Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Patterns of hypothalamic GnIH change over the reproductive period in starlings and rats.

Gonadotropin inhibitory hormone (GnIH) exerts powerful inhibitory effects on various levels of the vertebrate hypothalamic-pituitary-gonadal (reproductive) axis, yet little is known of how it might change naturally over the course of reproduction. We characterized patterns of hypothalamic GnIH cell abundance over the reproductive period in two popular models used for the study of reproductive endocrinology: European starlings (Sturnus vulgaris) and Sprague-Dawley rats (Rattus norvegicus). We also examined the effects on an unpredictable change in the environment on GnIH cell abundance during the reproductive period, specifically during the period of parental care, by simulating a nest predation event and removing eggs/pups. In both species, we report changes in GnIH cell abundance are occurring at similar reproductive time points but are not always directionally parallel; this may be due to a difference in life histories and physiology mediating parental care. We discovered that cells immunoreactive for the GnIH peptide in male and female starlings are most highly abundant on the first day of incubation and the first day after the first chick hatches. Conversely in rats, GnIH cell abundance decreases in dams on the first day after pups are born. In both male and female starlings and female rats, GnIH cell abundance increases in response to egg/pup loss, indicating that GnIH responds to an unpredictable change in the environment in a potentially conserved fashion. These changes in GnIH cell abundance during the reproductive period inspire further investigation of its adaptive role in reproductive physiological events and behaviors, especially parental care.

Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons.

Impaired regulation of emotional memory is a feature of several affective disorders, including depression, anxiety and post-traumatic stress disorder. Such regulation occurs, in part, by interactions between the hippocampus and the basolateral amygdala (BLA). Recent studies have indicated that within the adult hippocampus, newborn neurons may contribute to support emotional memory, and that regulation of hippocampal neurogenesis is implicated in depressive disorders. How emotional information affects newborn neurons in adults is not clear. Given the role of the BLA in hippocampus-dependent emotional memory, we investigated whether hippocampal neurogenesis was sensitive to emotional stimuli from the BLA. We show that BLA lesions suppress adult neurogenesis, while lesions of the central nucleus of the amygdala do not. Similarly, we show that reducing BLA activity through viral vector-mediated overexpression of an outwardly rectifying potassium channel suppresses neurogenesis. We also show that BLA lesions prevent selective activation of immature newborn neurons in response to a fear-conditioning task. These results demonstrate that BLA activity regulates adult hippocampal neurogenesis and the fear context-specific activation of newborn neurons. Together, these findings denote functional implications for proliferation and recruitment of new neurons into emotional memory circuits.

Cortical cholinergic denervation is associated with depressive symptoms in Parkinson's disease and parkinsonian dementia.

AIM: To investigate the relationship between ratings of depressive symptoms and in vivo cortical acetylcholinesterase (AChE) activity in subjects with Parkinson's disease (PD) and parkinsonian dementia (PDem). METHODS: Subjects (with PD, n = 18, including subjects with PDem, n = 6, and normal controls, n = 10) underwent [11C]methyl-4-piperidinyl propionate AChE positron emission tomography imaging and clinical assessment including the Cornell Scale for Depression in Dementia (CSDD). RESULTS: Subjects with PD and PDem had higher scores on the CSDD compared with normal controls: 7.3 (5.4) and 2.8 (2.6), respectively (F = 6.9, p = 0.01). Pooled analysis demonstrated a significant inverse correlation between cortical AChE activity and CSDD scores: R = -0.5, p = 0.007. This correlation remained significant after controlling for Mini-Mental State Examination scores. CONCLUSION: Depressive symptomatology is associated with cortical cholinergic denervation in PD that tends to be more prominent when dementia is present.

White matter hyperintensities and cortical acetylcholinesterase activity in parkinsonian dementia.

