Primary progressive aphasia and apraxia of speech.

Primary progressive aphasia is a neurodegenerative syndrome characterized by progressive language dysfunction. The majority of primary progressive aphasia cases can be classified into three subtypes: nonfluent/agrammatic, semantic, and logopenic variants. Each variant presents with unique clinical features, and is associated with distinctive underlying pathology and neuroimaging findings. Unlike primary progressive aphasia, apraxia of speech is a disorder that involves inaccurate production of sounds secondary to impaired planning or programming of speech movements. Primary progressive apraxia of speech is a neurodegenerative form of apraxia of speech, and it should be distinguished from primary progressive aphasia given its discrete clinicopathological presentation. Recently, there have been substantial advances in our understanding of these speech and language disorders. The clinical, neuroimaging, and histopathological features of primary progressive aphasia and apraxia of speech are reviewed in this article. The distinctions among these disorders for accurate diagnosis are increasingly important from a prognostic and therapeutic standpoint.

Band 4.1 proteins regulate integrin-dependent cell spreading.

Integrins link the extracellular matrix (ECM) to the cytoskeleton to control cell behaviors including adhesion, spreading and migration. Band 4.1 proteins contain 4.1, ezrin, radixin, moesin (FERM) domains that likely mediate signaling events and cytoskeletal reorganization via integrins. However, the mechanisms by which Band 4.1 proteins and integrins are functionally interconnected remain enigmatic. Here we have investigated roles for Band 4.1 proteins in integrin-mediated cell spreading using primary astrocytes as a model system. We demonstrate that Proteins 4.1B and 4.1G show dynamic patterns of sub-cellular localization in astrocytes spreading on fibronectin. During early stages of cell spreading Proteins 4.1B and 4.1G are enriched in ECM adhesion sites but become more diffusely localized at later stages of spreading. Combinatorial inactivation of Protein 4.1B and 4.1G expression leads to impaired astrocyte spreading. Furthermore, in exogenous expression systems we show that the isolated Protein 4.1 FERM domain significantly enhances integrin-mediated cell spreading. Protein 4.1B is dispensable for reactive astrogliosis in experimental models of cortical injury, likely due to functional compensation by related Protein 4.1 family members. Collectively, these findings reveal that Band 4.1 proteins are important intracellular components for integrin-mediated cell spreading.

ß8 integrin and band 4.1B cooperatively regulate morphogenesis of the embryonic heart.

Morphogenesis of the heart is regulated by various cues, including growth factors and extracellular matrix (ECM) proteins. The mechanisms by which cardiac cells properly integrate these cues to regulate growth, differentiation, and migration remain poorly understood. Here we have used genetic strategies in mice to identify αvß8 integrin and its cytoskeletal adaptor protein, Band 4.1B, as essential regulators of cardiac morphogenesis. We demonstrate that approximately 60% of mouse embryos genetically null for ß8 integrin and Band 4.1B display cardiovascular phenotypes and die by E11.5. This premature death is due, in part, to defective development of the cardiac outflow tract (OFT), with reduced expression of smooth muscle α-actin (SMAα-actin) in OFT cells derived from the cardiac neural crest. These data are the first to identify cell adhesion and signaling pathways regulated by αvß8 integrin and Band 4.1B as essential for normal formation and function of the heart during embryogenesis.

Normative and isolated rapid eye movement sleep without atonia in adults without REM sleep behavior disorder.

