Alzheimer Disease: Mohs RC

Mohs RC. · Neuroscience, Medical, Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN, USA. · Alzheimers Dement. · Pubmed #18632007 No free full text.

Abstract: Discovery, development, and testing of new drugs with novel mechanisms and new indications are extremely risky. The number of new drugs introduced into clinical practice with new mechanisms and novel indications has not increased during recent years in spite of advances in biologic science. The sources of uncertainty leading to failure in drug development are discussed in three categories: biologic or target risk, clinical development uncertainty, and market uncertainty. Efforts to develop drugs that modify the course of Alzheimer's disease and/or delay the initial clinical manifestations of disease are subject to all three types of risk. Opportunities for government, academic researchers, advocacy groups, and the pharmaceutical industry to mitigate some of these risks and possibly speed the introduction of new therapies are mentioned.

Mohs RC. · Eli Lilly and Company, Indianapolis, IN 46285, USA. · Genes Brain Behav. · Pubmed #15810901 No free full text.

Abstract: This paper describes the natural history of the clinical syndrome of Alzheimer's disease (AD) including the cognitive deficit, the neuropsychiatric symptoms, impact on daily functioning, risk factors, medical complications and impact on the use of health-care resources. The clinical presentation of the disease varies greatly from the prodrome through end stage; instruments used to quantify the severity of each aspect of the disease have been developed and are described along with their use in clinical drug trials. Drug treatments for AD are usually developed by first showing a positive effect on the cognitive deficit, with later studies investigating drug effects on other clinical aspects of the disease.

Mohs RC, Schmeidler J, Aryan M. · Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA. · Stat Med. · Pubmed #10844705 No free full text.

Abstract: This paper reviews data on the natural history of symptoms in patients with Alzheimer's disease (AD) and describes some of the problems encountered in analysing longitudinal data in this population. Data on cognition, functional ability and psychiatric or behavioural symptoms have all been obtained from AD patients. Because of attrition, the length of follow-up is not uniform for all patients and neither is the frequency of evaluation. Furthermore, patients enter longitudinal studies with a wide range of symptom severity and longitudinal decline in cognition and function is distinctly non-linear. Behavioural symptoms do not progress regularly in AD but are episodic phenomena not closely related to cognition or function. Strengths and limitations of various analytic techniques used for hypothesis testing with these longitudinal data are described.

Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, Pratt RD, Anonymous00310. · Mount Sinai School of Medicine, Bronx VA Medical Center, New York, NY 10468, USA. · Neurology. · Pubmed #11502917 No free full text.

Abstract: OBJECTIVE: To examine the effects of donepezil compared with placebo on the preservation of function in patients with AD over a 1-year period. METHODS: This was a prospective, 54-week, double-blind, placebo-controlled, survival to endpoint study. Patients were required to have at entry: a diagnosis of probable AD (National Institute of Neurological and Communicative Disorders and Stroke criteria); Mini-Mental State Examination score of 12 to 20; Clinical Dementia Rating of 1 or 2; modified Hachinski ischemia score < or =4; and capability of performing 8 of 10 instrumental activities of daily living and 5 of 6 basic activities of daily living. Patients (n = 431) were randomized to placebo or donepezil (5 mg/day for 28 days, 10 mg/day thereafter). Outcome measures were the AD Functional Assessment and Change Scale, the Mini-Mental State Examination, and Clinical Dementia Rating scale. At each visit, investigators determined whether predefined criteria for clinically evident decline in functional status had been met. Patients who met the endpoint criteria were discontinued per protocol. RESULTS: Donepezil extended the median time to clinically evident functional decline by 5 months versus placebo. The probability of patients treated with donepezil remaining in the study with no clinically evident functional loss was 51% at 48 weeks, compared with 35% for placebo. The Kaplan-Meier survival curves for the two treatment groups were different (p = 0.002, log-rank test). CONCLUSIONS: Patients with AD continue to show detectable disease progression over time, but treatment with donepezil for 1 year was associated with a 38% reduction in the risk of functional decline compared with placebo.

