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OBJECTIVE: This study investigated the reliability and validity of a chronic care facility adaptation of the Clinical Dementia Rating scale (CDR-CC). METHOD: Sixty-two residents in a chronic care facility participated in an inter-rater and 1 month test-retest reliability study. The instrument was validated against the Mini-Mental State Examination (MMSE). RESULTS: Inter-rater and 1 month test-retest reliability for the global CDR-CC score were excellent (intraclass correlation coefficients 0.99 and 0.92, respectively). The CDR-CC domain and global scores were negatively correlated with the MMSE. CONCLUSIONS: The CDR-CC is a global assessment tool that reliably and validly measures cognitive and functional impairment in a chronic care setting.

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Anti-inflammatory drugs may be useful in the treatment of Alzheimer disease (AD). In preparation for therapeutic trials, we conducted pilot feasibility studies of hydroxychloroquine alone and in combination with colchicine in subjects with AD. A total of 20 subjects with probable AD were treated with hydroxychloroquine 200 mg twice daily for 11 weeks, or hydroxychloroquine 200 mg twice daily plus colchicine 0.6 mg twice daily for 12 weeks; subjects were monitored for adverse medical, cognitive, or behavioral effects. Neither regimen caused adverse effects on cognitive or behavioral assessment scores. There were no significant side effects in subjects receiving hydroxychloroquine alone; 2 subjects receiving the two drugs together experienced diarrhea. We conclude that these regimens of anti-inflammatory therapy are well tolerated in subjects with AD, indicating the feasibility of large-scale therapeutic trials of these agents.

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Studies of the familial aggregation of Alzheimer's disease have primarily used samples ascertained from tertiary care clinics which may not be representative of many AD patients, for example those residing at geriatric nursing homes. Survival analysis was used to investigate whether estimates of familial aggregation of AD based on a clinic-based AD proband (C-AD) sample (probands: N=544; first degree relatives; N=4267) differ from one ascertained at a nursing home (NH-AD; probands: N=225; first degree relatives; N=1772). The cumulative survival from AD was significantly worse in relatives of the C-AD probands and the overall relative risk (RR) of AD in this group was greater than twice that of relatives of the NH-AD probands. However, age at onset in C-AD probands was significantly earlier than in the NH-AD group and in both groups this factor was negatively associated with familial aggregation. When, for this reason, the proband samples were matched one-to-one by age at onset, dropping those probands with no match, the two curves were close to identical and the RR for the C-AD group of relatives was 1.0 The results suggest that estimates of familial risk of AD based on C-AD samples are not applicable and overestimate the extent of increased risk for relatives of more prevalent, later onset AD probands. However, the overestimate can be explained by the typically earlier age at onset in C-AD samples as opposed to a sampling bias related to the proband's family history status per se. The relationship between onset age and familial aggregation suggests that no single estimate of the age-dependent risk (survival curve) is uniformly appropriate for relatives of AD probands.

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Family members incur substantial financial costs during the course of caring for an individual with Alzheimer's disease. Much of this cost is associated with time spent in caregiving tasks, including supervision and communication with the patient, and assisting with activities of daily living. We have previously reported on the cross sectional reliability and validity of a scale that measures time spent caregiving, the Caregiver Activity Survey (CAS). This study extends our results to a longitudinal study of the validity of the instrument. Forty-four outpatients with Alzheimer's disease who lived with a primary caregiver were followed over a period of 1 year 6 months. At six month intervals, the patients were administered the Mini Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale (ADAS), and the Physical Self Maintenance Scale (PSMS). Caregivers completed the CAS. Over time, the CAS correlated significantly with the MMSE (r=-0.58, p=0.000), ADAS cognitive subscale (r=0.56, p=0. 000) and PSMS (r=0.49, p=0.000). As patients declined, caregivers spent less time communicating with and more time supervising the patient. Excluding the communication item, time spent caregiving increased significantly over time. This prospective study longitudinally validates the CAS with Alzheimer's patients.

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Health care professionals often encounter patients who refuse a recommended treatment plan. Overriding a patient's right to autonomy has ethical, legal, and moral consequences. Incapacity is the determination by a physician that a patient lacks the ability to make informed decisions about his or her health care. The fundamentals needed for evaluating and documenting patients' capacity to make decisions regarding their personal medical care are provided.