STUDY OBJECTIVES: Values for normative REM sleep without atonia (RSWA) remain unclear. Older age and male sex are associated with greater RSWA, and isolated elevated RSWA has been reported. We aimed to describe normative RSWA and characterize isolated RSWA frequency in adults without REM sleep behavior disorder (RBD). METHODS: We visually quantified phasic, "any," and tonic RSWA in the submentalis (SM) and anterior tibialis (AT) muscles, and the automated Ferri REM Atonia Index during polysomnography in adults without RBD aged 21-88. We calculated RSWA percentiles across age and sex deciles and compared RSWA in older (≥ 65) versus younger (<65) men and women. Isolated RSWA (exceeding diagnostic RBD cutoffs, or >95th percentile) frequency was also determined. RESULTS: Overall, 95th percentile RSWA percentages were SM phasic, any, tonic = 8.6%, 9.1%, 0.99%; AT phasic and "any" = 17.0%; combined SM/AT phasic, "any" = 22.3%, 25.5%; and RAI = 0.85. Most phasic RSWA burst durations were ≤1.0 s (85th percentiles: SM = 1.07, AT = 0.86 seconds). Older men had significantly higher AT RSWA than older women and younger patients (all p < 0.04). Twenty-nine (25%, 18 men) had RSWA exceeding the cohort 95th percentile, while 17 (14%, 12 men) fulfilled diagnostic cutoffs for phasic or automated RBD RSWA thresholds. CONCLUSIONS: RSWA levels are highest in older men, mirroring the demographic characteristics of RBD, suggesting that older men frequently have altered REM sleep atonia control. These data establish normative adult RSWA values and thresholds for determination of isolated RSWA elevation, potentially aiding RBD diagnosis and discussions concerning incidental RSWA in clinical sleep medicine practice.

Clinicopathological and 123I-FP-CIT SPECT correlations in patients with dementia.

The relationship between clinicopathologic diagnosis and 123I-FP-CIT SPECT in 18 patients with dementia (12 with Lewy body disease) from one center in the United States was assessed. The sensitivity and specificity of abnormal 123I-FP-CIT SPECT with reduced striatal uptake on visual inspection for predicting Lewy body disease were 91.7% and 83.3%, respectively. The mean calculated putamen to occipital ratio (mPOR) based on regions of interest was significantly reduced in Lewy body disease compared to non-Lewy body disease cases (P = 0.002). In this study, abnormal 123I-FP-CIT SPECT was strongly associated with underlying Lewy body disease pathology, supporting the utility of 123I-FP-CIT SPECT in the clinical diagnosis of dementia with Lewy bodies.

The National Healthy Sleep Awareness Project Sleep Health Surveillance Questionnaire as an Obstructive Sleep Apnea Surveillance Tool.

STUDY OBJECTIVES: To validate the previously published National Healthy Sleep Awareness Project (NHSAP) Surveillance and Epidemiology Workgroup questionnaire for ability to determine risk for moderate to severe obstructive sleep apnea (OSA). METHODS: The NHSAP sleep questions, part of the next Behavioral Risk Factor Surveillance System (BRFSS), were constructed to mimic elements of the STOP sleep apnea questionnaire, and included number of days with sleep disruption and unintentional dozing and a history of snoring and apneas. The responses to four sleep questions from the BRFSS were collected from 352 adults undergoing in-laboratory polysomnography at Mayo Clinic, Rochester, Minnesota. Demographic and clinical information, including sex, age, body mass index (BMI), and presence of hypertension, which will be available in other parts of the complete BRFSS, were obtained by chart review. Univariate and logistic regression analyses were performed, and values of P < .05 were considered to be statistically significant. RESULTS: Fifty-five percent of subjects were men and 45% were women with a median age of 58 years and BMI 32.2 kg/m2. Sixty percent had no or mild OSA, and 40% had moderate to severe OSA. No single question was superior in screening for moderate to severe OSA, although a history of snoring and witnessed apneas was more likely to predict moderate to severe OSA. Male sex, age ≥ 50 years, BMI ≥ 30 kg/m2, presence of hypertension, and a history of snoring and witnessed apneas were the most highly weighted factors in predicting moderate to severe OSA. When each variable was dichotomized to a single point, a cutoff of 5 points significantly predicted a high risk of moderate to severe OSA with an odds ratio of 3.87 (2.39-6.27). CONCLUSIONS: Although many variables were positively associated with the apnea-hypopnea index, no single factor was superior in predicting moderate to severe OSA. Male sex, increased age, higher BMI, hypertension, and a history of snoring and witnessed apneas are the most highly predictive of moderate to severe OSA. Combined use of the NHSAP questionnaire and demographic and clinical characteristics could be considered for screening for moderate to severe OSA.