Green CR, Marin DB, Mohs RC, Schmeidler J, Aryan M, Fine E, Davis KL. · Department of Psychiatry, Mount Sinai School of Medicine, New York, USA. · Int J Geriatr Psychiatry. · Pubmed #10340193 No free full text.

Abstract: 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.

Khachaturian ZS, Snyder PJ, Doody R, Aisen P, Comer M, Dwyer J, Frank RA, Holzapfel A, Khachaturian AS, Korczyn AD, Roses A, Simpkins JW, Schneider LS, Albert MS, Egge R, Deves A, Ferris S, Greenberg BD, Johnson C, Kukull WA, Poirier J, Schenk D, Thies W, Gauthier S, Gilman S, Bernick C, Cummings JL, Fillit H, Grundman M, Kaye J, Mucke L, Reisberg B, Sano M, Pickeral O, Petersen RC, Mohs RC, Carrillo M, Corey-Bloom JP, Foster NL, Jacobsen S, Lee V, Potter WZ, Sabbagh MN, Salmon D, Trojanowski JQ, Wexler N, Bain LJ. · Lou Ruvo Brain Institute, Las Vegas, NV 89106, USA. · Alzheimers Dement. · Pubmed #19328434 No free full text.

Abstract: This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

Fillenbaum GG, van Belle G, Morris JC, Mohs RC, Mirra SS, Davis PC, Tariot PN, Silverman JM, Clark CM, Welsh-Bohmer KA, Heyman A. · Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA. · Alzheimers Dement. · Pubmed #18631955 No free full text.

Abstract: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer's disease (AD). The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.

Chappell AS, Gonzales C, Williams J, Witte MM, Mohs RC, Sperling R. · Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. · Neurology. · Pubmed #17389305 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy and safety of the positive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid modulator LY451395 in patients with mild to moderate Alzheimer disease (AD) (Mini-Mental State Examination scores 14 to 26). METHODS: One hundred eighty-one patients were randomized to treatment in an 11-week, double-blind, placebo-controlled trial. Patients received either LY451395 0.2 mg BID for 28 days and 1.0 mg BID thereafter (n = 90) or placebo (n = 91). The primary outcome measurement was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) with several secondary outcome measurements: Clinician's Interview-Based Impression of Change, Trail Making Part A, Stylus Tapping Test, Single Digit Modality Test, and Neuropsychiatric Inventory (NPI). RESULTS: Baseline demographics were similar between the two groups. Patients did not show any mean change from baseline in the ADAS-Cog after treatment with LY451395 for 4 weeks (p = 0.60) or 8 weeks (p = 0.83). The only secondary outcome measurement that showed changes from baseline compared with placebo was the NPI Total Score: p = 0.06 (marginal significance) after 4 weeks of treatment and p = 0.03 after 8 weeks of treatment. Ninety-two percent of LY451395-treated patients and 95% of placebo-treated patients completed the trial. Adverse events were experienced by 83% of LY451395-treated patients and 86% of placebo-treated patients, the majority of which were rated mild in severity. CONCLUSION: Patients treated with LY451395 did not show a statistically significant separation from patients taking placebo on the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the primary outcome measure.

Beeri MS, Silverman JM, Davis KL, Marin D, Grossman HZ, Schmeidler J, Purohit DP, Perl DP, Davidson M, Mohs RC, Haroutunian V. · Department of Psychiatry, Mount Sinai School of Medicine, New York, USA. · J Gerontol A Biol Sci Med Sci. · Pubmed #15933386 No free full text.

