Julie A. Fields

Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72

Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.

Reducing Suicidal Ideation in Depressed Older Primary Care Patients

OBJECTIVES: To determine the effect of a primary care–based collaborative care program for depression on suicidal ideation in older adults.

Neuropsychological deficits in essential tremor: an expression of cerebello‐thalamo‐cortical pathophysiology?

Few studies have been published regarding the neuropsychological characteristics of patients with essential tremor (ET), but preliminary findings suggest that mild attentional and executive dysfunction accompany the disorder. A consecutive series of 101 patients with ET referred for thalamotomy and/or thalamic deep brain stimulation candidacy work‐up also underwent neuropsychological evaluation. Average neuropsychological test scores were calculated, along with the proportions of subjects whose scores fell within or more than one SD above or below the mean (using demographically corrected normative data). Significantly lower than average (T‐score of 50) scores were evident on measures of complex auditory attention, visual attention and response inhibition, recall of a word list, verbal fluency, and visual confrontation naming. A significantly greater proportion of patients (ranging from about 34 to 60%) than might be expected on the basis of a normal distribution obtained scores more than one SD below the normative mean on select measures of attention, verbal fluency, immediate word list recall, semantic encoding, and facial matching. Consistent with prior research, notable, albeit clinically subtle, deficits in attention and select executive functions are evident in patients with ET. Although not specific to ET or cerebellar dysfunction, the observed pattern of cognitive deficits is consistent with cerebello‐thalamo‐cortical circuit dysfunction.

Neuropsychological Sequelae of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A Critical Review

Neuropsychologists are increasingly involved in surgical candidacy evaluations and postoperative neurobehavioral assessments of patients with movement disorders, most notably those with disease (PD). We review here the initial studies regarding neuropsychological outcomes of deep brain stimulation (DBS) within the subthalamic nucleus (STN) for treatment of PD. Overall, these initial investigations provide preliminary support for the cognitive and neurobehavioral safety of STN DBS. Improvements in self-reported symptoms of depression and diminished verbal fluency were the most common findings, whereas changes in global cognitive abilities, memory, attention, and frontal/executive functions were inconsistent and most often described as nominal and/or transient. The generalizability of this literature is hindered by several methodological limitations, including small samples and the absence of appropriate control participants. The clinical and theoretical implications of these initial studies are highlighted and recommendations are offered to guide future research.

Neuropsychological and quality of life outcomes 12 months after unilateral thalamic stimulation for essential tremor

Objectives: To evaluate the one year cognitive, mood state, and quality of life (QoL) outcomes of unilateral thalamic deep brain stimulation (DBS) for essential tremor (ET). Methods: 40 patients diagnosed with ET completed comprehensive neuropsychological assessments about one month before and three and 12 months after DBS electrode implantation. Data were subjected to multivariate analyses, and significant results were further analysed using univariate techniques. Results: Analyses revealed statistically significant improvements on a cognitive screening measure and in aspects of fine visuomotor and visuoperceptual functions, verbal memory, mood state, and QoL. No group-wise declines in cognition were observed, but more patients showed declines than improvements on language and visual memory tests. Semantic verbal fluency declined significantly in four (10%) of the patients. In these four patients, diminished lexical verbal fluency was present at baseline. Conclusion: Cognitive, mood, and QoL outcomes after one year of DBS for ET are favourable; there were no overall deleterious effects on cognition, and DBS was accompanied by a significant reduction in anxiety and improvements in quality of life. However, preoperative verbal fluency diminution may predispose to further fluency declines after DBS.

Modeling the impact of COPD on the brain

Previous studies have shown that COPD adversely affects distant organs and body systems, including the brain. This pilot study aims to model the relationships between respiratory insufficiency and domains related to brain function, including low mood, subtly impaired cognition, systemic inflammation, and brain structural and neurochemical abnormalities. Nine healthy controls were compared with 18 age- and education-matched medically stable COPD patients, half of whom were oxygen-dependent. Measures included depression, anxiety, cognition, health status, spirometry, oximetry at rest and during 6-minute walk, and resting plasma cytokines and soluble receptors, brain MRI, and MR spectroscopy in regions relevant to mood and cognition. ANOVA was used to compare controls with patients and with COPD subgroups (oxygen users [n = 9] and nonusers [n = 9]), and only variables showing group differences at p ≤ 0.05 were included in multiple regressions controlling for age, gender, and education to develop the final model. Controls and COPD patients differed significantly in global cognition and memory, mood, and soluble TNFR1 levels but not brain structural or neurochemical measures. Multiple regressions identified pathways linking disease severity with impaired performance on sensitive cognitive processing measures, mediated through oxygen dependence, and with systemic inflammation (TNFR1), related through poor 6-minute walk performance. Oxygen desaturation with activity was related to indicators of brain tissue damage (increased frontal choline, which in turn was associated with subcortical white matter attenuation). This empirically derived model provides a conceptual framework for future studies of clinical interventions to protect the brain in patients with COPD, such as earlier oxygen supplementation for patients with desaturation during everyday activities.