Phenoconversion from probable rapid eye movement sleep behavior disorder to mild cognitive impairment to dementia in a population-based sample.

INTRODUCTION: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with synucleinopathies. In 2012, we reported an increased risk of mild cognitive impairment (MCI) and Parkinson disease (PD) in cognitively normal Olmsted County, Minnesota, residents, aged 70 to 89 years with probable RBD. Here, we examine their progression to dementia and other neurodegenerative phenotypes. METHODS: Fifteen participants with RBD who were diagnosed with either MCI or PD were longitudinally followed, and their subsequent clinical courses were reviewed. RESULTS: Over 6.4 ± 2.9 years, six of the 14 participants with MCI developed additional neurodegenerative signs, five of whom had Lewy body disease features. Four of them progressed to dementia at a mean age 84.8 ± 4.9 years, three of whom met the criteria for probable dementia with Lewy bodies. One subject with PD developed MCI, but not dementia. DISCUSSION: Our findings from the population-based sample of Olmsted County, Minnesota, residents suggest that a substantial number of RBD patients tend to develop overt synucleinopathy features over time, and RBD patients who develop MCI and subsequent dementia have clinical features most consistent with dementia with Lewy bodies.

Treatment of REM Sleep Behavior Disorder.

OPINION STATEMENT: REM sleep behavior disorder (RBD) is a common parasomnia disorder affecting between 1 and 7 % of community-dwelling adults, most frequently older adults. RBD is characterized by nocturnal complex motor behavior and polysomnographic REM sleep without atonia. RBD is strongly associated with synucleinopathy neurodegeneration. The approach to RBD management is currently twofold: symptomatic treatment to prevent injury and prognostic counseling and longitudinal follow-up surveillance for phenoconversion toward overt neurodegenerative disorders. The focus of this review is symptomatic treatment for injury prevention. Injury occurs in up to 55 % of patients prior to treatment, even when most behaviors seem to be infrequent or minor, so patients with RBD should be treated promptly following diagnosis to prevent injury risk. A sound evidence basis for symptomatic treatment of RBD remains lacking, and randomized controlled treatment trials are needed. Traditional therapeutic mainstays with relatively robust retrospective case series level evidence include melatonin and clonazepam, which appear to be equally effective, although melatonin is more tolerable. Melatonin also has one small randomized controlled crossover trial supporting its use for RBD treatment. Melatonin dosed 3-12 mg at bedtime should be considered as the first-line therapy, followed by clonazepam 0.25-2.0 mg at bedtime if initial melatonin is judged ineffective or intolerable. However, neither agent is likely to completely stop dream enactment behaviors, so choosing a moderate target dosage of melatonin 6 mg or clonazepam 0.5 mg, or the highest tolerable dosage that reduces attack frequency and avoids adverse effects from overtreatment, is currently the most reasonable strategy. Alternative second- and third-line therapies with anecdotal efficacy include temazepam, lorazepam, zolpidem, zopiclone, pramipexole, donepezil, ramelteon, agomelatine, cannabinoids, and sodium oxybate. A novel non-pharmacological approach is a bed alarm system, although this may be most useful in patients who also report sleep walking or a history of leaving their bed during dream enactment episodes. The benefit of hypnosis, especially in those with psychiatric RBD, also requires further study. RBD is an attractive target for future neuroprotective treatment trials to prevent evolution of overt parkinsonism or memory decline, but currently, there are no known effective treatments and future trials will be necessary to determine if RBD is an actionable time point in the evolution of overt synucleinopathy.

Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage.

