Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations

Paisán-Ruı́z, Coro; Li, Abi; Schneider, Susanne A.; Holton, Janice L.; Johnson, Robert M.; Kidd, Desmond P.; Chataway, Jeremy; Bhatia, Kailash P.; Lees, Andrew J.; Hardy, John; Révész, Tamás; Houlden, Henry

doi:10.1016/j.neurobiolaging.2010.05.009

Cited by 181 publications

(188 citation statements)

References 31 publications

(18 reference statements)

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“…In line with early clinical and imaging signs of cerebellar involvement, variable depletion of cerebellar cortical neurons (granular cells more than Purkinje cells) accompanied by marked astrocytosis was present [99]. Accumulation of hyperphosphorylated tau in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles, corresponding to Braak and Braak stage 5, has also been observed, again in contrast to PKAN [99]. Milder phenotypes in late-onset disease tended to show less tau involvement [106,107].…”

Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 74%

“…Notably, the signal abnormality differs from the "eye of the tiger" sign of PKAN in that there is no central hyperintensity. Iron deposits in the SN are present in some atypical cases [98,99]. Contrary to PKAN, iron accumulation is not a universal feature of PLAN.…”

Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 94%

“…Changes were particularly severe in the neocortex, corresponding to Braak stage 6 of the "diffuse neocortical type" of idiopathic PD [99]. In line with early clinical and imaging signs of cerebellar involvement, variable depletion of cerebellar cortical neurons (granular cells more than Purkinje cells) accompanied by marked astrocytosis was present [99]. Accumulation of hyperphosphorylated tau in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles, corresponding to Braak and Braak stage 5, has also been observed, again in contrast to PKAN [99].…”

Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 99%

“…the pyramidal, spinocerebellar, spinothalamic, and the gracile and cuneate fasciculi. In recent studies in both gene-proven mouse models [100] and human brains [99,105] widespread alpha-synuclein-positive Lewy pathology has been identified strengthening the link of PLA2G6 to idiopathic PD. Changes were particularly severe in the neocortex, corresponding to Braak stage 6 of the "diffuse neocortical type" of idiopathic PD [99].…”

Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 99%

“…In recent studies in both gene-proven mouse models [100] and human brains [99,105] widespread alpha-synuclein-positive Lewy pathology has been identified strengthening the link of PLA2G6 to idiopathic PD. Changes were particularly severe in the neocortex, corresponding to Braak stage 6 of the "diffuse neocortical type" of idiopathic PD [99]. In line with early clinical and imaging signs of cerebellar involvement, variable depletion of cerebellar cortical neurons (granular cells more than Purkinje cells) accompanied by marked astrocytosis was present [99].…”

Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 99%

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Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Schneider

Dušek²,

Hardy³

et al. 2013

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Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age-dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic.Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes.

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Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 74%

Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 94%

Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 99%

Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 99%

Section: Nbia Type 2 -Pla2g6-associated Neuro-degeneration (Plan)mentioning

confidence: 99%

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Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Schneider

Dušek²,

Hardy³

et al. 2013

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Parkin Disease

et al. 2013

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Importance Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. Objective To investigate whether parkin -linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). Design, Setting, and Participants We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. Results Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). Conclusions and Relevance These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.

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