Abstract: BACKGROUND: In cross-sectional and longitudinal studies, type 2 diabetes has been positively associated with the risk of Alzheimer's disease (AD). The present descriptive study compared diabetic and nondiabetic subjects on the severity of neuritic plaques and neurofibrillary tangles (NFTs) in the cerebral cortex and in the hippocampus. METHODS: The study included specimens from 385 consecutive autopsies of residents of a nursing home (15.8% diabetics). Mean age at death = 84 years [standard deviation (SD) = 10], 66% were female, Clinical Dementia Rating mean = 3.0 (SD = 1.6), and 32.5% had an APOE4 allele. Additional analyses limited the sample to 268 subjects (14.1% diabetics) without neuropathology other than AD. RESULTS: Analyses of covariance controlling for age at death, dementia severity (Clinical Dementia Rating score), and APOE4 allele indicated that diabetics had significantly fewer neuritic plaques (p =.008) and NFTs (p =.047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (p =.019), but the lower ratings of NFTs did not achieve statistical significance (p =.082). In the entire sample, diabetics had significantly less AD-associated neuropathology in all four analyses. CONCLUSIONS: These results raise the possibility that the varied associations observed between diabetes and AD may be specific to as yet ill-defined subgroups of dementia and diabetic patients or may be more characteristic of younger patients than of those who survive to a mean age of 84 years. Future studies are encouraged to examine a variety of other characteristics such as age that may interact with diabetes affecting the incidence of AD.

Serby M, Brickman AM, Haroutunian V, Purohit DP, Marin D, Lantz M, Mohs RC, Davis KL. · Departments of Psychiatry and Psychology, Mount Sinai School of Medicine, New York, NY, USA. · Am J Geriatr Psychiatry. · Pubmed #12724118 No free full text.

Abstract: OBJECTIVES: Authors compared the degrees of cognitive deficit among individuals with Alzheimer disease (AD), the Lewy-body variant of AD (LBV), and "pure" dementia with Lewy bodies (DLB); and compared cortical Lewy body (LB) counts in LBV versus DLB and neuritic plaque and neurofibrillary tangle severity in LBV versus AD. METHODS: Authors examined brain specimens from consecutive autopsies of elderly nursing home subjects. Numbers and densities of plaques, Lewy bodies, and tangle severity were determined in multiple cortical regions, and demographic and clinical variables were compared among the three groups. RESULTS: The three groups did not differ in demographic or clinical variables. The LBV group was significantly more impaired than the other groups. Cortical LB counts were significantly higher in LBV than in DLB. There was no evidence of increased plaque or tangle severity in LBV than in AD. CONCLUSION: The co-occurrence of AD and LB pathology is associated with higher numbers of LBs and more severe dementia than when classical AD or LB lesions occur alone.

Silverman JM, Smith CJ, Marin DB, Mohs RC, Propper CB. · Department of Psychiatry, Box 1230, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. · Arch Gen Psychiatry. · Pubmed #12578437 links to  free full text

Abstract: BACKGROUND: The incidence of Alzheimer disease (AD) peaks after 85 years of age. Although genetic factors are implicated in AD with substantially earlier onset, the familial characteristics of high-incidence very late-onset AD (VLOAD, defined here as AD with onset age >/=85 years) remain unknown. METHODS: We collected information pertaining to the cognitive status and demographics of 809 parents and siblings of 144 VLOAD probands, 4235 parents and siblings of 793 earlier-onset AD probands, and 7646 parents and siblings of 1493 nondemented elderly probands. Cumulative risks and 5-year interval-specific hazard rate ratios were calculated for AD in relatives of the 2 AD proband groups and relatives of the nondemented elderly group. RESULTS: The cumulative risk for AD in the relatives of VLOAD probands was significantly different than that in the relatives of earlier-onset AD probands (P<.001), but not in the relatives of nondemented elderly probands. Also, the relatives of earlier-onset AD probands had hazard rate ratios ranging from 19.7 in those aged 50 to 54 years to 1.2 in those aged 90 to 94 years. Rates successively dropped as age intervals increased. CONCLUSIONS: At least through the middle of the ninth decade of life, relatives of VLOAD probands have a lower risk for AD than those of earlier-onset AD probands. In addition, the relatively increased risk of relatives of earlier-onset AD probands is highest at younger ages and diminishes with increasing age. In counseling family members of patients with AD concerned about their own risk, the onset age of the patient and the age of the concerned relative should be considered. Very late-onset AD may be a good target for investigating environmental factors associated with AD.