OBJECTIVE: To investigate the relationship between the severity of white matter hyperintensities (WMH) and cortical acetylcholinesterase (AChE) activity in parkinsonian dementia (PDem). METHODS: PDem (n = 11) and control subjects (n = 14) underwent [11C]methyl-4-piperidinyl propionate (11C-PMP) AChE brain positron emission tomography and magnetic resonance (MR) imaging. Presence of WMH on proton density and T2 MR images was scored using a modified version of the semi-quantitative rating scale by Scheltens et al. [J Neurol Sci114 (1993)]. RESULTS: Analysis demonstrated significantly lower mean cortical (11)C-PMP k3 hydrolysis rates in PDem (-19.9%) when compared with control subjects (P < 0.0001). PDem subjects had higher mean severity of WMH (+20.1%) when compared with control subjects (P < 0.05). When WMH severity was entered into the analysis of variance model, there was no significant co-variate effect on cortical AChE activity (F = 0.24, ns). CONCLUSIONS: The concomitant presence of mild to moderate WMH in patients with PDem does not have a significant effect on cortical AChE activity.

Cognitive correlates of cortical cholinergic denervation in Parkinson's disease and parkinsonian dementia.

We recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer's disease (AD). In this study we determined cognitive correlates of in vivo cortical AChE activity in patients with parkinsonian dementia (PDem, n = 11), Parkinson's disease without dementia (PD, n = 13), and in normal controls (NC, n = 14) using N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET). Cortical AChE activity was significantly reduced in the PDem (-20.9%) and PD (-12.7 %) subjects (P < 0.001) when compared with the control subjects. Analysis of the cognitive data within the patient groups demonstrated that scores on the WAIS-III Digit Span, a test of working memory and attention, had most robust correlation with cortical AChE activity (R = 0.61, p < 0.005). There were also significant correlations between cortical AChE activity and other tests of attentional and executive functions, such as the Trail Making and Stroop Color Word tests. There was no significant correlation between cortical AChE activity and duration of motor disease (R = -0.01, ns) or severity of parkinsonian motor symptoms (R = 0.14, ns). We conclude that cortical cholinergic denervation in PD and parkinsonian dementia is associated with decreased performance on tests of attentional and executive functioning.

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Cognitive performance in Alzheimer's disease patients receiving rivastigmine for up to 5 years.

This analysis aimed to assess mini-mental state examination (MMSE) scores in patients with Alzheimer's disease who received rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, for up to 5 years. Rivastigmine data came from two pooled open-label extensions of four 6-month, randomised, placebo-controlled trials. Projections of decline, had the same patients not been treated, were made using a baseline-dependent mathematical model. MMSE data were available for 1998 rivastigmine-treated patients and 657, 298 and 83 were still on treatment at 3, 4 and 5 years, respectively. The mean (+/-SD) baseline MMSE score was 19.3 (+/-4.9). Projected mean scores in model-based untreated patients declined below 10 points on the MMSE at about 3 years, while the mean MMSE score of patients who remained on rivastigmine stayed above 10 points for 5 years.

Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease.

OBJECTIVES: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy. METHODS: Cognitive and N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy. RESULTS: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = -7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = -14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R(2) = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = -2.7; p<0.05). CONCLUSIONS: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.

Right prosubiculum amyloid plaque density correlates with anosognosia in Alzheimer's disease.

BACKGROUND: Anosognosia is a common manifestation of Alzheimer's disease. There is an association between impaired awareness and frontal-executive cognitive deficits. Anosognosia is also correlated with decreased metabolism in the right hemisphere, particularly in frontal lobe regions. OBJECTIVE: To investigate pathological correlates of anosognosia in Alzheimer's disease. DESIGN: 41 subjects followed longitudinally in the University of Pittsburgh memory disorders clinic and with necropsy verified Alzheimer's disease were divided into two groups, based on previous clinical assessment: +Aware (n = 23) and -Aware (n = 18). A subset analysis matching subjects for dementia severity using mini-mental state examination scores was also carried out (13 +Aware; 13 -Aware). Histopathological data from necropsy brain tissue consisted of senile plaque (SP) and neurofibrillary tangle (NFT) counts (regional density) from four different brain regions in the right and left hemispheres: superior and middle frontal gyri (SMF), superior temporal isocortex (ST), the prosubiculum of the hippocampus (PRO), and the entorhinal cortex (EC). RESULTS: SP density was greater in the right PRO region of -Aware subjects (F = 6.54, p = 0.015) than +Aware subjects. Significant differences between SP or NFT density were not observed in any other regions. In the subset analysis matching for dementia severity, SP density was again greater in the right PRO region of -Aware subjects than in the other regions (F = 12.72, p = 0.002). CONCLUSIONS: Increased SP density in the right PRO region suggests that selective pathological involvement of this area contributes to awareness deficits in Alzheimer's disease. The putative role of the PRO in self appraisal may reflect its interconnections with other medial temporal and prefrontal regions.

