Aaron McMurtray

Preliminary findings : Behavioral worsening on donepezil in patients with frontotemporal dementia

OBJECTIVE The objective of this study was to evaluate donepezil, an acetylcholinesterase inhibitor, in the treatment of frontotemporal dementia (FTD). METHODS Twelve patients with FTD who received donepezil for six months were compared with 12 FTD controls on behavioral measures. RESULTS The groups did not differ on most variables at baseline or at six months; however, the donepezil group had greater worsening on the FTD Inventory. Four treated patients had increased disinhibited or compulsive acts, which abated with discontinuation of the medication. CONCLUSION There were no changes in global cognitive performance or dementia severity; however, a subgroup of patients with FTD can experience worsening of symptoms with donepezil.

Early-Onset Dementia: Frequency and Causes Compared to Late-Onset Dementia

Background: Research on the epidemiology of dementia has focused on the elderly. Few investigations have studied differences in etiologic frequencies between early-onset dementia (EOD), with onset at an age of less than 65 years old, and the more common late-onset disorder. Objectives: To determine relative frequencies and characteristics of EOD versus late-onset dementia (LOD; age of onset ≧65 years) diagnosed in a large memory disorders program over a 4-year period. Methods: We reviewed medical records, including an extensive neurobehavioral and neurological evaluation, of all patients seen at a large Veteran’s Affairs Medical Center Memory Disorders clinic between 2001 and 2004 and assessed demographic variables, final diagnoses, presence of dementia, and differential diagnosis of dementing illnesses. Results: Among 1,683 patients presenting for evaluation of an acquired decline in memory or cognition, 948 (56%) met established clinical criteria for a dementing illness. About 30% (n = 278) of these had an age of onset of <65 years, compared to 670 with LOD. Patients were predominantly male (98%). Compared to the late-onset group, the EOD patients were less severely impaired on presentation, but they did not differ in gender distribution or educational background. The EOD group had significantly more dementia attributed to traumatic brain injury, alcohol, human immunodeficiency virus (HIV), and frontotemporal lobar degeneration compared to the LOD patients. In contrast, the LOD group had significantly more Alzheimer’s disease compared to the EOD group. Conclusions: This study, conducted at a Veterans Affairs Hospital, is the largest series to date on EOD, and found a previously unexpectedly large number of patients below the age of 65 with cognitive deficits and impaired functioning consequent to head trauma, alcohol abuse, and HIV. These findings highlight the differential distribution and importance of preventable causes of dementia in the young.

Variations in regional SPECT hypoperfusion and clinical features in frontotemporal dementia

Objective: To characterize the presenting clinical features for frontotemporal dementia (FTD) and contrast them with the degree of frontal and temporal hypoperfusion on SPECT imaging. Methods: The authors evaluated 74 patients who eventually met Consensus Criteria for the FTD form of frontotemporal lobar degeneration (excluding primary progressive aphasia and semantic dementia) on 2-year follow-up. On first presentation, these patients had undergone both an FTD Inventory for 12 features based on core and supportive Consensus Criteria and SPECT imaging. The initial clinical diagnostic features were contrasted with variations in regional SPECT hypoperfusion. Results: The patients with FTD had more hypoperfusion in the right frontal lobe than in other regions; the subgroup of 25 patients who met Consensus Criteria from the first presentation had the most right frontal hypoperfusion. Frontal lobe involvement was associated with significant apathy, whereas temporal lobe involvement was associated with hypomania-like behavior. Right frontal lobe hypoperfusion further predicted loss of insight, environmental dependency, and stereotyped behaviors. Other associations included left frontal hypoperfusion with a decline in personal hygiene and left temporal hypoperfusion with compulsions and mental rigidity. Conclusions: On first presentation, frontotemporal dementia (FTD) is disproportionately a right frontal disease evident on behavioral measures and on SPECT. Nonetheless, patients with FTD can initially present with further regional differences in clinical diagnostic features, such as apathy with bifrontal hypoperfusion and hypomania-like behaviors with anterior temporal involvement.