Parvathy S, Davies P, Haroutunian V, Purohit DP, Davis KL, Mohs RC, Park H, Moran TM, Chan JY, Buxbaum JD. · Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY 10029, USA. · Arch Neurol. · Pubmed #11735776 links to  free full text

Abstract: CONTEXT: Accumulation of senile plaques containing amyloid beta (Abeta)-protein is a pathologic hallmark of Alzheimer disease. Amyloid beta-peptide is heterogeneous, with carboxyterminal variants ending at residues Val40 (Abetax-40), Ala42 (Abetax-42), or Thr43 (Abetax-43). The relative importance of each of these variants in dementia or cognitive decline remains unclear. OBJECTIVE: To study whether Abeta deposition correlates with dementia and occurs at the earliest signs of cognitive decline. DESIGN, SETTING, AND PATIENTS: Postmortem cross-sectional study comparing the deposition of Abeta variants in the prefrontal cortex of 79 nursing home residents having no, questionable, mild, moderate, or severe dementia. MAIN OUTCOME MEASURES: Levels of staining of Abeta-peptides ending at amino acid 40, 42, or 43 in the frontal cortex, as a function of Clinical Dementia Rating score. RESULTS: There were significant deposits of all 3 Abeta species that strongly correlated with cognitive decline. Furthermore, deposition of Abetax-42 and Abetax-43 occurred very early in the disease process before there could be a diagnosis of Alzheimer disease. Levels of deposited Abetax-43 appeared surprisingly high given the low amounts synthesized. CONCLUSIONS: These data indicate that Abetax-42 and Abetax-43 are important species associated with early disease progression and suggest that the physiochemical properties of the Abeta species may be a major determinant in amyloid deposition. The results support an important role for Abeta in mediating initial pathogenic events in Alzheimer disease dementia and reinforce that treatment strategies targeting the formation, accumulation, or cytotoxic effects of Abeta should be pursued.

Ho L, Purohit D, Haroutunian V, Luterman JD, Willis F, Naslund J, Buxbaum JD, Mohs RC, Aisen PS, Pasinetti GM. · Neuroinflammation Research Laboratories, Department of Psychiatry, Box 1229, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029, USA. · Arch Neurol. · Pubmed #11255454 links to  free full text

Abstract: BACKGROUND: Prior studies have shown that cyclooxygenase 2 (COX-2), an enzyme involved in inflammatory mechanisms and neuronal activities, is up-regulated in the brain with Alzheimer disease (AD) and may represent a therapeutic target for anti-inflammatory treatments. OBJECTIVE: To explore COX-2 expression in the brain as a function of clinical progression of early AD. DESIGN AND MAIN OUTCOME MEASURES: Using semiquantitative immunocytochemistry, we analyzed COX-2 protein content in the hippocampal formation in 54 postmortem brain specimens from patients with normal or impaired cognitive status. SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: The immunointensity of COX-2 signal in the CA3 and CA2 but not CA1 subdivisions of the pyramidal layers of the hippocampal formation of the AD brain increased as the disease progressed from questionable to mild clinical dementia as assessed by Clinical Dementia Rating. COX-2 signal was increased in all 3 regions examined among cases characterized by severe dementia. CONCLUSION: Neuronal COX-2 content in subsets of hippocampal pyramidal neurons may be an indicator of progression of dementia in early AD.

Gibson GE, Haroutunian V, Zhang H, Park LC, Shi Q, Lesser M, Mohs RC, Sheu RK, Blass JP. · Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, NY 10605, USA. · Ann Neurol. · Pubmed #10976635 No free full text.