Restructuring the neuronal stress response with anti-glucocorticoid gene delivery.

Glucocorticoids, the adrenal steroids released during stress, compromise the ability of neurons to survive neurological injury. In contrast, estrogen protects neurons against such injuries. We designed three genetic interventions to manipulate the actions of glucocorticoids, which reduced their deleterious effects in both in vitro and in vivo rat models. The most effective of these interventions created a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the estrogen receptor. Expression of this chimeric receptor reduced hippocampal lesion size after neurological damage by 63% and reversed the outcome of the stress response by rendering glucocorticoids protective rather than destructive. Our findings elucidate three principal steps in the neuronal stress-response pathway, all of which are amenable to therapeutic intervention.

[Dementia and Lewy bodies]. / Demencia y cuerpos de Lewy.

Consensus diagnostic criteria for dementia with Lewy bodies (DLB) proposed in 1996 have provided a useful foundation for research in the field. As a clinicopathologically defined entity, DLB has overlapping features of both Alzheimer s disease (AD) and Parkinson's disease (PD). Consensus criteria for DLB distinguish it from PD dementia by the earlier appearance of motor signs in the latter. Studies evaluating the standardized clinical diagnostic criteria for DLB have generally found them to be highly predictive of Lewy body pathology. However, many cases with Lewy body pathology and concomitant pathological features of AD elude clinical detection. Emerging data suggests that AD pathological features mask the clinical expression of concomitant Lewy body pathology, and that DLB and PD dementia may be more similar than distinct.

[Treatment of neuropsychiatric symptoms in Alzheimer's disease]. / Tratamiento de los síntomas neuropsiquiátricos en la enfermedad de Alzheimer.

The overall goal of all therapeutic interventions in Alzheimer s disease (AD) is the optimisation of the adaptive functions and quality of life of these patients. The general strategy for the use of pharmacological interventions in the treatment of neuropsychiatric manifestations of AD includes the following: 1) An exhaustive evaluation of the psychiatric symptomatology; 2) Establish a hierachy of the simptoms to treat based on their severity of symptoms and on their impact on the caregiver; 3) The identification of an adequate agent based on the type of symptoms and subject s characteristics; 4) The initial use of low doses with gradual titration, and 5) Changing one drug at a time. Regarding psychotic symptons, the introduction of new agents (e.g., risperidone) has replaced the use of traditional treatments (e.g., thioridazine) in patients with AD. The presence of psychomotor agitation and aggression can be treated with great variety of drugs, such as antipsychotics, anticonvulsants, antidepressants, and sedatives. Selective serotonine re uptake inhibitors are the treatment of choice for depressive symptomatology. The cholinesterase inhibitors have shown to be useful in the treatment of hallucinations, anxiety and apathy.

Tratamiento de los síntomas neuropsiquiátricosen la enfermedad de Alzheimer / Treatment of neuropsychiatric symptoms in alzheimer's disease

