Since the original 1995 report of a parkinsonian kindred, four individuals have been affected (mean age at onset, 65 years). All four had cardinal signs of Parkinson disease (PD) and good response to ...levodopa. Four autopsies showed neuronal loss and gliosis in the substantia nigra. Lewy bodies (LB) limited to brainstem nuclei were detected in one case, diffuse LB in the second, neurofibrillary tangles (NFT) without LB in the third, and neither NFT nor LB in the fourth. Genetic studies suggested linkage to the PARK8 locus on chromosome 12.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is a rare neurodegenerative disease resulting from mutations in the colony stimulating factor 1 receptor gene. Accurate ...diagnosis can be difficult because the associated clinical and MR imaging findings are nonspecific. We present 9 cases with intracranial calcifications distributed in 2 brain regions: the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter. Thin-section (1-mm) CT scans are particularly helpful in detection due to the small size of the calcifications. These calcifications had a symmetric "stepping stone appearance" in the frontal pericallosal regions, which was clearly visible on reconstructed sagittal CT images. Intrafamilial variability was seen in 2 of the families, and calcifications were seen at birth in a single individual. These characteristic calcification patterns may assist in making a correct diagnosis and may contribute to understanding of the pathogenesis of leukoencephalopathy.
To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to ...determine whether TMEM106B modulates GRN expression.
We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD-TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls.
In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, p(allelic) = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p(allelic) = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected p(recessive) = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = -0.63, p = 7.7 × 10(-5)) and controls (r = -0.49, p = 2.2 × 10(-10)).
In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD.
To determine the proportion of individuals in a clinic-based setting that present with asymmetric Parkinson disease (PD) and identify predictive factors associated with asymmetric symptoms.
The ...authors examined right vs left difference scores on the Unified Parkinson Disease Rating Scale motor subscale in a consecutive clinical series of 1,277 individuals diagnosed with PD. Predictors of asymmetry included sex, symptomatic disease duration, age at onset, initial motor symptom laterality, handedness, and medical history variables (e.g., family history of PD).
Nearly half the sample (46%) met criteria for asymmetric disease based on a right vs left difference score of > or =5 points, and 12% of the sample had a difference score of > or =10 (difference score: mean = 4, SD = 3.4). All three cardinal features of PD showed characteristics of asymmetric disease presentation. Multiple regression analyses showed that an increased discrepancy between right- and left-sided symptoms was significantly associated with a shorter disease duration, younger age at symptomatic onset, asymmetric initial symptom onset, hand dominance, and a positive self-reported family history of "other" neurodegenerative disorder. Hand dominance was related to the side of asymmetric disease such that left-handed individuals tended to have more severe disease on the left side of the body.
Asymmetric presentation of Parkinson disease features was a common occurrence in the clinical cohort. Asymmetry was reliably predicted by several clinical characteristics, although the moderate level of explained variance (i.e., between 16 and 23%) highlighted the need for additional research examining predictive models of asymmetric disease. Recommendations for the classification and measurement of asymmetric disease are discussed.
REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology ...relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease (‘secondary RBD’) is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with ‘idiopathic’ RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.
A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral ...sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level.
Objective Marchiafava–Bignami disease (MBD) is a rare condition mainly associated with alcoholism, although it may be mimicked by several other disorders that cause corpus callosum lesions. Our ...objective was to identify helpful features for differential diagnosis and assess whether any treatment can be recommended. Methods We reviewed 122 reports containing data on 153 subjects with confirmed MBD that was associated with either alcoholism or malnutrition, and 20 reports with data on 53 subjects with conditions mimicking MBD. All the cases had been verified antemortem by brain imaging. Unconditional logistic regression was used to demonstrate factors that were associated with the outcome of MBD. Results The mimicking conditions were differentiated from MBD by the occurrence of solitary and rapidly disappearing splenial lesions; fewer signs and symptoms with exception of seizures, hemiparesis and tetraparesis; nystagmus; and rapid and complete recovery. MBD occurred most frequently among alcoholics, but it was also reported in 11 non-alcoholics (7.2% of all the MBD cases). A better outcome was observed among those who were treated within 2 weeks after onset of symptoms with parenteral thiamine (p=0.033). Conclusions As thiamine deficiency is frequently associated with alcoholism, malnutrition and prolonged vomiting; we recommend prompt treatment of MBD with parenteral thiamine in such subjects. Recovery should be followed by repeated neuropsychological and MRI examinations, preferably using diffusion tensor imaging.
To determine whether adding REM sleep behavior disorder (RBD) to the dementia with Lewy bodies (DLB) diagnostic criteria improves classification accuracy of autopsy-confirmed DLB.
We followed 234 ...consecutive patients with dementia until autopsy with a mean of 4 annual visits. Clinical diagnoses included DLB, Alzheimer disease (AD), corticobasal syndrome, and frontotemporal dementia. Pathologic diagnoses used the 2005 DLB consensus criteria and included no/low likelihood DLB (non-DLB; n = 136) and intermediate/high likelihood DLB (DLB; n = 98). Regression modeling and sensitivity/specificity analyses were used to evaluate the diagnostic role of RBD.
Each of the 3 core features increased the odds of autopsy-confirmed DLB up to 2-fold, and RBD increased the odds by 6-fold. When clinically probable DLB reflected dementia and 2 or more of the 3 core features, sensitivity was 85%, and specificity was 73%. When RBD was added and clinically probable DLB reflected 2 or more of 4 features, sensitivity improved to 88%. When dementia and RBD were also designated as probable DLB, sensitivity increased to 90% while specificity remained at 73%. The VH, parkinsonism, RBD model lowered sensitivity to 83%, but improved specificity to 85%.
Inclusion of RBD as a core clinical feature improves the diagnostic accuracy of autopsy-confirmed DLB.
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