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BACKGROUND: Deficits in somatostatin-like immunoreactivity (SLI) and corticotropin-releasing factor immunoreactivity (CRF-IR) are well recognized as prominent neurochemical deficits in Alzheimer disease (AD). The question of whether these profound neuropeptidergic deficits found in patients with end-stage disease extend into those with much earlier disease is relatively unanswered. To determine the relation between level of SLI and CRF-IR in different cerebrocortical regions to the earliest signs of cognitive deterioration in AD. METHODS: We examined SLI and CRF-IR levels in 9 neocortical brain regions of 66 elderly patients in a postmortem study of nursing home residents who had either no significant neuropathologic lesions or lesions associated only with AD. Patients were assessed by the Clinical Dementia Rating scale (CDR) to have no dementia or questionable, mild, or moderate dementia, and were compared with 15 patients with severe dementia. RESULTS: Both CRF-IR and SLI were significantly reduced in the cortices of patients with the most severe dementia, but only the levels of CRF-IR were reduced in those with mild (CDR = 1.0) and moderate dementia (CDR = 2.0). Levels of CRF-IR and SLI correlated significantly with CDR, but this correlation was more robust for CRF-IR and persisted even when severely cognitively impaired patients were eliminated from analysis. CONCLUSIONS: Although SLI and CRF-IR levels are significantly reduced in patients with severe dementia, only CRF-IR is reduced significantly in the cortices of those with mild dementia. Thus, CRF-IR can serve as a potential neurochemical marker of early dementia and possibly early AD.

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This study sought to determine the relationship between behavioral disturbance and functional status in a longitudinally studied sample of patients with Alzheimer's disease (AD). One hundred and forty-nine patients meeting NINCDS-ADRDA criteria for probable AD were followed for an average of 37.3 months, with follow-up assessments every 6 months. Subjects were seen at the Alzheimer's Disease Research Center clinics at the Mt Sinai Medical Center, New York, and the Veterans Affairs Medical Center, Bronx, New York. Measures included the Physical and Self-Maintenance Scale (PSMS) and Instrumental Activities of Daily Living Scale (IADLS) of Lawton and Brody and the cognitive and non-cognitive subscales of the Alzheimer's Disease Assessment Scale (ADAS). For each patient the assessment at which they had their most severe non-cognitive symptoms as measured by the non-cognitive part of the ADAS (ADAS-NC) was determined. ADAS-NC scores at that assessment were correlated with IADLS and PSMS scores at the same assessment and at the next assessment 6 months later. While there was some modest association of ADAS-NC scores with functional impairment using pairwise correlation coefficients, none of the correlations remained significant when the severity of cognitive impairment was controlled statistically. Findings were not significantly changed when drug status was controlled. These results suggest that behavioral disturbance, while very troubling to caregivers and patients, does not substantially worsen functional ability beyond the contribution of cognitive impairment in AD. Together with previous results indicating that non-cognitive symptoms in AD are episodic and fluctuating rather than progressive, the present data suggest that interventions for non-cognitive disturbances in AD should be viewed as ways to increase patient comfort, safety and ease of care and not as ways to improve functional autonomy. The latter can be achieved only by improving the progressive cognitive deficits of AD.

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Elderly individuals who lived beyond the age of 90 years without dementia were hypothesized to have increased concentrations of genetic protective factors against Alzheimer disease (AD), conferring a reduced liability for this disease relative to less-aged nondemented elderly. However, testing this hypothesis is complicated by having to distinguish such a group from those who may lack genetic risk factors for AD, have had protective environmental exposures, or have escaped dementia for other reasons. Probands carrying genetic protective factors, however, should have relatives with lower illness rates not only for earlier-onset disease, when genetic risk factors are a strong contributing factor to the incidence of AD, but also for later-onset disease, when the role of these factors appears to be markedly diminished. AD dementia was assessed through family informants in 6,660 first-degree relatives of 1,049 nondemented probands aged 60-102 years. The probands were grouped by age (60-74, 75-89, and 90-102 years), and the cumulative survival from AD and 10-year-age-interval hazard rates of AD were calculated in their first-degree relatives. Cumulative survival from AD was significantly greater in the relatives of the oldest proband group (aged 90-102 years) than it was in the two younger groups. In addition, the reduction in the rate of illness for this group was relatively constant across the entire late life span. The results suggest that genetic factors conferring a lifelong reduced liability of AD may be more highly concentrated among nondemented probands aged >/=90 years and their relatives. Efforts to identify protective allele-bearing genes that are associated with very late-onset AD should target the families of nonagenarians and centenarians.