In Alzheimer's disease (AD) pathogenesis, increasing evidence implicates mitochondrial dysfunction resulting from molecular defects in oxidative phosphorylation (OXPHOS). The objective of the present study was to determine the role of mRNA expression of mitochondrial genes responsible for OXPHOS in brain specimens from early AD and definite AD patients. In the present article, using quantitative real-time polymerase chain reaction (PCR) techniques, we studied mRNA expression of 11 mitochondrial-encoded genes in early AD patients (n = 6), definite AD patients (n = 6), and control subjects (n = 6). Using immunofluorescence techniques, we determined differentially expressed mitochondrial genes NADH 15-kDa subunit (complex I), cytochrome oxidase subunit 1 (complex IV), and ATPase delta-subunit (complex V) in the brain sections of AD patients and control subjects. Our quantitative reverse transcription (RT)-PCR analysis revealed a downregulation of mitochondrial genes in complex I of OXPHOS in both early and definite AD brain specimens. Further, the decrease of mRNA fold changes was higher for subunit 1 compared to all other subunits studied, suggesting that subunit 1 is critical for OXPHOS. Contrary to the downregulation of genes in complex I, complexes III and IV showed increased mRNA expressions in the brain specimens of both early and definite AD patients, suggesting a great demand on energy production. Further, mitochondrial gene expression varied greatly across AD patients, suggesting that mitochondrial DNA defects may be responsible for the heterogeneity of the phenotype in AD patients. Our immunofluorescence analyses of cytochrome oxidase and of the ATPase delta-subunit suggest that only subpopulations of neurons are differentially expressed in AD brains. Our double-labeling immunofluorescence analyses of 8-hydroxyguanosine and of cytochrome oxidase suggest that only selective, overexpressed neurons with cytochrome oxidase undergo oxidative damage in AD brains. Based on these results, we propose that an increase in cytochrome oxidase gene expression might be the result of functional compensation by the surviving neurons or an early mitochondrial alteration related to increased oxidative damage.

TDP-43 in Alzheimer's disease is not associated with clinical FTLD or Parkinsonism.

Widespread deposition of TAR DNA-binding protein of 43 kDa (TDP-43), a major protein inclusion commonly found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) can also be seen in a subset of cases with Alzheimer's disease (AD). Some of these AD cases have TDP-43 immunoreactivity in basal ganglia (BG) and substantia nigra (SN), regions that when affected can be associated with parkinsonian signs or symptoms, or even features suggestive of frontotemporal dementia. Here, we examined the presence of clinical features of FTLD, parkinsonian signs and symptoms, and BG atrophy on MRI, in 51 pathologically confirmed AD cases (Braak neurofibrillary tangle stage IV-VI) with widespread TDP-43 deposition, with and without BG and SN involvement. All 51 cases had presented with progressive cognitive impairment with prominent memory deficits. None of the patients demonstrated early behavioral disinhibition, apathy, loss of empathy, stereotyped behavior, hyperorality, and/or executive deficits. Furthermore, TDP-43 deposition in BG or SN had no significant association with tremor (p = 0.80), rigidity (p = 0.19), bradykinesia (p = 0.19), and gait/postural instability (p = 0.39). Volumes of the BG structures were not associated with TDP-43 deposition in the BG. The present study demonstrates that TDP-43 deposition in pathologically confirmed AD cases is not associated with a clinical manifestation suggestive of FTLD, or parkinsonian features.

Time-course of mitochondrial gene expressions in mice brains: implications for mitochondrial dysfunction, oxidative damage, and cytochrome c in aging.