El objetivo final de todas las intervenciones terapéuticas en la enfermedad de Alzheimer (EA) es la optimización de las funciones adaptativas y la mejoría de la calidad de vida. La estrategia general respecto al empleo de las intervenciones farmacológicas para tratar los síntomas neuropsiquiátricos en la EA es: 1) Evaluación exhaustiva de los síntomas neuropsiquiátricos presentes; 2) Establecimiento de una jerarquía de síntomas objetivos basada en las tasas de síntomas e impacto en el cuidador; 3) Identificación de los agentes adecuados para abordar los síntomas objetivos sobre la base de los factores individuales; 4) Empleo de la dosis inicial más baja posible, con una valoración gradual de las dosis; y 5) Cambio de una sola variable de fármaco a la vez. Con respecto al tratamiento de los síntomas psicóticos, la introducción reciente de nuevos agentes antipsicóticos (p. ej., risperidona) ha sustituido en gran medida el empleo de agentes antipsicóticos tradicionales (p. ej., tioridacina) en la EA.La agitación psicomotora y la agresividad pueden tratarse con una gran variedad de fármacos, entre los que se encuentran agentes antipsicóticos, anticonvulsionantes y antidepresivos. Los inhibidores selectivos de la reabsorción de serotonina constituyen el tratamiento de elección para los síntomas depresivos. Los inhibidores de las colinesterasas han mostrado tener un efecto positivo en pacientes con alucinaciones, ansiedad y apatía (AU)

[Neuropsychiatric inventory questionnaire (NPI-Q): Spanish validation of an abridged form of the Neuropsychiatric Inventory (NPI)]. / Neuropsychiatric Inventory Questionnaire (NPI-Q): validación española de una forma abreviada del Neuropsychiatric Inventory (NPI)*

BACKGROUND: The Neuropsychiatric Inventory (NPI) is a validated clinical instrument for the evaluation of psychopathology in dementia. OBJECTIVE: To validate a brief questionnaire form of the NPI (NPI-Q) in Spanish from NPI-Q original version, intended for use in routine clinical practice. PATIENTS AND METHOD: We have developed a crossed validated form between NPI and NPI-Q in 120 Alzheimer's disease patients. RESULTS: Test-retest reliability of the NPI-Q, using Pearson correlation index was r = 0.89 for total symptom scale and r = 0.90 for distress scale. The prevalence of analogous symptom ratings differed by less than 6.7%. Convergent validity between NPI-Q and NPI, using Pearson correlation index was r = 0.879 for total symptom and r = 0.92 for distress scale. CONCLUSIONS: The NPI-Q Spanish version offers the possibility to use a reliable and brief instrument that can be used as a screening in the evaluation of neuropsychiatric symptoms in dementia and associated caregiver distress. It may be suitable for use in general clinical practice and it could be used as a brief neuropsychiatric interview.

Neuropsychiatric Inventory Questionnaire (NPI-Q): validación española de una forma abreviada del Neuropsychiatric Inventory (NPI) / Neuropsychiatric Inventory Questionnaire (NPI-Q): Spanish validation of a brief clinical form of the Neuropsychiatric inventory (NPI)

FUNDAMENTOS: El Neuropsychiatric Inventory (NPI) es un instrumento validado para la evaluación clínica de la sintomatología neuropsiquiátrica para las enfermedades que cursan con demencia. OBJETIVO: Ofrecer una validación en castellano de un instrumento breve que se ha desarrollado desde el NPI, llamado NPI-Q, diseñado para el uso en la práctica clínica diaria como método de cribado. PACIENTES Y MÉTODO: Se ha desarrollado una validación cruzada entre NPI y NPI-Q en 120 pacientes con enfermedad de Alzheimer. RESULTADOS: El test-retest de la escala NPI-Q, mediante el empleo del índice de correlación de Pearson, fue de r = 0,89 para la escala de total de presencia de síntomas y de r = 0,90 para la escala de estrés del cuidador. La prevalencia de síntomas análogos difiere en menor del 6,7 per cent. La validez convergente entre el NPI-Q y el NPI, usando el índice de correlación de Pearson, fue r = 0,879 para la escala gravedad y r = 0,92 para la escala de estrés. CONCLUSIONES: La versión castellana del NPI-Q ofrece la posibilidad de usar un instrumento válido y fiable, a la par que breve, lo que favorece su uso como método de cribado en la evaluación de los síntomas neuropsiquiátricos en la demencia, así como para la valoración del agotamiento emocional provocado en el cuidador, pudiendo ser utilizada en la práctica clínica diaria, ya como entrevista breve, ya en forma autoadministrada. (AU)

Cholinesterase inhibitor treatment alters the natural history of Alzheimer's disease.

