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.

Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response.

Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Pyridostigmine is also recommended by most Western armies for use as pretreatment under threat of chemical warfare, because of its protective effect against organophosphate poisoning. Because of this drug's quaternary ammonium group, which prevents its penetration through the blood-brain barrier, the symptoms associated with its routine use primarily reflect perturbations in peripheral nervous system functions. Unexpectedly, under a similar regimen, pyridostigmine administration during the Persian Gulf War resulted in a greater than threefold increase in the frequency of reported central nervous system symptoms. This increase was not due to enhanced absorption (or decreased elimination) of the drug, because the inhibition efficacy of serum butyryl-cholinesterase was not modified. Because previous animal studies have shown stress-induced disruption of the blood-brain barrier, an alternative possibility was that the stress situation associated with war allowed pyridostigmine penetration into the brain. Here we report that after mice were subjected to a forced swim protocol (shown previously to simulate stress), an increase in blood-brain barrier permeability reduced the pyridostigmine dose required to inhibit mouse brain AChE activity by 50% to less than 1/100th of the usual dose. Under these conditions, peripherally administered pyridostigmine increased the brain levels of c-fos oncogene and AChE mRNAs. Moreover, in vitro exposure to pyridostigmine increased both electrical excitability and c-fos mRNA levels in brain slices, demonstrating that the observed changes could be directly induced by pyridostigmine. These findings suggest that peripherally acting drugs administered under stress may reach the brain and affect centrally controlled functions.

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.

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.

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.

Antisense prevention of neuronal damages following head injury in mice.

Closed head injury (CHI) is an important cause of death among young adults and a prominent risk factor for nonfamilial Alzheimer's disease. Emergency intervention following CHI should therefore strive to improve survival, promote recovery, and prevent delayed neuropathologies. We employed high-resolution nonradioactive in situ hybridization to determine whether a single intracerebro-ventricular injection of 500 ng 2'-O-methyl RNA-capped antisense oligonucleotide (AS-ODN) against acetylcholinesterase (AChE) mRNA blocks overexpression of the stress-related readthrough AChE (AChE-R) mRNA splicing variant in head-injured mice. Silver-based Golgi staining revealed pronounced dendrite outgrowth in somatosensory cortex of traumatized mice 14 days postinjury that was associated with sites of AChE-R mRNA overexpression and suppressed by anti-AChE AS-ODNs. Furthermore, antisense treatment reduced the number of dead CA3 hippocampal neurons in injured mice, and facilitated neurological recovery as determined by performance in tests of neuromotor coordination. In trauma-sensitive transgenic mice overproducing AChE, antisense treatment reduced mortality from 50% to 20%, similar to that displayed by head-injured control mice. These findings demonstrate the potential of antisense therapeutics in treating acute injury, and suggest antisense prevention of AChE-R overproduction to mitigate the detrimental consequences of various traumatic brain insults.

Neuropsychiatric aspects of Alzheimer's disease: the cholinergic hypothesis revisited.

Altered cholinergic function is a prominent feature of AD. The neuropsychological impairments of AD are attributed, at least partially, to the cholinergic disturbance, and current approaches to treatment of the cognitive abnormalities attempt to enhance cholinergic function. Behavioral changes are common in AD and include psychosis, agitation, depression, anxiety, personality alterations, and neurovegetative changes. The contribution of the cholinergic deficiency to the behavioral alterations has been little explored, but neurochemical, neuroanatomic, pharmacologic, and clinical observations suggest that the cholinergic deficiency contributes importantly to the neuropsychiatric dimension of AD. Investigation of the role of cholinergic dysfunction in the behavioral changes of AD will improve understanding of the pathophysiologic basis of these abnormalities and may lead to new types of therapy for the neuropsychiatric disturbances associated with this common dementing disorder.

The apolipoprotein E epsilon 4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease.

