Robin Ketelle

Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion

Background Some patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD ‘phenocopies’ or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described. Methods 384 patients with an FTD clinical spectrum and Alzheimers disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls. Results Both patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable. Conclusions C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.

Let's Inhibit Our Excitement: The Relationships Between Stroop, Behavioral Disinhibition, and the Frontal Lobes

OBJECTIVE The Stroop (Stroop, 1935) is a frequently used neuropsychological test, with poor performance typically interpreted as indicative of disinhibition and frontal lobe damage. This study tested those interpretations by examining relationships between Stroop performance, behavioral disinhibition, and frontal lobe atrophy. METHOD Participants were 112 patients with mild cognitive impairment or dementia, recruited through UCSFs Memory and Aging Center. Participants received comprehensive dementia evaluations including structural MRI, neuropsychological testing, and informant interviews. Freesurfer, a semiautomated parcellation program, was used to analyze 1.5T MRI scans. Behavioral disinhibition was measured using the Neuropsychiatric Inventory (Cummings, 1997; Cummings et al., 1994) Disinhibition Scale. The sample (n = 112) mean age was 65.40 (SD = 8.60) years, education was 16.64 (SD = 2.54) years, and Mini-Mental State Examination (MMSE; Folstein et al., 1975) was 26.63 (SD = 3.32). Hierarchical linear regressions were used for data analysis. RESULTS Controlling for age, MMSE, and color naming, Stroop performance was not significantly associated with disinhibition (β = 0.01, ΔR² = 0.01, p = .29). Hierarchical regressions controlling for age, MMSE, color naming, intracranial volume, and temporal and parietal lobes, examined whether left or right hemisphere regions predict Stroop performance. Bilaterally, parietal lobe atrophy best predicted poorer Stroop (left: β = 0.0004, ΔR² = 0.02, p = .002; right: β = 0.0004, ΔR² = 0.02, p = .002). Of frontal regions, only dorsolateral prefrontal cortex atrophy predicted poorer Stroop (β = 0.001, ΔR² = 0.01, p = .03); left and right anterior cingulate cortex atrophy predicted better Stroop (left: β = -0.003, ΔR² = 0.01, p = .02; right: β = -0.004, ΔR² = 0.01, p = .02). CONCLUSION These findings suggest Stroop performance is a poor measure of behavioral disinhibition and frontal lobe atrophy even among a relatively high-risk population.

Interpersonal traits change as a function of disease type and severity in degenerative brain diseases

Background Different degenerative brain diseases result in distinct personality changes as a result of divergent patterns of brain damage; however, little is known about the natural history of these personality changes throughout the course of each disease. Objective To investigate how interpersonal traits change as a function of degenerative brain disease type and severity. Methods Using the Interpersonal Adjective Scales, informant ratings of retrospective premorbid and current scores for dominance, extraversion, warmth and ingenuousness were collected annually for 1 to 4 years on 188 patients (67 behavioural variant frontotemporal dementia (bvFTD), 40 semantic dementia (SemD), 81 Alzheimers disease (AD)) and 65 older healthy controls. Using random coefficient models, interpersonal behaviour scores at very mild, mild or moderate-to-severe disease stages were compared within and between patient groups. Results Group-level changes from premorbid personality occurred as a function of disease type and severity, and were apparent even at a very mild disease stage (Clinical Dementia Rating=0.5) for all three diseases. Decreases in interpersonal traits were associated with emotional affiliation (ie, extraversion, warmth and ingenuousness) and more rigid interpersonal behaviour differentiated bvFTD and SemD patients from AD patients. Conclusions Specific changes in affiliative interpersonal traits differentiate degenerative brain diseases even at a very mild disease stage, and patterns of personality change differ across bvFTD, SemD and AD with advancing disease. This study describes the typical progression of change of interpersonal traits in each disease, improving the ability of clinicians and caregivers to predict and plan for symptom progression.