The study of aging is critical for a better understanding of many age-related diseases. The free radical theory of aging, one of the prominent aging hypotheses, holds that during aging, increasing reactive oxygen species in mitochondria causes mutations in the mitochondrial DNA and damages mitochondrial components, resulting in senescence. Understanding a mitochondrial gene expression profile and its relationship to mitochondrial function becomes an important step in understanding aging. The objective of the present study was to determine mRNA expression of mitochondrial-encoded genes in brain slices from C57BL6 mice at four ages (2, 12, 18, and 24 months) and to determine how these altered mitochondrial genes influence age-related changes, including oxidative damage and cytochrome c in apoptosis. Using northern blot analysis, in situ hybridization, and immunofluorescence analyses, we analyzed changes in the expression of mitochondrial RNA encoding the mitochondrial genes, oxidative damage marker, 8-hydroxyguanosine (8-OHG), and cytochrome c in brain slices from the cortex of C57BL6 mice at each of the four ages. Our northern blot analysis revealed an increased expression of mitochondrial-encoded genes in complexes I, III, IV, and V of the respiratory chain in 12- and 18-month-old C57BL6 mice compared to 2-month-old mice, suggesting a compensatory mechanism that allows the production of proteins involved in the electron transport chain. In contrast to the up-regulation of mitochondrial genes in 12- and 18-month-old C57BL6 mice, mRNA expression in 24-month-old C57BL6 mice was decreased, suggesting that compensation maintained by the up-regulated genes cannot be sustained and that the down-regulation of expression results in the later stage of aging. Our in situ hybridization analyses of mitochondrial genes from the hippocampus and the cortex revealed that mitochondrial genes were over-expressed, suggesting that these brain areas are critical for mitochondrial functions. Our immunofluorescence analysis of 8-OHG and cytochrome c revealed increased 8-OHG and cytochrome c in 12-month-old C57BL6 mice, suggesting that age-related mitochondrial oxidative damage and apoptosis are associated with mitochondrial dysfunction. Our double-labeling analysis of in situ hybridization of ATPase 6 and our immunofluorescence analysis of 8-OHG suggest that specific neuronal populations undergo oxidative damage. Further, double-labeling analysis of in situ hybridization of ATPase 6 and immunofluorescence analysis of cytochrome c suggest cytochrome c release is related to mitochondrial dysfunction in the aging C57BL6 mouse brain. This study also suggests that these mitochondrial gene expression changes may relate to the role of mitochondrial dysfunction, oxidative damage, and cytochrome c in aging and in age-related diseases such as Alzheimer's disease and Parkinson's disease.

Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the impairment of cognitive functions and by beta amyloid (Abeta) plaques in the cerebral cortex and the hippocampus. Our objective was to determine genes that are critical for cellular changes in AD progression, with particular emphasis on changes early in disease progression. We investigated an established amyloid precursor protein (APP) transgenic mouse model (the Tg2576 mouse model) for gene expression profiles at three stages of disease progression: long before (2 months of age), immediately before (5 months) and after (18 months) the appearance of Abeta plaques. Using cDNA microarray techniques, we measured mRNA levels in 11 283 cDNA clones from the cerebral cortex of Tg2576 mice and age-matched wild-type (WT) mice at each of the three time points. This gene expression analysis revealed that the genes related to mitochondrial energy metabolism and apoptosis were up-regulated in 2-month-old Tg2576 mice and that the same genes were up-regulated at 5 and 18 months of age. These microarray results were confirmed using northern blot analysis. Results from in situ hybridization of mitochondrial genes-ATPase-6, heat-shock protein 86 and programmed cell death gene 8-suggest that the granule cells of the hippocampal dentate gyrus and the pyramidal neurons in the hippocampus and the cerebral cortex are up-regulated in Tg2576 mice compared with WT mice. Results from double-labeling in situ hybridization suggest that in Tg2576 mice only selective, over-expressed neurons with the mitochondrial gene ATPase-6 undergo oxidative damage. These results, therefore, suggest that mitochondrial energy metabolism is impaired by the expression of mutant APP and/or Abeta, and that the up-regulation of mitochondrial genes is a compensatory response. These findings have important implications for understanding the mechanism of Abeta toxicity in AD and for developing therapeutic strategies for AD.