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OBJECTIVES: We examined the relationship between CSF amyloid beta peptide (A beta) concentration and AD severity in 31 probable AD patients and explored whether APOE genotype modifies this relationship. BACKGROUND: A beta deposition in AD brains has been correlated with disease severity and with APOE-epsilon4 allele frequency. Few studies have examined the effects of APOE genotype on the relationship between CSF A beta and disease severity in an antemortem sample. METHODS: Patients carried the clinical diagnosis of probable AD and did not have serious medical illness, current or past diagnosis of mood disorder, schizophrenia or alcoholism, or current psychotic features. The Mini-Mental State Examination (MMSE) was administered to the patient within 3 months of CSF collection. CSF was analyzed for A beta1-40 and A beta1-42 by sandwich ELISAs, and APOE genotype was determined by PCR run from blood. Correlations were performed between MMSE score and A beta1-40 and A beta1-42 concentrations while controlling for potential confounding variables. RESULTS: CSF measures of A beta1-40 and A beta1-42 concentrations were correlated with each other (r = 0.56, df = 28, p < 0.01). CSF A beta1-40 and A beta1-42 concentrations were positively correlated with MMSE score. The negative association between CSF A beta measures and disease severity remained significant after controlling for age (A beta1-40 and MMSE score: r = 0.46, df = 28, p = 0.01; A beta1-42 and MMSE score: r = 0.35, df = 28, p = 0.05). Among the APOE-epsilon3/3 homozygotes there was a significant positive correlation only between A beta1-42 and MMSE score (A beta1-42, r = 0.94, p = 0.02; A beta1-40, r = 0.79, p = 0.11). CONCLUSIONS: We hypothesize that an increased deposition of A beta in plaques results in decreased CSF A beta concentration. The stronger relationship between MMSE score and CSF A beta, specifically in APOE-epsilon3/3 homozygotes, suggests that patients with APOE-epsilon3/3 genotype may have different pathogenic mechanisms than the other genotypes for A beta deposition or clearance.

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BACKGROUND: Although significant progress has been made in the implementation of advance directive counseling programs for cognitively intact patients, there is a paucity of information on the outcome of these programs with patients with Alzheimer's disease. This study investigated the prevalence of completed healthcare proxies in a sample of Alzheimer's disease outpatients, and the feasibility of a systematic proxy counseling program for this population. METHODS: The setting was a geriatric psychiatry clinic. Ninety-four patients with Alzheimer's disease were surveyed for their previous completion of a healthcare proxy. All patients with capacity and without a proxy were approached to complete the advance directive with a lay counselor. RESULTS: Thirty-two percent (n = 30) of patients had completed a proxy prior to the initiation of a counseling program. Of patients without proxies (n = 64), 89% had capacity to complete one. Seventy-nine percent subsequently completed a proxy through the counseling program. Hispanics were least likely to have had a proxy prior to initiation of the program, yet were very willing to complete the document. CONCLUSIONS: The majority of patients with Alzheimer's disease in an outpatient setting did not have healthcare proxies, yet had the capacity and motivation to complete this advance directive. With physician input regarding the presence of decisional capacity, a lay counselor successfully implemented the counseling process. These results support the initiation of similar counseling programs for Alzheimer's outpatients.

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The purpose of this study was to concurrently assess the relationship of Apolipoprotein E (APOE) with both dementias and vascular illnesses in the very old. Nine hundred and fifty nine subjects (mean age 85 years) in a long-term care facility were genotyped and cognitively tested with the Mini Mental State Exam. All subjects were studied for the relationship of APOE with atherosclerotic heart disease, hypertension, or stroke without concomitant dementia. Four hundred fifty individuals met criteria for inclusion into one of the following groups: Alzheimer's disease (n = 318), vascular dementia (n = 49), or not demented controls (n = 83) and were investigated for the relationship between APOE and these diagnostic categories. APOE epsilon4 was not associated with atherosclerotic heart disease, hypertension, or stroke without concomitant dementia. The APOE epsilon3 allele was more common in men with atherosclerotic heart disease. In contrast, the APOE epsilon4 allele was more common in patients with Alzheimer's disease (22%) and vascular dementia (26%) than in not demented controls (7%). APOE epsilon4 is associated with dementias in the very old, whereas its relationship with either peripheral or central nervous system vascular disease without dementia is not as robust.

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OBJECTIVE: The authors investigated the relationships between concentrations of two acute-phase proteins, alpha 1-antichymotrypsin (ACT) and alpha 2-macroglobulin (MAC), and cognitive impairment in the very old. METHOD: Concentrations of ACT and MAC were determined in a prospective study using sera from medically stable elderly nursing home residents. Cognitive impairment was assessed with the Mini-Mental State. RESULTS: Concentrations of ACT were associated with greater cognitive impairment, as reflected by lower Mini-Mental State scores. This relationship did not exist for MAC. CONCLUSIONS: These data extend previous reports that patients with Alzheimer's disease have greater concentrations of ACT in their blood by demonstrating in a diagnostically diverse nursing home population a relationship between serum ACT and mental status. Elevated serum ACT in patients with compromised mental status may reflect a cerebral acute-phase response.

