Search

Objective: To describe the assessment and treatment of an elderly woman with parkinsonism, progressive memory and cognitive deficits, and visual hallucinations., Method: The patient presented with a 10-year history of hand tremors, an 8-year history of short-term memory problems, and a 3-4-year history of visual hallucinations. Treatment with donepezil and rivastigmine (successively) did not produce the desired benefits. Then she was started on galantamine 4 mg b.i.d. (escalated to 8 mg b.i.d.)., Results: The patient's social interaction improved and cognitive decline appeared to be stabilized; hallucinations and agitation were also better controlled., Conclusion: By current criteria, this subject would be labeled as having Parkinson's disease with dementia, although she exhibited the core features of dementia with Lewy body disease. As suggested in previous studies, cholinesterase inhibitors may be effective in treating psychotic symptoms; however, all currently available agents may not be equally effective., (Copyright Blackwell Munksgaard 2004.)

Recently recognized as an entity separate from Alzheimer's disease (AD) and Parkinson's disease with dementia, dementia with Lewy bodies (DLB) is a frequent cause of dementia. It is characterized by progressive cognitive decline and attention deficits, but in contrast to AD, the cognitive changes typically fluctuate over time. Patients with DLB often experience Parkinson-like spontaneous motor features as well as recurrent visual hallucinations. Another frequent finding in DLB is rapid eye movement (REM) sleep disorder. Ideally, each of the major symptom domains associated with DLB (behavioral, motor, and cognitive) would be treated, but drug interactions in these patients are a serious concern. In addition, many patients with DLB are hypersensitive to neuroleptics, which can induce severe extrapyramidal and other symptoms--sometimes ending in death. Compared with conventional neuroleptics, the newer atypical antipsychotic agents may be associated with lower rates of extrapyramidal side effects. Cholinergic deficits in DLB are even more severe than in AD, whereas the extent of cerebral atrophy and neuronal damage may be less. These observations and emerging clinical data support the treatment of DLB with acetylcholinesterase inhibitors. Encouraging results have been obtained from studies of DLB patients treated with rivastigmine, donepezil, and galantamine, but large-scale, controlled trials are needed to confirm the efficacy and safety of acetylcholinesterase inhibitors in patients with DLB., (Copyright 2004 S. Karger AG, Basel)

Background: Pathology reports have shown that cholinergic forebrain neuronal losses in parkinsonian dementia (PDem) are equal to or greater than those in Alzheimer disease (AD). We hypothesized that patients with PDem would have cholinergic deficits that were similar to or greater than those of patients with AD., Objective: To determine in vivo cortical acetylcholinesterase (AChE) activity in healthy control subjects and in patients with mild AD, PDem, and Parkinson disease without dementia using AChE positron emission tomography., Setting: University and Veterans' Administration medical center. Design and Patients Group comparison design of patients with AD (n = 12), PDem (n = 14), and Parkinson disease without dementia (n = 11), and controls (n = 10) who underwent AChE imaging between July 1, 2000, and January 31, 2003. Patients with AD and PDem had approximately equal dementia severity., Main Outcome Measures: Cerebral AChE activity., Results: Compared with controls, mean cortical AChE activity was lowest in patients with PDem (-20.0%), followed by patients with Parkinson disease without dementia (-12.9%; P<.001). Mean cortical AChE activity was relatively preserved in patients with AD (-9.1%), except for regionally selective involvement of the lateral temporal cortex (-15%; P<.001)., Conclusion: Reduced cortical AChE activity is more characteristic of patients with PDem than of patients with mild AD.

The authors examined the pattern of use of psychiatric medication as prescribed by community physicians in 1,155 patients with probable Alzheimer's disease (AD) referred to the Alzheimer's Disease Research Center of Pittsburgh between April 1983 and July 2000. The use of antidepressants and of sedatives, hypnotics, and anxiolytics (SHA) increased over time, while the use of antipsychotics decreased. The increased use of antidepressants and decreased use of antipsychotics may reflect the growing evidence that newer antidepressants (e.g., selective serotonin reuptake inhibitors) can be used to treat not only mood-related disorders, but also abnormal behavior (e.g., aggression, agitation) and sleep disorders in AD. Although the use of SHA has a proven deleterious effect on patients with AD, their use has increased over the past two decades.

Objective: Psychotic symptoms in Alzheimer disease (AD) identify a phenotype with distinct neurobiology and genetic architecture. The authors investigated whether AD with psychosis is homogeneous or is a composite of subtypes., Methods: Authors performed factor and cluster analyses of the psychotic-symptom items of the CERAD Behavioral Rating Scale in 188 probable and possible AD subjects who have displayed at least one psychotic symptom., Results: Exploratory factor analysis resulted in a one-factor solution that comprised misidentification delusions, auditory and visual hallucinations, and the misidentification of people. Persecutory delusions were also frequently present and were independent of the misidentification/hallucination factor. Cluster analysis yielded similar results., Conclusion: Misidentification/hallucinations and persecutory delusions may identify two subtypes of psychosis in AD. Longitudinal study is needed to determine whether these proposed subtypes remain stable and independent over time or merge into a single group over the course of illness.