Characterization of Apathy in Persons with Frontotemporal Dementia and The Impact on Family Caregivers

This study characterized daytime activity and apathy in patients with behavioral variant frontotemporal dementia (bvFTD) and semantic dementia (SD) and their family caregivers. Twenty-two patient-caregiver dyads were enrolled: 13 bvFTD and 9 SD. Data were collected on behavior and movement. Patients and caregivers wore Actiwatches for 2 weeks to record activity. We predicted that bvFTD patients would show greater caregiver report of apathy and less daytime activity compared with patients diagnosed with SD. Patients with bvFTD spent 25% of their day immobile, whereas patients with SD spent 16% of their day inactive. BvFTD caregivers spent 11% of their day immobile and SD caregivers were immobile 9% of their day. Apathy was present in all of the patients with bvFTD and in all but one patient with SD; the severity of apathy was greater in bvFTD compared with SD. Apathy correlated with caregiver emotional distress in both groups. In conclusion, apathy has been defined as a condition of diminished motivation that is difficult to operationalize. Among patients with frontotemporal dementia, apathy was associated with lower levels of activity, greater number of bouts of immobility, and longer immobility bout duration. Apathy and diminished daytime activity appeared to have an impact on the caregiver. Objective measures of behavioral output may help in formulation of a more precise definition of apathy.

The Experience of Caregiving: Differences Between Behavioral Variant of Frontotemporal Dementia and Alzheimer Disease

OBJECTIVE To examine caregiver strain, depression, perceived sense of control, and distress from patient neuropsychiatric symptoms in family caregivers of persons with Alzheimer disease (AD) and behavioral variant of frontotemporal dementia (bvFTD) and determine whether group differences exist. METHODS Family caregivers were recruited from the Memory and Aging Center in San Francisco, California. Analyses of cross-sectional data on 53 family caregivers (AD = 31, bvFTD = 22) were performed. The Mann-Whitney U test was used to contrast groups. RESULTS There were statistically significant differences between the AD and bvFTD caregivers in strain, distress, and perceived control but not in depression. On average, bvFTD caregivers experienced greater strain and distress, more depressive symptoms, and lower perceived control. CONCLUSIONS Findings support that experiences of AD and bvFTD caregivers may differ. Further study is needed to identify possible explanatory factors for these group differences.

Verbal creativity in semantic variant primary progressive aphasia

Emergence of visual and musical creativity in the setting of neurologic disease has been reported in patients with semantic variant primary progressive aphasia (svPPA), also called semantic dementia (SD). It is hypothesized that loss of left anterior frontotemporal function facilitates activity of the right posterior hemispheric structures, leading to de novo creativity observed in visual artistic representation. We describe creativity in the verbal domain, for the first time, in three patients with svPPA. Clinical presentations are carefully described in three svPPA patients exhibiting verbal creativity, including neuropsychology, neurologic exam, and structural magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) was performed to quantify brain atrophy patterns in these patients against age-matched healthy controls. All three patients displayed new-onset creative writing behavior and produced extensive original work during the course of disease. Patient A developed interest in wordplay and generated a large volume of poetry. Patient B became fascinated with rhyming and punning. Patient C wrote and published a lifestyle guidebook. An overlap of their structural MR scans showed uniform sparing in the lateral portions of the language-dominant temporal lobe (superior and middle gyri) and atrophy in the medial temporal cortex (amygdala, limbic cortex). New-onset creativity in svPPA may represent a paradoxical functional facilitation. A similar drive for production is found in visually artistic and verbally creative patients. Mirroring the imaging findings in visually artistic patients, verbal preoccupation and creativity may be associated with medial atrophy in the language-dominant temporal lobe, but sparing of lateral dominant temporal and non-dominant posterior cortices.

Psychiatric symptom burden in older people living with HIV with and without cognitive impairment: the UCSF HIV over 60 cohort study

ABSTRACT Psychiatric comorbidities are common in people living with HIV (PLWH) and adversely affect life satisfaction, treatment adherence and disease progression. There are few data to inform the burden of psychiatric symptoms in older PLWH, a rapidly growing demographic in the U.S. We performed a cross-sectional analysis to understand the degree to which symptom burden was associated with cognitive disorders in PLWH over age 60. Participants completed a standardized neuropsychological battery and were assigned cognitive diagnoses using Frascati criteria. We captured psychiatric symptom burden using the Geriatric Depression Scale (GDS) and proxy-informed Neuropsychiatric Inventory-Questionnaire (NPI-Q). Those diagnosed with HIV-associated neurocognitive disorders (HAND, n = 39) were similar to those without HAND (n = 35) by age (median = 67 years for each group, p = 0.696), education (mean = 16 years vs. 17 years, p = 0.096), CD4+ T-lymphocyte counts (mean = 520 vs. 579, p = 0.240), duration of HIV (median = 21 years for each group, p = 0.911) and sex (92% male in HAND vs. 97% in non-HAND, p = 0.617). Our findings showed similarities in HAND and non-HAND groups on both NPI-Q (items and clusters) and GDS scores. However, there was a greater overall symptom burden in HIV compared to healthy elder controls (n = 236, p < 0.05), with more frequent agitation, depression, anxiety, apathy, irritability and nighttime behavior disturbances (p < 0.05). Our findings demonstrate no differences in psychiatric comorbidity by HAND status in older HIV participants; but confirm a substantial neurobehavioral burden in this older HIV-infected population.