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BACKGROUND: Most instruments that measure the impairments associated with Alzheimer's disease assess symptom severity. Little attention has been paid to the illness's impact on the time formal and informal caregivers spend caring for Alzheimer's individuals. A tool that measures the time spent caregiving would help to determine the economic impact of the illness. The Caregiver Activity Survey (CAS) was developed to measure the time caregivers spend aiding Alzheimer's patients with their day-to-day activities. METHODS: The test-retest reliability of the CAS was assessed during a 3-week study with 42 Alzheimer's patients and their caregivers. The CAS was validated with the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog), the Mini Mental State Exam (MMSE) and the Physical Self Maintenance Scale (PSMS). RESULTS: The final version of the CAS consists of six items (communicating with the person, using transportation, eating, dressing, looking after one's appearance and supervising the person). The six-item CAS total score has high test-retest reliability, with ICC = 0.88 between weeks 1 and 3. The scale has strong convergent validity with the ADAS-Cog (r = 0.61), MMSE (r = -0.57) and PSMS (r = 0.43). Efforts to include a dimension that reflects caregiver burden were not successful, in part due to the reluctance of caregivers to acknowledge that caregiving is bothersome. CONCLUSIONS: The CAS provides a new tool that measures time spent caring for Alzheimer's individuals. The instrument may be used to augment existing clinical assessments that measure the efficacy of potentially therapeutic agents for persons with Alzheimer's disease.

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OBJECTIVE: To investigate the frequency and longitudinal course of symptoms of depression, agitation, and psychosis in a longitudinally studied sample of patients with Alzheimer's disease (AD). DESIGN: Longitudinal study of AD patients with follow-up assessments at 6-month intervals for an average of more than 3 years. SETTING: Alzheimer's Disease Research Center of the Mount Sinai Medical Center and the Bronx VA Medical Center, New York. PARTICIPANTS: A total of 153 AD patients. MEASUREMENTS: Blessed Test of Information, Memory and Concentration (BIMC) and the Alzheimer's Disease Assessment Scale cognitive (ADAS-Cog) and noncognitive (ADAS-NC) subscales. RESULTS: At entry into the study, more than 90% of patients had a behavioral disturbance that was rated as mild or worse on one of the 10 ADAS noncognitive items; and 40% had at least one rating that was moderate or severe. Correlational analyses indicated that, with the exception of the two mood-related items, noncognitive symptoms on the ADAS were not highly correlated with one another. Only one of the noncognitive items, concentration, was strongly correlated with the severity of cognitive impairment. On average, patients showed progressively worse cognitive functioning over time as measured both by the ADAS-Cog and the BIMC. The mean severity of noncognitive symptoms did not change during the course of a 5-year follow up. The severity of behavioral disturbance at any one evaluation was negatively correlated with change in behavior during the next 6 months and was not correlated with cognitive decline. CONCLUSION: Mild behavioral disturbances are common, whereas moderate to severe behavioral symptoms are less frequent in this population of AD patients. Disturbances in mood and manifestations of agitation and psychotic symptoms are not closely related to one another and show little progressive worsening over time. Rather, they tend to be episodic such that increasing severity at one time is usually followed by improvement later. Concentration problems are a manifestation of cognitive dysfunction rather than behavioral disturbance in AD. Implications of these results for treatment of noncognitive disturbances in AD are discussed.

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OBJECTIVE: To examine the validity of the family history method for identifying Alzheimer disease (AD) by comparing family history and neuropathological diagnoses. METHODS: Seventy-seven former residents of the Jewish Home and Hospital for the Aged, New York, NY, with neuropathological evaluations on record were blindly assessed for the presence of dementia and, if present, the type of dementia through family informants by telephone interviews. The Alzheimer's Disease Risk Questionnaire was used to collect demographic information and screen for possible dementia. If dementia was suspected, the Dementia Questionnaire was administered to assess the course and type of dementia, i.e., primary progressive dementia (PPD, likely AD), multiple infarct dementia, mixed dementia (i.e., PPD and multiple infarct dementia), and other dementias based on the modified Diagnostic and Statistical Manual of Mental Disorders, Third Edition, criteria. RESULTS: Sixty (77.9%) of 77 elderly subjects were classified as having dementia and 17 (22.1%) were without dementia by family history evaluation. Of the 60 elderly subjects with dementia, 57 (95%) were found at autopsy to have had neuropathological changes related to dementia. The sensitivity of the family history diagnosis for dementia with related neuropathological change was 0.84 (57 of 68) and the specificity was 0.67 (6 of 9). Using family history information to differentiate the type of dementia, the sensitivity for definite or probable AD (with or without another condition) was 0.69 (36 of 51) and the specificity was 0.73 (19 of 26). The majority (9 of 15) of patients testing false negative for PPD had a history of stroke associated with onset of memory changes, excluding a diagnosis of PPD. CONCLUSIONS: Identifying dementia, in general, and AD, in particular, has an acceptable sensitivity and specificity. As is true for direct clinical diagnosis, the major issue associated with misclassifying AD in a family history assessment is the masking effects of a coexisting non-AD dementia or dementia-related disorders, such as stroke. Including mixed cases, ie, PPD and multiple infarct dementia in estimates of the familial risk for AD can reduce the extent of underestimation of PPD.