This cross-sectional study examines relationships among the constellation of psychiatric syndromes in Alzheimer's disease (AD) as a function of dementia severity in 1155 patients with probable AD. The frequency of major depression decreased in severe stages, while agitation, aggression, and psychosis were more frequent in late stages. Major depression was associated with anhedonia, sleep disorders, depressed mood, low self-esteem, anxiety, and hopelessness in mild/moderate and severe stages. Agitation was associated with aggression and psychosis in mild/moderate stages, and psychosis was associated with aggression in moderate/severe stages. In addition, there was a constellation of psychiatric symptoms (e.g., anxiety, wandering, irritability, inappropriate behavior, uncooperativeness, emotional lability) associated with agitation, aggression, and psychosis, which varied according to the severity of the dementia, suggesting a progressive deterioration of frontal-temporal limbic structures. Education and race were independently associated with psychosis. However, while education was associated with psychosis in mild/moderate stages, race was associated with psychosis in moderate/severe stages.

Two middle-aged patients presented with rapidly progressive dementia and ataxia, nonspecific electroencephalography findings, and negative cerebrospinal fluid (CSF) protein 14-3-3. Both patients underwent brain magnetic resonance imaging (MRI) scans that demonstrated abnormalities on diffusion-weighted imaging (DWI) sequences, and both were later confirmed to have Creutzfeldt-Jakob disease. (CJD) by tissue examination. Because a recent position paper from the American Academy of Neurology characterized CSF protein 14-3-3 as a gold standard for clinically diagnosing CJD, the authors reviewed studies of CJD in which DWI-MRI imaging and CSF protein 14-3-3 studies were both performed. Among 19 reported cases of CJD with DWI-MRI lesions, CSF protein 14-3-3 was negative in 6 cases and positive in 2 others. The authors' findings suggest that multifocal cortical and subcortical hyperintensities confined to gray matter regions in DWI-MRI may be a more useful noninvasive diagnostic marker for CJD than CSF protein 14-3-3. These observations provide a compelling rationale for a prospective comparative study.

alpha-1-Antichymotrypsin (ACT) is present in neuritic plaques in which it participates in the inflammatory cascade of Alzheimer's disease (AD). Reports of blood ACT levels in AD, and its usefulness as a disease biomarker, have been conflicting. In an effort to clarify this, we measured plasma ACT levels in 516 white subjects including 359 subjects with probable or possible AD, 44 subjects with other late-life dementias, and 113 nondemented people. Subjects with systemic inflammatory diseases or who were taking antiinflammatory medications were excluded. All patients underwent extensive medical and detailed neuropsychological examinations at the time their blood was drawn. We found that plasma ACT levels were elevated in AD patients compared with the control group (p = 0.01) and were associated with severity of AD dementia; there was a negative association with the Mattis Dementia Rating Scale (a global measure of cognition) and a positive association with the Clinical Dementia Rating Scale (a global functional assessment). These relationships remained significant after controlling for demographic and genetic variables. When AD subjects were stratified into subgroups by dementia severity, matched by age, education, and gender, increased serum ACT correlated with Clinical Dementia Rating Scale (p = 0.0041) or Mattis Dementia Rating Scale (p = 0.0031) scores. ACT measurements in cerebrospinal fluid from an additional 34 AD cases and 16 controls showed elevated levels (p = 0.02) in AD. There was a negative correlation (p = 0.037) between cerebrospinal fluid ACT levels and clinical severity as measured by the Mini-Mental State Examination. Our results demonstrate that peripheral ACT levels are elevated in AD, but not in dementias other than AD, and they increase with progression of AD dementia. Although not useful as a diagnostic biomarker, ACT may reflect disease severity and may be helpful as a within subject biomarker in interventions (particularly with antiinflammatory agents) directed at slowing or halting progression of disease.