The objective of our study was to examine the relationship between the presence of the apolipoprotein E (apo E) epsilon 4 allele, psychiatric symptoms, and extrapyramidal signs (EPS) in probable Alzheimer's disease (AD). The apo E epsilon 4 allele modifies the risk and age at onset of AD. However, it still needs to be determined whether it is a marker for specific clinical subgroups. The frequency of clinical signs and symptoms was examined in 194 AD patients with the apo E epsilon 3/3 (N = 79), epsilon 3/4 (N = 96), and epsilon 4/4 (N = 19) genotypes participating in a longitudinal study of dementia. Each patient was assessed with semistructured psychiatric and neurologic examinations. Patients with the epsilon 4/4 genotype had an earlier age at onset of dementia (p = 0.03). However, no individual psychiatric symptom or neurologic sign was associated with the presence of the apo E epsilon 4 allele, including major depression (odds ratio [OR], 1.14; CI, 0.50 to 2.45; p = 0.78), psychosis (e.g., delusions and hallucinations) (OR, 0.66, CI, 0.35 to 1.25; p = 0.20), and EPS (in neuroleptic-free patients) (OR, 0.82, CI, 0.45 to 1.49; p = 0.52), after controlling by age at onset, duration of the symptoms, education, and severity of dementia. The presence of the apo E epsilon 4 allele has limited utility in the characterization of neurologic and psychiatric subgroups in probable AD patients. The apo E epsilon 4/4 genotype appears to be related to age at onset of AD, consistent with previous findings.

Midline cerebral morphometry distinguishes frontotemporal dementia and Alzheimer's disease.

We investigated and contrasted midline cerebral structures in frontotemporal dementia (FTD) and Alzheimer's disease (AD). FTD and AD may be difficult to distinguish clinically. FTD typically affects frontal and anterior temporal regions, whereas AD tends to involve more posterior temporal and parietal areas. We hypothesized that disease-specific cerebral alterations would be differentially reflected in corresponding regions of the corpus callosum (CC), pericallosal CSF space (PCS), or their ratio (CC:PCS). Regions-of-interest (ROIs) from midsagittal MRIs in 17 AD, 16 FTD, and 12 elderly control (EC) subjects were analyzed. ROIs were divided into four regions using an anatomic landmark-based computer algorithm and were adjusted for head size variation. FTD subjects had a much smaller anterior CC region and significantly larger PCS area, particularly in anterior regions. AD and EC subjects did not differ significantly in any total or regional ROI measure. Total and anterior CC:PCS ratios were markedly lower in FTD patients. Across groups, total CC:PCS correlated significantly with midsagittal cerebral area and was similarly associated with Mini-Mental State Examination score. Anterior CC (AD) and PCS (FTD) regions exhibited disease-specific relationships to these variables. A discriminant model using two ROI variables correctly classified 91% of AD and FTD patients, comparing favorably with blind clinical MRI diagnostic ratings. Midline cerebral structural alterations reflect differential patterns of cerebral degeneration in AD and FTD, yielding morphometric indices that may facilitate the study of brain-behavior relationships and differential diagnosis of dementia.

Predictors of progression in patients with AD and Lewy bodies.

OBJECTIVE: To examine the differences in the pattern of progression between AD and AD with Lewy bodies (AD+LB). METHODS: The authors examined predictors of functional and cognitive disability, institutionalization, and death, as well as time to the development of psychosis (e.g., delusions, hallucinations), extrapyramidal signs (EPS), diurnal hypersomnia, and depression in 185 patients with definite AD and 60 with autopsy-confirmed AD+LB. In addition, they analyzed a selected group of patients who did not have comorbid systemic or CNS disease that may have affected progression of the disease (AD = 98 versus AD+LB = 44). The mean follow-up was 58.91 +/- 35.2 months. RESULTS: All cases: Patients with AD+LB had faster time to the development of EPS and diurnal hypersomnia, but not to the development of psychosis or depression. The rate of cognitive and functional decline, time to institutionalization, and physical survival was not different between AD+LB and AD. Selected cases: Patients with AD+LB developed earlier EPS and diurnal hypersomnia than AD patients, and there was a trend to develop earlier major depression, but no differences were noted in time to psychosis. Patients with AD+LB had a faster time to institutionalization than those with AD. The rate of cognitive and functional decline and physical survival was not different between AD+LB and AD in these selected cases. CONCLUSION: Patients with AD+LB can develop EPS and diurnal hypersomnia earlier and have faster time to institutionalization than those with AD alone, but cognitive and functional decline and physical survival are similar between these two entities.