OBJECTIVE: To describe the effect of cholinesterase inhibitors (CEIs) on the natural course of Alzheimer's disease (AD). METHODS: The short and long term effects of CEIs were evaluated in 135 patients with probable Alzheimer's disease relative to 135 patients who were never exposed to CEIs matched by age, education, duration of the symptoms, and cognitive status. We measured 1 year change in cognitive and functional performance, and the likelihood of arriving at each of four end points: (1) mini mental state examination (MMSE) of 9 or lower, (2) Blessed dementia rating scale for activities of daily living of 12 or higher, (3) nursing home admission, and (4) death, over an average 3 years of observation (36.7 (SD 21.5) months). RESULTS: Patients on CEIs were better cognitively and functionally after 1 year compared with those patients who never used CEIs. A proportional hazard analysis with CEI use as a time dependent covariate showed that the use of CEIs decreased the risk of nursing home admission. There was no association, however, between use of CEIs and time to cognitive and functional end points, or to death. CONCLUSIONS: This observational study showed that there was an initial cognitive and functional benefit from the use of CEIs in Alzheimer's disease, which waned as the disease progressed. However, the results suggest that there is a long term beneficial effect of the use of CEIs, as indicated by the delay in admission to nursing homes.

ARP, a peptide derived from the stress-associated acetylcholinesterase variant, has hematopoietic growth promoting activities.

BACKGROUND: Psychological stress induces rapid and long-lasting changes in blood cell composition, implying the existence of stress-induced factors that modulate hematopoiesis. Here we report the involvement of the stress-associated "readthrough" acetylcholinesterase (AChE-R) variant, and its 26 amino acid C-terminal domain (ARP) in hematopoietic stress responses. MATERIALS AND METHODS: We studied the effects of stress, cortisol, antisense oligonucleotides to AChE, and synthetic ARP on peripheral blood cell composition and clonogenic progenitor status in mice under normal and stress conditions, and on purified CD34 cells of human origin. We employed in situ hybridization and immunocytochemical staining to monitor gene expression, and 5-bromo-2-deoxyuridine (BrdU), primary liquid cultures, and clonogenic progenitor assays to correlate AChE-R and ARP with proliferation and differentiation of hematopoietic progenitors. RESULTS: We identified two putative glucocorticoid response elements in the human ACHE gene encoding AChE. In human CD34+ hematopoietic progenitor cells, cortisol elevated AChE-R mRNA levels and promoted hematopoietic expansion. In mice, a small peptide crossreacting with anti-ARP antiserum appeared in serum following forced swim stress. Ex vivo, ARP was more effective than cortisol and equally as effective as stem cell factor in promoting expansion and differentiation of early hematopoietic progenitor cells into myeloid and megakaryocyte lineages. CONCLUSIONS: Our findings attribute a role to AChE-R and ARP in hematopoietic homeostasis following stress, and suggest the use of ARP in clinical settings where ex vivo expansion of progenitor cells is required.

Long-term care in dementia: patients and caregivers.

General principles of managing chronic, age-associated diseases apply as much to Alzheimer's disease (AD) and other late-life dementing disorders as they do to congestive heart failure or osteoarthritis. Beyond efforts to maintain residual tissue or organ function, important physician roles include promoting general well-being and helping patients and their caregivers adjust to disease-related limitations. Physicians provide essential information to patients and their families about the disease, its social and legal ramifications, and community resources to facilitate care. Therefore, physicians must be knowledgeable about broadly intersecting medical, legal, financial, and ethical issues surrounding the long-term management of AD and other dementias. The many challenges faced by patients with dementia and their caregivers over time underscore the need for an ongoing diagnostic and therapeutic alliance with primary care physicians. This article reviews salient aspects of long-term care for patients with AD and other dementias, highlighting the vital and varied roles of physicians in managing these chronic brain disorders.