Implementation of advanced practice nurse clinic for management of behavioral symptoms in dementia: A dyadic intervention (innovative practice)

Behavioral symptoms are common in all types of dementia and often result in significant caregiver stress and illness, institutionalization of the patient, and reduced quality of life for the patient and caregiver. Health care practitioners often lack the expertise or time to adequately assess behavioral symptoms or counsel caregivers about interventions. Our goal was to implement a specialty clinic managed by advanced practice nurses to assess and manage behavioral symptoms associated with dementia. The clinic evaluations consisted of an assessment of the patient by the Nurse Practitioner during the time that the family caregiver(s) was interviewed by the Clinical Nurse Specialist and focused on an assessment of the cognitive and functional abilities of the patient, identification of triggers for the problematic behaviors, and assessment of caregiver coping. We evaluated 66 dyads since implementation in February 2010. The patients were primarily female, Caucasian, 74.3 years of age with Alzheimer’s disease. The majority of caregivers were spouses (n = 44) followed by adult children (n = 20) and then siblings (n = 2). Targeted interventions were developed and caregiver counseling, support, and education were an integral part of the consultation and included written information, video instruction, and internet resources. Evaluations indicated caregivers and referring providers found the appointment helpful in managing behavioral symptoms and caregiver stress.

Neuropsychiatric Symptoms Predict Functional Status in Alzheimer's Disease.

BACKGROUND Cognitive deficits are presumed to be the primary driver of functional impairment in Alzheimers disease (AD); however, functional impairment is likely multifactorially determined. OBJECTIVE Our objective was to determine the relative contribution of neuropsychiatric symptoms in predicting ratings of functional status. METHODS A total of 223 patients received routine neurological and neuropsychological evaluations and met criteria of probable AD dementia based on the McKhann criteria. Demographic, cognitive, and neuropsychiatric variables were entered in a hierarchical linear regression analysis to predict functional status as measured by the Functional Activities Questionnaire (FAQ). RESULTS The total model explained 29.7% of the variance (p <  0.001) in FAQ. Importantly, neuropsychiatric variables explained 12.7% of the unique variance, with apathy and sleep as significant contributors. CONCLUSION Two neuropsychiatric variables, apathy and changes in sleep/nighttime behaviors, predicted ratings of functional status in AD patients independent of age, global cognition, memory and executive function measures, and depressive symptoms. These results highlight the importance of neuropsychiatric symptoms in understanding and potentially treating the functional limitations so prevalent in AD.

Anomalous functional language lateralization in semantic variant PPA

In 1982, Marsel Mesulam detailed a series of cases with primary progressive aphasia (PPA). Originally defined, PPA was restricted to patients with focal left hemisphere involvement. As cases with right hemisphere disease appeared,1–3 an amended theory proposed that PPA arose from a “locus of least resistance” within the dominant language network.4 Ultimately, this explanation was unable to account for a specific subtype of semantic variant PPA (svPPA) where pathology first involved the nondominant hemisphere and subsequently attacked the dominant anterior temporal lobe language network.5 With the discovery of increased non-right-handedness (nRH) and planum temporale symmetry within our svPPA cohort,6 we put forward a refinement of the prevailing hypothesis and suggested that mechanisms of lateralization and neurodevelopment that shape the language network also generate a differential pattern of disease susceptibility within specific PPA variants. We postulated that the increased nRH observed in svPPA might be secondary to an increased incidence of anomalous language laterality. In this report, we describe the magnetoencephalography (MEG) pattern of language lateralization in a single svPPA case with left temporal predominant atrophy despite a clinical presentation of a right temporal syndrome.