PARK6-LINKED AUTOSOMAL RECESSIVE EARLY-ONSET PARKINSON’S DISEASE

Two studies in the October 26 Neurology examined the role of PARK6 genes in autosomal recessive early-onset Parkinson’s disease (AR-EOPD). Although the clinical features of PARK6-linked AR-EOPD are similar to those of PARK2- and PARK7-linked AR-EOPD, those with PARK6-linked AR-EOPD usually lack dystonia at onset. While previous studies have identified the PARK6 locus in several European families, the current studies assessed its prevalence in Irish and Asian populations.

In the first study, conducted by Hatano et al, eight families—three Japanese, two Taiwanese, one Turkish, one Israeli, and one Filipino—showed linkage to PARK6. After performing linkage analysis in 84 individuals without parkin or DJ-1 mutations, the researchers found that five of the eight families showed linkage with PARK6 as homozygous, while the other three showed linkage as heterozygous—these individuals shared the same haplotypes with siblings. They also found that, as has been previously reported in European families with PARK6 linkage, three families showed slow progression, lack of dystonia at onset, and sleep benefit.

So far, several genes have been mapped in the PARK6 locus—USP31 (ubiquitin specific protease 31), HTR6 (serotonin receptor), and ECE1 (neprilysin activity). According to the investigators, these genes, as well as other genes in the PARK6 locus, should be investigated in those with PARK6-linked AR-EOPD.

The second study, conducted by Healy et al, found a low prevalence of PINK1 mutations, which are located in PARK6, in a sample of Irish Parkinson’s disease patients. A total of 290 patients participated in the study. Patients with homozygous parkin mutations were excluded from the study; however, four patients with heterozygous parkin mutations were included “to explore the possibility of digenic mendelian inheritance involving mutations in the parkin and PINK1 genes.”

The researchers identified a heterozygous mutation in exon 2 of the PINK1 gene in only one of the 290 patients studied. They said that “the phenotype of this patient was similar to the few existing descriptions of PARK6 and, apart from a slightly younger age of symptom onset, appears indistinguishable from idiopathic Parkinson’s disease.” The patient had not experienced early dystonia, psychiatric symptoms, or diurnal variation. The researchers also noted that no evidence of digenic inheritance between the PINK1 and parkin genes was found in any of the subjects.

Healy et al offered two possible explanations for the association between the PINK1 mutation and AR-EOPD in this patient. The first explanation was that the patient was a rare carrier of a PINK1 mutation and incidentally had Parkinson’s disease of another etiology. The second explanation was that since the mother of the patient also had Parkinson’s disease, there is a possibility that a heterozygous effect for the PINK1 mutation increased the risk of Parkinson’s disease.

In an accompanying editorial, Andrew Singleton, PhD, discussed the role of PINK1 mutations in Parkinson’s disease. “It is likely that some but probably not all of the molecular events that cause PINK1 parkinsonism are relevant to Parkinson’s disease,” he said. Dr. Singleton stated that although it is possible that a PINK1 mutation in the heterozygous state leads to a dopaminergic deficit that may predispose to disease, claims of pathogenicity should be viewed with caution.

He also emphasized that researchers need to take into account the differences between all parkinsonisms in terms of pathology and molecular etiology when designing studies and interpreting results. He noted that because cellular and transgenic modeling experiments are often costly and influential, “it is vital that we are as confident as reasonably possible when claiming a mutation is pathogenic.”

Hatano Y, Sato K, Elibol B, et al. PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations. Neurology. 2004;63:1482-1485.
Healy DG, Abou-Sleiman PM, Gibson JM, et al. PINK1 (PARK6) associated Parkinson disease in Ireland. Neurology. 2004;63:1486-1488.
Singleton A. What does PINK1 mean for Parkinson diseases? Neurology. 2004;63:1350-1351.

METABOLIC SYNDROME, INFLAMMATION, AND RISK OF COGNITIVE IMPAIRMENT

Elderly people with metabolic syndrome are at a higher risk of cognitive impairment than are those without the syndrome, according to a report in the November 10 JAMA. Researchers found an even higher risk of cognitive impairment in those individuals who had both metabolic syndrome and high levels of serum markers of inflammation.

These findings are based on a five-year study conducted by Kristine Yaffe, MD, of the University of California, San Francisco, and the San Francisco VA Medical Center. A total of 2,632 people ages 70 to 79 participated in the study. The Teng Modified Mini-Mental State Examination (3MS) was administered to all participants at baseline. This test was readministered at the three- and five-year follow-up visits. Cognitive impairment was defined as a score at least 5 points lower than the score at baseline.

Results indicated that 1,016 participants had metabolic syndrome. These participants were more likely to be women, to be white, and to smoke. They had higher depression scores, higher body mass index, and a history of myocardial infarction. They were also more likely to use statins and nonsteroidal anti-inflammatory drugs. The researchers found that 26% of participants with metabolic syndrome had cognitive impairment, compared with 21% of participants without the syndrome.

To test for inflammation, the researchers measured for interleukin-6 and C-reactive protein in serum taken at baseline. They found that 30% of participants with metabolic syndrome and high inflammation had cognitive impairment. These participants experienced a greater four-year decline in 3MS scores. However, those with metabolic syndrome and low inflammation were not more likely to develop cognitive impairment.

Dr. Yaffe and her colleagues did not reach any conclusions about the possible causes of cognitive decline in the presence of metabolic syndrome and high inflammation—they are unsure of the interactions between the syndrome and inflammation. “Future studies will need to address whether preventing the metabolic syndrome or lowering inflammation prevents cognitive impairment in elderly individuals,” said the researchers.

Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292:2237-2242.

CLINICAL SYMPTOMS AND FEATURES OF NEURONAL INTERMEDIATE FILAMENT INCLUSION DISEASE

A study in the October 26 Neurology provided a detailed description of the clinical symptoms and features of neuronal intermediate filament inclusion disease (NIFID). Nigel J. Cairns, PhD, and colleagues conducted a retrospective chart review of 10 NIFID cases and concluded that “NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia.”

Among the 10 cases, the mean age at onset was 40.8 and the mean age at death was 45.3. Four cases were female and six were male. In addition, none of the cases had a family history of psychiatric or neurologic disorder.

According to the researchers, behavioral or personality changes, apathy, and disinhibition were present in seven cases. Extrapyramidal features were present in eight cases. Memory deficits were reported in nine cases and language deficits in seven. In addition, nine cases had hyperreflexia. The researchers also indicated that “a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease, and limb dystonia.”

Histologic changes included neuronal loss, status spongiosis, and astrocytosis in the temporal and frontal isocortex, all of which are stereotypic lesions of frontotemporal dementia. “The hallmark lesions of NIFID were unique neuronal intermediate filament inclusions detected most robustly by antibodies to neurofilament triplet proteins and α-internexin,” said the researchers. The researchers commented that although α-internexin was found to be a major component of the pathologic inclusions in NIFID, its role in this process is unknown.

In an accompanying editorial, Steven T. DeKosky, MD, and Milos D. Ikonomovic, MD, said that although the study by Cairns et al provides detailed clinical descriptions of these cases, “we are left with uncertainty about when to consider NIFID as a clinical diagnosis.”

Drs. DeKosky and Ikonomovic pointed out that “while NIFID may be an immunohistopathologically distinct form of frontotemporal dementia, the clinical manifestations are not unique.” Therefore, they proposed that the absence of family history with extrapyramidal symptoms, diffuse hyperreflexia, and supranuclear ophthalmoplegia should be suggestive of a diagnosis.

More importantly, however, they concluded that characteristic functional imaging, PET studies, biomarkers related to the specific internexin pathology, or a CSF marker might also be necessary to diagnose NIFID.

Cairns NJ, Grossman M, Arnold SE, et al. Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease. Neurology. 2004;63:1376-1384.
DeKosky ST, Ikonomovic MD. NIFID: a new molecular pathology with a frontotemporal dementia phenotype. Neurology. 2004;63:1348-1349.

NEUROLOGICAL ACTIVATION AND NEUROINFLAMMATION IN PATIENTS WITH AUTISM

An active neuroinflammatory process has been observed in the brains of patients with autism, according to a study in the November 15 online edition of Annals of Neurology. Researchers, led by Diana L. Vargas, MD, examined brain tissue samples taken from 15 patients with autism and 12 control subjects, as well as the cerebrospinal fluid of patients with autism, to determine the extent of neuroglial and inflammatory reactions and their cytokine profiles.

One major finding of the study was that extensive neuroglial responses, characterized by microglial and astroglial activation, were present in the brains of patients with autism. According to the researchers, “immunocytochemical analysis of microglial and astroglial reactions in the brains of these patients showed that regardless of age, history of epilepsy, developmental regression, or mental retardation, marked morphological changes consistent with chronic and sustained neuroglial inflammatory responses were present in cortical and subcortical white matter as well as in the cerebellum.”

The researchers found that astroglial activation was characterized by an increase in the volume of perikarya and glial processes. According to the researchers, “The most prominent histological changes were observed in the cerebellum, characterized by a patchy loss of neurons in the Purkinje cell layer and the granular cell layer.” No significant histological changes were seen in either of these regions in the brains of control subjects.

The researchers also observed that microglial activation in the brains of patients with autism resembled reactions seen in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and dementia associated with HIV. They said, “In the case of autism, the presence of microglial activation supports the view that innate immune responses are present in cortical and subcortical regions and that a state of chronic activation and reactivity may be involved in the mechanisms of neuronal and synaptic dysfunction.”

Because Dr. Vargas and her colleagues observed a lack of T-cell responses and antibody-mediated reactions in the brains of patients with autism, they suggested that the adaptive immune system does not have a significant pathogenic role in autism.

The investigators also observed unique profiles of cytokine expression in the brain and cerebrospinal fluid of patients with autism. Two proinflammatory chemokines, macrophage chemoattractant protein–1 (MCP-1) and thymus and activation-regulated chemokine (TARC), as well as an anti-inflammatory and modulatory cytokine known as tumor growth factor–β1 (TGF-β1), were elevated in the brain regions studied. MCP-1 levels, in particular, were elevated in both brain tissue and cerebrospinal fluid. The researchers “believe its elevation in the brain is linked to microglial activation and perhaps to the recruitment of monocytes/macrophages to areas of neurodegeneration, such as those we observed in the cerebellum.”

Dr. Vargas and her colleagues concluded that “the pathologic changes observed in the cerebellum in autistic patients do not occur exclusively during prenatal development but appear to involve an ongoing chronic neuroinflammatory process that involves both microglia and astroglia.” Additionally, the investigators observed, “this process continues beyond early neurodevelopment and is present even at very late stages in the life of patients with autism.” They also suggested that future therapies for patients with autism might involve modifying neuroglial responses.

Vargas DL, Nascimbene C, Krishnan C, et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2004. [E-pub ahead of print].

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