Severity of cognitive impairment and the clinical diagnosis of AD with Lewy bodies.

OBJECTIVE: 1) To examine the clinical differences between AD and AD with Lewy bodies (AD+LB); and 2) to determine the accuracy of Consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) at different levels of dementia severity. METHODS: The authors examined the clinical characteristics of 185 patients with pathologically diagnosed AD alone and 60 with AD+LB. The relationship between clinical symptoms and AD+LB was determined by multivariate analyses, controlled by age, duration of symptoms, presence of cerebrovascular disease, and dementia severity. RESULTS: Mild dementia syndrome: No specific clinical symptom was associated with the presence of AD+LB. The sensitivity of the diagnosis of DLB was 62% and specificity was 54%. Moderate dementia syndrome: Extrapyramidal signs (EPS), especially cogwheel rigidity, and major depression were associated with AD+LB. The sensitivity for DLB was 82% and specificity was 31%. Severe dementia syndrome: Cogwheel rigidity and diurnal hypersomnia were associated with AD+LB. The sensitivity for DLB was 93% and specificity was 16%. CONCLUSIONS: The presence of EPS is not useful in differentiating AD+LB from AD in patients with mild dementia. However, as the disease progressed, they emerge as defining features, especially cogwheel rigidity. The accuracy of AD+LB diagnosis varies according the severity of the dementia syndrome. The low sensitivity and specificity in AD+LB patients with mild dementia suggest that in early stages AD+LB patients do not present the clinical characteristics of DLB. By contrast, the high sensitivity and low specificity for the diagnosis of DLB in moderate/severe dementia stages suggests that AD patients can also have characteristic symptoms of DLB. These results indicate that the antemortem diagnosis of AD+LB is difficult in all dementia stages, and better clinical and biologic differentiations of these entities are needed.

Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias.

OBJECTIVE: To evaluate the inter-rater reliability and validity of clinical diagnostic criteria for neurodegenerative dementias. BACKGROUND: Inter-rater accuracy of the diagnosis of AD has been explored, but there are few accuracy studies for progressive supranuclear palsy (PSP) and frontotemporal lobe dementia (FTD). Furthermore, there have been no simultaneous accuracy studies in a mixed sample of patients with cortical and subcortical neurodegenerative processes. METHODS: Four experienced clinicians reviewed first-visit clinical data abstracted from the records of 40 pathologically diagnosed demented subjects. They were asked to apply the NINCDS-ADRDA criteria for AD, the NINDS-SPSP clinical criteria for PSP, the Lund and Manchester criteria for FTD, and the Consensus Guidelines for the Clinical Diagnosis of Dementia with Lewy Bodies (DLB). RESULTS: The generalized K for AD was 0.73, for PSP 0.82, for FTD 0.75, and for DLB 0.37. The K pool test showed a statistically significant difference between DLB and the other disease processes, and no differences were observed among AD, FTD, and PSP. The mean sensitivity for AD was 95%, for PSP 75%, for FTD 97%, and for DLB 34%. The mean specificity for AD was 79%, for PSP 98.5%, for FTD 97%, and for DLB 94%. CONCLUSIONS: We found improved inter-rater reliability for the diagnosis of AD among clinicians compared with earlier studies. Similarly, there was a near-perfect and substantial inter-rater agreement for the diagnosis of PSP and FTD. The sensitivity for the diagnosis of AD was high, although clinicians overdiagnosed this condition. However, there was a reasonable accuracy for the diagnosis of PSP and FTD. Heterogeneity of the clinical presentation of DLB significantly affected inter-rater agreement and accuracy. The use of multiple diagnostic criteria for cortical and subcortical dementia increases the level of clinical diagnostic accuracy.

Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades: I.

OBJECTIVE: To describe the experience of a research clinic diagnosing AD during the last two decades, with special emphasis on patients who meet the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD, their patterns of clinical presentation, and neuropathologic outcomes. BACKGROUND: Probable AD has a heterogeneous clinical presentation, and can occur in the context of complicating factors. There are few reports, and none with this large of a sample, about the pattern of presentation, the nature of comorbidities, and the sensitivity and specificity of diagnosis. RESULTS: The AD Research Center of Pittsburgh examined 1139 patients with probable AD between April 1983 and February 2000. Of these 1139 probable AD patients, 29 (2.5%) had slow progression, 27 (2%) had rapid progression, 70 (6%) had an atypical presentation, and 85 (7%) had coexistent cerebrovascular disease. Confluent periventricular white matter lesions were found in 348 (30.5%) patients with probable AD. The overall sensitivity for the diagnosis of AD was 97% and the specificity 80%. However, the accuracy for the diagnosis of AD varied over the years: from 1983 to 1989, the sensitivity was 94% and specificity 52%, and from 1990 to 2000, the sensitivity was 98% and specificity 88%. CONCLUSION: Although the diagnosis of probable AD has been used to indicate the presence of a homogeneous clinical entity, these patients can vary in presentation, onset, or clinical course. This finding is of particular importance for the understanding of the pathophysiologic basis of the disease, and for the better identification of responders to dementia treatments. Although the sensitivity for the diagnosis of AD remained above 90% over the last two decades, the specificity increased, reflecting progressive improvement in the diagnosis of other dementing disorders.

Research evaluation and diagnosis of possible Alzheimer's disease over the last two decades: II.

OBJECTIVE: To describe the experience of a research clinic diagnosing possible AD during the last two decades. BACKGROUND: The National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for possible AD are generally used to indicate that a patient has AD in association with another disease process that could by itself cause dementia. There are no studies describing how these criteria should be applied, and there are no descriptions of functional and cognitive progression or survival in possible AD. METHODS: The authors examined the clinical characteristics of 267 patients diagnosed with possible AD at the AD Research Center of Pittsburgh from 1983 to 2000 and the likelihood of arriving at four endpoints: Mini-Mental State Examination score of /= 12, nursing home admission, and death. RESULTS: The possible AD classification has been simplified in six categories: possible AD with cerebrovascular disease (CVD) (69%), with history of alcohol abuse (15%), with history of depression (7%), with thyroid disease (4%), with history of head trauma (6%), with vitamin B12 deficiency (6%), and with other disease process that may have affected the clinical presentation of AD (4%). The presence of CVD, history of alcohol abuse, and history of depression concomitant with the onset of dementia were associated with time to death. Neither thyroid disease, history of head trauma, nor vitamin B12 deficiency were associated with any of the four endpoints. CONCLUSION: This cohort showed that comorbid conditions that can affect cognition delineate clearly defined subgroups in AD. The presence of environmental or other brain disorders sufficient to produce dementia appears to affect physical survival in patients with AD, but not functional and cognitive decline or institutionalization.

Dementia with Lewy bodies: reliability and validity of clinical and pathologic criteria.