As a clinicopathologically defined entity, dementia with Lewy bodies (DLB) has overlapping features of Alzheimer's disease (AD) and Parkinson's disease (PD). Analogous characteristics of DLB offer a provisional rationale for pharmacologic therapy based on remediating cholinergic and dopaminergic deficits, respectively. However, the distinct clinical manifestations and pathophysiologic substrates of DLB pose unique therapeutic opportunities and challenges. More severe cholinergic deficits in DLB relative to AD support clinical evidence that cholinergic therapy may be particularly beneficial in DLB patients. In contrast, DLB patients are generally more sensitive to the adverse effects of antipsychotic agents, warranting caution in treating visual hallucinations and other psychotic symptoms. Similarly, parkinsonian motor signs in DLB, often manifest as rigidity and bradykinesia, may be less amenable to dopaminergic therapies than in PD. Increasing recognition of DLB as a common form of dementia in the elderly underscores the need for large-scale, placebo-controlled therapeutic trials.

Historically, drugs that increase central cholinergic transmission have primarily been investigated for relieving cognitive symptoms in mild-to-moderate Alzheimer's disease. These efforts have led to the somewhat unexpected findings that cholinergic therapy has a beneficial effect on selected neuropsychiatric symptoms in AD across disease stages. In Parkinson's disease with dementia and dementia with Lewy bodies, cholinergic deficits are more severe than in AD, and there is emerging evidence that cholinesterase inhibitors are efficacious in treating core symptoms of attentional disturbance and psychosis. Recent data also suggest a rational basis for cholinergic therapy in vascular dementia. The cognitive and neuropsychiatric effects of cholinergic therapy observed in AD and other dementias form the crux of an integrative model of cholinergic therapeutic efficacy that encompasses the diverse central nervous system actions of acetylcholine and its complementary interactions with central monoamine transmitters. This heuristic framework highlights the broader therapeutic potential of cholinergic therapy for symptom-based indications in other neuropsychiatric disorders.

This report reviews the state of the literature and opportunities for research related to "executive control function" (ECF). ECF has recently been separated from the specific cognitive domains (memory, language, and praxis) traditionally used to assess patients. ECF impairment has been associated with lesions to the frontal cortex and its basal ganglia-thalamic connections. No single putative ECF measure can yet serve as a "gold standard." This and other obstacles to assessment of ECF are reviewed. ECF impairment and related frontal system lesions and metabolic disturbances have been detected in many psychiatric and medical disorders and are strongly associated with functional outcomes, disability, and specific problem behaviors. The prevalence and severity of ECF deficits in many disorders remain to be determined, and treatment has been attempted in only a few disorders. Much more research in these areas is necessary.

Background: The presence of psychotic symptoms in Alzheimer Disease subjects (AD+psychosis, AD+P) is a marker for a phenotype characterized by more severe cognitive impairment and a more rapidly deteriorating course. Although AD+P has been inconsistently associated with more severe neuropathology, no prior studies have examined measures of neuronal and synaptic integrity., Objective: To determine whether AD+P is associated with evidence of disrupted neuronal and synaptic integrity, as indicated by magnetic resonance spectroscopy (MRS) measurement of N-acetyl-L-aspartate and the membrane breakdown products, glycerophosphocholine and glycerophosphoethanolamine., Methods: 31P and 1H MRS studies of perchloric acid extract from postmortem brain of AD subjects with and without a history of psychotic symptoms. All subjects were characterized for the presence of comorbid cortical Lewy body pathology and for history of neuroleptic use. Brain tissue from dorsolateral prefrontal, superior temporal, inferior parietal, and occipital cortex, amygdala, and cerebellum were examined in all subjects. Statistical analysis accounted for correlated observations across brain regions within-subjects., Results: AD+P subjects demonstrated significant elevations of glycerophosphoethanolamine and significant reductions of N-acetyl-L-aspartate. Between group differences were greatest in neocortical brain regions., Conclusion: Excess impairment of neocortical neuronal and synaptic integrity may provide the structural substrate underlying AD+P. Confirmation of these findings using in vivo MRS measures is indicated.

Psychotic symptoms occurring in Alzheimer's disease (AD + psychosis, AD + P) are a marker for a more rapidly deteriorating phenotype. We have developed a polygenic model of AD + P risk, conditioned on the presence of AD. Whether risk genes for AD itself contribute to AD + P risk is not established, although our model predicts they will not. The most important identified genetic determinant of sporadic, late-onset AD is the apolipoprotein E epsilon 4 allele (APOE4). The effect of APOE4 on AD phenotype is to reduce the age of onset of AD. Prior studies examining the association of APOE4 with AD + P have reported conflicting results. However, no prior studies have examined if APOE4 reduces time to onset of psychosis in AD. The objective of this study was to examine the effect of APOE4 and alpha1-antichymotrypsin/AA (ACT/AA) genotypes on time to psychosis onset in subjects with AD. A longitudinal study of psychosis incidence in 316 subjects with AD with no history of current or prior psychotic symptoms at entry was undertaken. APOE and ACT genotyping was conducted per established protocols. Data were analyzed by survival analysis and Cox proportional hazards models. There were no significant associations of APOE or ACT genotypes with time to psychosis onset and no significant interaction of these genotypes with time to psychosis onset. There remained no significant associations after covarying for age, age of AD onset, degree of cognitive impairment, gender, race, and education. This is the first study to examine the genetic prediction of psychosis onset in AD. The findings support the hypothesis that these two genetic determinants of AD risk do not contribute to the risk of development of psychotic symptoms in AD.

