests a prominent role for this cell type in the neurodegenerative process. In frontotemporal lobar degeneration, a significant proportion of the activated white matter microglia were tau-2-immunoreactive, suggesting direct involvement in axonal degeneration, possibly via immune processes.

Therapy and management of frontal lobe dementia patients.

Patients with frontal lobe dementia (FLD) include those who suffer from Pick's disease, corticobasal degeneration, FLD without specific histopathologic features, as well as the infrequent families with frontotemporal dementia and parkinsonism associated with chromosome 17. Currently there have been no systematic efforts to manage and to treat patients with FLD. Drawing on the accumulated experience of clinicians and the known therapeutic approaches for patients with other neurodegenerative disorders such as AD and PD, the author discusses possible neurotransmitter replacement and biologic therapeutic approaches for patients with FLD.