Functional neuroimaging and presenting psychiatric features in frontotemporal dementia

Background: Frontotemporal dementia (FTD) is a behavioural syndrome caused by degeneration of the frontal and anterior temporal lobes. Behavioural disturbances include psychiatric features. Whether patients with FTD present with psychiatric features varies with the initial neuroanatomical variability of FTD. Objective: To identify presenting psychiatric changes not part of diagnostic criteria of FTD and contrast them with the degree of hemispheric asymmetry and frontal and temporal hypoperfusion on single photon emission computed tomography (SPECT) imaging. Methods: 74 patients who met consensus criteria for FTD were evaluated at a two year follow up. All had brain SPECT on initial presentation. Results of an FTD psychiatric checklist were contrasted with ratings of regional hypoperfusion. Results: The regions of predominant hypoperfusion did not correlate with differences on FTD demographic variables but were associated with presenting psychiatric features. Dysthymia and anxiety were associated with right temporal hypoperfusion. “Moria” or frivolous behaviour also occurred with temporal lobe changes, especially on the right. The only significant frontal lobe feature was the presence of a peculiar physical bearing in association with right frontal hypoperfusion. Conclusions: Patients with FTD may present with psychiatric changes distinct from the behavioural diagnostic criteria for this disorder. Early temporal involvement is associated with frivolous behaviour and right temporal involvement is associated with emotional disturbances. In contrast, those with right frontal disease may present with alterations in non-verbal behaviour.

Aging exacerbates extrapyramidal motor signs in the era of highly active antiretroviral therapy

The phenotype of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) in the developed world has changed with the broad institution of highly active antiretroviral theray (HAART) and with aging of the HIV+ population. Extrapyramidal motor signs were a prominent feature of HAND as defined in the early stages of the epidemic but has not been reevaluated in the era of HAART. Moreover, the contribution of aging to extrapyramidal motor signs in the context of HIV remains undefined. We examined these questions among the 229 HIV+ participants in the Hawaii Aging with HIV Cohort compared to age-, gender-, and ethnicity-matched HIV-negative controls. Extrapyramidal motor signs were quantified using the motor exam of the Unified Parkinson’s Disease Rating Scale (UPDRSmotor) and compared to concurrent neuropsychological and clinical cognitive diagnostic categorization. The mean UPDRSmotor score increased with older age (1.68 versus 3.35; P <.001) and with HIV status (1.18 versus 3.56; P <.001). Age group (P =.024), HIV status (P <.001), and the interaction between age and HIV (P =.026) were significantly associated with UPDRSmotor score. Among HIV+ patients, the mean UPDRSmotor score increased with worsening cognitive diagnostic category (P <.001) where it was 2.06 (2.31) in normal cognition (n = 110), 3.21 (3.48) in minor cognitive motor disorder (MCMD) (n = 84), and 5.72 (5.01) in HIV-associated dementia (HAD) (n = 37). We conclude that extrapyramidal motor signs are increased in HIV in the era of HAART and that the impact of HIV on extrapyramidal motor signs is exacerbated by aging. These results highlight the importance of a careful neurological examination in the evaluation of HIV patients.

Cognitive Differences between Early- and Late-Onset Alzheimer's Disease:

Although neuropathologic studies showed that early-onset Alzheimers disease (EAD) and “senile dementia” were indistinguishable, clinical studies suggested that EAD and late-onset Alzheimers disease (LAD) were cognitively distinct. We sought to investigate whether EAD and LAD are cognitively different by comparing patients at the extremes of the ages of onset in order to maximize features that might separate them. We compared 44 men with EAD (age of onset less than 65 years) with 44 men with LAD (age of onset 84 years or older) on an intake cognitive screening examination on initial presentation. The EAD and LAD groups did not differ on dementia or most cognitive variables. Compared with EAD, the LAD group had worse verbal fluency and motor-executive functions. These differences disappeared when age differences were taken into account. We conclude that Alzheimers disease is a clinically heterogeneous disorder whose manifestations can vary with age of onset. These differences indicate age-related vulnerabilities in this disease.

Frontotemporal Dementia-like Phenotypes Associated With Presenilin-1 Mutations:

Frontal behavioral changes may be the presenting features of single-photon emission tomography (presenilin-1 [PS-1]) mutations, the most common cause of familial Alzheimers disease (AD). The authors describe a PS-1 (M233L) mutation with the features of frontotemporal dementia (FTD) and review the literature. PS-1 mutations may produce FTD-like phenotypes with the neuropathology of AD. Some PS-1 mutations have additional Picks bodies, a neuropathological marker of FTD, and a report of a PS-1 (G183V) mutation found Picks bodies without amyloid plaques. The patient and the literature suggest that PS-1 mutations result in an overlapping continuum of the clinical and neuropathological features of AD and FTD. In PS-1 mutations, the expression of AD or FTD may depend on the degree of loss of function of the PS-1 gene and the resultant τ pathophysiology.