Objective: To evaluate the relative merits of recently developed criteria for dementia with Lewy bodies (DLBs) in a longitudinal study of dementia., Design: The diagnosis of DLBs was used in combination with other clinical diagnosis. Patients were classified primarily based on the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) clinical criteria for probable or possible Alzheimer disease, or with other disease process that can cause dementia (eg, Parkinson disease), and secondarily according to the consensus guidelines for DLBs. This "double" clinical diagnosis was implemented to capture different pathological entities. The neuropathological diagnosis of Lewy bodies was made with monoclonal antibodies against alpha-synuclein., Setting: Multidisciplinary research clinic., Results: Prospective application of the consensus guidelines for DLBs from January 1, 1997, to September 29, 2000, identified 11 patients having the diagnosis of probable DLBs and 35 having possible DLBs. The diagnosis of probable or possible DLBs was associated with probable Alzheimer disease in 34 patients, with possible Alzheimer disease in 5 patients, with Parkinson disease in 2 patients, and with other disease processes in 2 patients. Three patients were diagnosed as having probable DLBs alone. An autopsy was performed in 26 of the cases who were clinically examined during the study period. Cortical Lewy bodies were identified in 13 cases; 4 had had premortem diagnosis of DLBs (sensitivity, 30.7%; specificity, 100%)., Conclusions: The prospective validation of the clinical criteria for DLBs showed poor accuracy in this series. We believe that current criteria for DLBs are useful when DLBs occur in isolation, but have low sensitivity when Lewy bodies coexist with the pathological abnormalities of Alzheimer disease.

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.

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.

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.

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.

Growing numbers of people throughout the United States (40% in 1998) are using various forms of alternative therapies. A MEDLINE literature search of journals from the past three decades and an Internet database query were performed to determine the types and frequency of alternative therapies used, with special attention given to the herbal medicines used in neuropsychiatric disorders. Clinical effects, mechanisms of action, interactions, and adverse reactions of the herbal treatments are detailed. Objective controlled trials will be needed to establish safety and efficacy of herbal supplements. Knowledge of the properties of these therapies can improve the care of neuropsychiatric patients.

The Neuropsychiatric Inventory (NPI) is a validated clinical instrument for evaluating psychopathology in dementia. The authors developed a brief questionnaire form of the NPI (NPI-Q), intended for use in routine clinical practice, and cross-validated it with the NPI in 60 Alzheimer's patients. Test-retest reliability of the NPI-Q was acceptable. The prevalence of analogous symptoms reported on the NPI and NPI-Q differed on average by 5%; moderate or severe symptom ratings differed by less than 2%. The NPI-Q provides a brief, reliable, informant-based assessment of neuropsychiatric symptoms and associated caregiver distress that may be suitable for use in general clinical practice.

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.

Acetylcholine is a modulatory central nervous system (CNS) neurotransmitter involved in diverse brain processes. Historically, drugs that increase CNS cholinergic transmission have been investigated primarily for relieving cognitive symptoms in Alzheimer"s disease (AD). Emerging from these efforts are recent findings that several cholinesterase-inhibitor agents also have a beneficial effect on selected noncognitive symptoms in AD, such as apathy, psychosis, and purposeless motor behaviors. The broad psychotropic effects of cholinergic agents observed in AD and other degenerative conditions highlight potential symptom-based therapeutic indications for these drugs across a variety of neurologic disorders.

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.

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.

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.

We conducted an open-label study designed to assess the effects of tacrine on behavioral changes in patients with Alzheimer's disease (AD). Twenty-eight subjects completed a baseline evaluation and at least one assessment during treatment. Behavioral symptoms and cognitive function were assessed with the Neuropsychiatric Inventory (NPI) and Mini-Mental State Examination (MMSE), respectively. The mean NPI score at the maximum individual dose of tacrine attained was markedly decreased (behavior improved, compared to baseline). Symptoms of anxiety, apathy, hallucinations, aberrant motor behaviors, and disinhibition were most responsive. Subject stratification by dementia severity revealed a substantially reduced mean NPI score only in the group with moderate dementia, independent of cognitive response. Over half of the subjects with cognitive improvement had a marked reduction in behavioral symptoms, particularly apathetic behaviors. These data suggest that tacrine may be beneficial for selected behavioral symptoms in AD patients, particularly at higher doses and in those with moderate cognitive deficits.