Effect of Motor Improvement on Quality of Life following Subthalamic Stimulation Is Mediated by Changes in Depressive Symptomatology

Background/Aims: Subthalamic deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) improves motor symptoms and quality of life (QOL). Because depression is a potent correlate of QOL, and STN-DBS may be associated with changes in mood, this study sought to determine whether QOL improvement is a direct or indirect consequence of motor improvement. Methods: 26 patients with PD, free of dementia and major depression, who consecutively underwent bilateral, microelectrode-guided STN-DBS, underwent preoperative and 3-month postoperative neuropsychological evaluation, including measures of QOL (PD Questionnaire –39) and depressive symptoms (Beck Depression Inventory). Results: Motor score in the Unified Parkinson’s Disease Rating Scale (UPDRS Part III) improved significantly with STN-DBS relative to preoperative ‘on’ and ‘off’ scores, as did QOL and depressive symptoms. Extent of QOL improvement tended to be associated with improvement in motor score from presurgical on to postsurgical on stimulation and on medication state. QOL improvement was significantly related to amelioration of depressive symptoms. Partial correlations revealed that the association between QOL improvement and depression remained significant when influence of motor improvement on QOL and depression was controlled for. The motor-QOL association was no longer significant when effects of depression were controlled for. Conclusions: Significant QOL improvements after STN-DBS are associated with improved motor ‘on’ state and depressive symptoms. The influence of motor improvement on QOL may be largely indirect by reducing depression.

Action verbal fluency normative data for the elderly

An emerging body of literature points to the prominent role of the frontal lobes in the retrieval of verbs, whereas production of common and proper nouns arguably is mediated primarily by posterior and anterior temporal regions, respectively. Although the majority of studies examining the neuroanatomic distinctions between verb and noun retrieval have relied on action naming tasks (naming depicted activities, e.g., running) as indicators of verb retrieval abilities, recent studies have utilized an action (verb) verbal fluency measure, the Action Fluency Test (AFT), to assess verb retrieval. Findings from these studies suggest that action fluency is sensitive to the integrity of fronto-subcortical neural circuitry and that it is a valid measure of executive and language functions. The AFT is an easily administered executive function measure, but no normative data for the AFT or other action fluency tasks has been published. This study was undertaken to provide initial AFT normative data for a sample of 145 healthy elderly subjects. As education is significantly correlated with AFT scores, the normative data are stratified by educational level.

Neuropsychological and quality of life changes following unilateral thalamic deep brain stimulation in Parkinson's disease: a one-year follow-up.

Summary.Background: The long-term neuropsychological and quality of life (QOL) outcomes of unilateral thalamic deep brain stimulation (DBS) in patients with intractable Parkinsons disease (PD) have not heretofore been described. Method: Six patients diagnosed with PD underwent unilateral DBS implantation into a verified thalamic VIM nucleus target. Participants completed presurgical neuropsychological evaluation and follow-up assessment at approximately one year postsurgery. Findings: Compared to their presurgical scores, PD patients exhibited significant improvement on measures of conceptualization, verbal memory, emotional adjustment, and QOL at one-year follow-up. A few nominal declines were observed across the battery of tests. Interpretation: These data provide preliminary support for the long-term neurocognitive safety and QOL improvements following thalamic stimulation in patients with PD.

Executive dysfunction and neuropsychiatric symptoms predict lower health status in essential tremor.

ObjectiveTo evaluate the hypothesis that increased neuropsychiatric distress and cognitive impairment are associated with lower perceived health status in essential tremor (ET). BackgroundMany patients with ET experience nonmotor complications, including lower perceived health status and poor health-related quality of life, which are associated with tremor severity, age, and personality factors. No studies, however, have examined the potential contribution of neuropsychiatric symptoms and cognitive deficits to health status in ET. MethodForty-five patients with ET underwent comprehensive neurologic and neuropsychologic evaluations, including self-report measures of physical and psychosocial health status (ie, the Sickness Impact Profile) and neuropsychiatric distress (ie, the Profile of Mood States). ResultsA series of hierarchical multiple regressions showed that after considering the effects of ET disease severity, lower vigor, and deficits in executive functions were independently predictive of poorer physical health status, whereas increased symptoms of depression were uniquely associated with lower psychosocial health status. ConclusionsFindings indicate that reduced vigor (ie, apathy), executive deficits, and depression are important predictors of poorer perceived health status in ET. Given the prevalence of such nonmotor symptoms, these data highlight the potential value of considering neuropsychiatric and neurocognitive assessments in the management of patients with ET.