Small-Vessel Vascular Disease in Human Immunodeficiency Virus Infection: The Hawaii Aging with HIV Cohort Study

Background: This study is designed to determine the relationship between age and occurrence of cerebral manifestations of small-vessel ischemic vascular disease in human immunodeficiency virus (HIV)-seropositive individuals. Methods: Periventricular leukoaraiosis severity and white matter lesion volume were determined by magnetic resonance imaging of the brain of 57 HIV-seropositive individuals. Results: Cerebral small-vessel ischemic vascular disease manifestations correlated with age and systolic blood pressure, but not with HIV infection-related parameters. Conclusions: These findings suggest that, in the era of highly active antiretroviral therapy, leukoaraiosis severity and white matter lesion volume may be more indicative of small-vessel ischemic vascular disease than HIV-related CNS pathology, and support the need for aggressive treatment of vascular risk factors in HIV-seropositive individuals.

Cortical atrophy and white matter hyperintensities in HIV: the Hawaii Aging with HIV Cohort Study.

BACKGROUND As many human immunodeficiency virus (HIV)-seropositive individuals are now living longer after infection because of highly active antiretroviral therapy, aging-related manifestations of cerebral small-vessel ischemic vascular disease, such as brain white matter hyperintensities (WMHs), are becoming increasingly important in this population. GOALS This study was designed to determine the relationship between WMHs and cortical volumes in HIV-seropositive individuals. MATERIALS AND METHODS Voxel-based morphometry was used to compare cortical volumes among 62 HIV-seropositive individuals participating in the Hawaii Aging with HIV Cohort Study, 30 with moderate WMHs and 32 with minimal or no WMHs. RESULTS Presence of moderate WMHs was associated with decreased cortical volumes in the frontal lobes bilaterally. CONCLUSION These findings suggest that age-related WMHs are associated with reduced frontal gray matter volumes in HIV-seropositive individuals, supporting the hypothesis that the frontal lobes may have greater susceptibility to the effects of small-vessel ischemic vascular disease.

Outbreak of pertussis among healthcare workers in a hospital surgical unit.

BACKGROUND In September 1999, a pertussis outbreak was detected among surgical staff of a 138-bed community hospital. Patients were exposed to Bordetella pertussis during the 3-month outbreak period. OBJECTIVE To describe the outbreak among surgical staff, to evaluate implemented control measures, and to determine whether nosocomial transmission occurred. METHODS Clinical pertussis was defined as acute cough illness with a duration of 14 days or more without another apparent cause; persons with positive culture, PCR, or serologic test results were defined as having laboratory-confirmed pertussis. Surgical healthcare workers (HCWs) were interviewed regarding pertussis symptoms, and specimens were obtained for laboratory analysis. Patients exposed to B. pertussis during an ill staff members 3-week infectious period were interviewed by phone to determine the extent of nosocomial spread. PARTICIPANTS A total of 53 HCWs assigned to the surgical unit and 146 exposed patients. HCWs with pertussis were defined as case subjects; HCWs without pertussis were defined as non-case subjects. RESULTS Twelve (23%) of 53 HCWs had clinical pertussis; 6 cases were laboratory confirmed. The median cough duration in the 12 case subjects was 27 days (range, 20-120 days); 10 (83%) had paroxysms. Eleven (92%) of 12 case subjects and 28 (86%) of 41 non-case subjects received antibiotic treatment or prophylaxis. Seven case subjects (58%) reported they always wore a mask when near patients. Of 146 patients potentially exposed to pertussis from the 12 case subjects, 120 (82%) were interviewed; none reported a pertussis-like illness. CONCLUSIONS Surgical staff transmitted B. pertussis among themselves; self-reported data suggests that these HCWs did not transmit B. pertussis to their patients, likely because of mask use, cough etiquette, and limited face-to-face contact. Control measures might have helped limit the outbreak once pertussis was recognized.