Clinical criteria for dementia with Lewy bodies (DLB) have been proposed, but their formulation, reliability, and validity require further study. Pathologic criteria for DLB are also undergoing evolution. Two studies were conducted with the goal of identifying the components of these evolving criteria that may benefit from further refinement; one study evaluated the components of the clinical criteria and another study operationalized the pathologic criteria for DLB. Twenty-four patients with a premorbid diagnosis of probable or possible Alzheimer's disease (AD) (n = 18), Parkinson's disease (PD) (n = 5), or progressive supranuclear palsy (PSP) (n = 1) were studied. Inter-rater reliability and validity of the clinical criteria were determined by a retrospective chart review, done by five neurologists, and a blinded pathologic evaluation. The Consortium on dementia with Lewy bodies (CDLB) pathologic criteria were operationalized to compare past criteria and test the validity of the evolving clinical criteria on the dementia patients. Three or more cortical fields (at 250 x magnification) with many (four or more) Lewy bodies (LBs) on ubiquitin immunoreactive sections were required to meet the CDLB neocortical score of > 6. Fifteen of the AD patients had at least one LB in a cortical section, four had many LBs, while three had no LBs; all patients with movement disorder had at least one LB in a cortical section. The sensitivity/specificity ratio of the CDLB probable DLB clinical criteria based upon many LBs being present was 75%/79%. Reformulated clinical criteria that require the presence of extrapyramidal signs significantly predicted those patients with many LBs versus those with few or no LBs (chi 2 = 5.48, p = 0.02) and increased clinical specificity to 100%. This preliminary study identifies components of the evolving clinical and pathologic criteria for DLB that require further refinement.

Assessing the impact of neuropsychiatric symptoms in Alzheimer's disease: the Neuropsychiatric Inventory Caregiver Distress Scale.

OBJECTIVES: To develop an adjunct scale to the Neuropsychiatric Inventory (NPI) for assessing the impact of neuropsychiatric symptoms in Alzheimer's disease (AD) patients on caregiver distress. DESIGN: Cross-sectional descriptive and correlational study. SETTING: University out-patient memory disorders clinics. PARTICIPANTS: Eighty-five AD subjects and their caregivers (54 spouses, 31 children). MEASUREMENTS: The NPI and NPI Caregiver Distress Scale (NPI-D) were used to assess neuropsychiatric symptoms in AD patients and related caregiver distress, respectively. Criterion validity of the NPI-D was examined (N = 69) by comparison with an abridged version of the Relatives' Stress Scale (RSS'), a general measure of caregiver stress, using item clusters that had previously been correlated to behavioral disturbances in demented patients. Test-retest (n = 20) and inter-rater reliability (n = 16) of the NPI-D were also assessed. RESULTS: Test-retest and interrater reliability of the NPI-D were both adequate. Overall, caregiver NPI-D distress ratings were correlated significantly with the RSS' (r = .60, P < .001). RSS' ratings correlated strongly with NPI scores (r = .64, P < .001), even after controlling for degree of cognitive impairment based on the Mini-Mental State Exam (MMSE) score (r = .61). MMSE scores showed a moderate correlation to RSS' ratings (-.30, P = .02), but this association was markedly attenuated when controlling for the degree of neuropsychiatric disturbance based on the NPI score (r = -. 14). NPI-D ratings for 9 of 10 NPI symptom domains correlated most strongly with either NPI symptom severity or total (frequency x severity) scores. Agitation, dysphoria, irritability, delusions, and apathy were the symptoms most often reported to be severely distressing to caregivers. CONCLUSIONS: The NPI-D provides a reliable and valid measure of subjective caregiver distress in relation to neuropsychiatric symptoms measured by the NPI. Neuropsychiatric alterations are more strongly associated than cognitive symptoms to caregiver distress. The NPI-D may be useful in both clinical and research settings for assessing the contribution to caregiver distress of neuropsychiatric symptoms in AD patients.

Cholinergic excitation induces activity-dependent electrophysiological and transcriptional responses in hippocampal slices.

To explore the correlations between short-term neurophysiological events initiated by over-activation of acetylcholine receptors, and long-lasting changes in brain function, we combined electrophysiology and PCR-based measurements in hippocampal slices or live mice subjected to stress or drug-induced cholinergic activation. Our findings reveal a common cascade of neuronal events resulting in delayed suppression of cholinergic transmission.