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The present study evaluated the safety of and obtained preliminary data on the cognitive effects of L-deprenyl and physostigmine in patients with Alzheimer's Disease. Seventeen outpatients with Alzheimer's Disease participated in a double-blind crossover study in which they received 4 weeks of L-deprenyl at a dose of 10 mg p.o., q.d., and 4 weeks of placebo in random order. During both the L-deprenyl and placebo periods, patients received cognitive assessments during physostigmine (0.5 mg) and placebo infusions separated by 2 days. The cognitive effects of these agents alone and in combination were measured with digit span, verbal fluency, list learning, praxis, delayed recall, and delayed recognition tasks. Fifteen patients completed the study. The two drugs, used alone or in combination, were safe and well tolerated. Analyses of variance demonstrated that neither physostigmine nor L-deprenyl, whether given alone or in combination, significantly improved cognition, when compared with the double placebo condition.

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OBJECTIVE: The DSM-IV mood disorders field trial, a multisite collaborative study, was designed to explore the reliability of a course-based diagnostic classification system for major depression, evaluate the symptom criteria for dysthymia, and explore the need for additional diagnostic categories for milder forms of mood disorder (e.g., minor and recurrent brief depression). METHOD: Five hundred twenty-four depressed subjects were recruited from inpatient, outpatient, and community settings at five sites and evaluated with structured interviews according to DSM-III and DSM-III-R criteria, with careful attention to longitudinal course. Within- and across-site interrater reliability studies and 6-month test-retest reliability studies were also conducted on subsets of the sample. RESULTS: For evaluations of major depression and dysthymia, intrasite reliability was good to excellent and intersite reliability was fair to good; 6-month test-retest reliability was fair for dysthymia and poor to fair for major depression. Interrater reliability for six course of illness specifiers was fair to good, and almost all subjects could be assigned to a specific type of course. CONCLUSIONS: The results supported the use of a course-based classification system for major depression. They also suggested that the content validity of the DSM-III-R symptom criteria for dysthymia could be improved by emphasizing cognitive and social/motivational symptoms, although such changes are unlikely to sharpen the distinction between dysthymia and major depression. Finally, 91% of the subjects met the criteria for current or lifetime major depression or dysthymia, suggesting that additional categories for milder forms of depression are not needed.

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The authors report results of an 8-week, open trial of desipramine in 42 patients with DSM-III-R dysthymia with a concurrent diagnosis of major depression ("double" depression) and 33 patients with dysthymia who had no other depressive diagnosis ("pure" dysthymia). Either complete or partial remission was achieved by 70% of the patients with "pure" dysthymia. This compared favorably with but was not significantly different from results in the "double" depression group.

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Dopaminergic mechanisms have been implicated in depression, agitation, and psychosis--symptoms that are frequently observed in patients with Alzheimer's disease (AD). In a longitudinal study, 23 prospectively assessed AD patients underwent autopsies in which concentrations of dopamine, homovanillic acid, and dihydroxyphenylacetic acid were assayed in the temporal lobe (Brodmann areas 20 and 21). Data-reduction techniques were used to minimize the number of relationships tested. For this series of AD patients, no significant correlation was found between indices of dopaminergic neurotransmission and maximal severity of psychosis, depression, or agitation.

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Eleven percent (N = 25) of 232 dementia patients seen in an active geropsychiatry service also met criteria for major depression. Ten patients with dementia/depression were prospectively compared with 10 non-depressed demented and 33 nondemented depressed patients on pretreatment and posttreatment ratings of depression and cognition/memory. Seventy percent (N = 7) of the dementia/depression group and 73% (N = 24) of the depression-only group responded to antidepressant therapy. Signs and symptoms of depression complicating dementia were similar to depressive phenomena in the depression-only group. Depression with dementia appeared to lower performance on cognitive tests. Following treatment, although cognitive impairment remained in the demented range, test performance improved.

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