Abstract: Brain metabolism and the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a mitochondrial enzyme, are diminished in brains from patients with Alzheimer's disease (AD). In 109 subjects, the Clinical Dementia Rating (CDR) score was highly correlated with brain KGDHC activity. In AD patients who carried the epsilon 4 allele of the apolipoprotein E gene (ApoE4), the CDR score correlated better with KGDHC activity than with the densities of neuritic plaques or neuritic tangles. In contrast, in patients without ApoE4, the CDR score correlated significantly better with tangles and plaques than with KGDHC activity. The results suggest that mitochondrial/oxidative damage may be more important for the cognitive dysfunction in AD patients who carry ApoE4 than in those who do not.

Haroutunian V, Serby M, Purohit DP, Perl DP, Marin D, Lantz M, Mohs RC, Davis KL. · Psychiatry Research, Room 3F-02, Bronx VA Medical Center, 130 W Kingsbridge Rd, Bronx, NY 10468, USA. · Arch Neurol. · Pubmed #10927794 links to  free full text

Abstract: CONTEXT: Lewy bodies (LBs) are intraneuronal inclusions in the brain that have been increasingly recognized as neuropathological lesions with relevance not only to Parkinson disease but also to Alzheimer disease. However, the degree to which the density of LBs in the brain contributes to the severity of dementia has not been clear. OBJECTIVE: To determine the degree to which LB "burden" contributes to dementia. DESIGN: Brain specimens were examined from 273 consecutive autopsies of elderly subjects residing in a nursing home. The numbers and densities of LBs were determined in multiple brain regions, and their correlation with a measure of cognition and functional status (Clinical Dementia Rating) during the 6 months preceding death was determined. SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: The severity of dementia correlated significantly and positively with the density of LBs. These correlations were independent of other neuropathological disorders commonly associated with dementia, including Alzheimer disease. The density of LBs correlated significantly with dementia severity whether or not the diagnostic criteria for Alzheimer disease were met and after the contribution of classical Alzheimer disease lesions, neuritic plaques, and neurofibrillary tangles had been accounted for by partial correlation analysis. CONCLUSION: Lewy body inclusions appear to contribute significantly to cognitive deficits in the elderly in a manner that is independent of other neuropathological disorders. Arch Neurol. 2000;57:1145-1150

Silverman JM, Smith CM, Marin DB, Schmeidler J, Birstein S, Lantz M, Davis KL, Mohs RC. · Department of Psychiatry, Mt. Sinai School of Medicine, New York, NY 10029, USA. · Int J Geriatr Psychiatry. · Pubmed #10918344 No free full text.

Abstract: 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.

Davis KL, Mohs RC, Marin DB, Purohit DP, Perl DP, Lantz M, Austin G, Haroutunian V. · Department of Psychiatry, Mount Sinai School of Medicine, and Jewish Home and Hospital, New York, NY 10029, USA. · Arch Gen Psychiatry. · Pubmed #10565496 links to  free full text

Abstract: 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.

Ehrenkrantz D, Silverman JM, Smith CJ, Birstein S, Marin D, Mohs RC, Davis KL. · Department of Psychiatry, Mt. Sinai School of Medicine, New York, New York 10029, USA. · Am J Med Genet. · Pubmed #10402505 No free full text.

Abstract: Recent evidence for mitochondrial mutations associated with Alzheimers disease (AD) suggests the possibility of maternal transmission of this illness. We investigated this hypothesis by examining, in a variety of ways, the risk of a primary progressive dementia (PPD) in the parents (n = 650) and siblings (n = 1,220) of 325 AD probands. The results did not support maternal transmission in AD: The mothers of AD probands were not at greater risk of PPD than the fathers or the sisters of AD probands; the offspring of affected mothers were not at greater risk than the offspring of affected fathers or families with no affected parent; and, after selecting those proband families with evidence for increased familial loading, such families did not more frequently have affected mothers than fathers. In contrast, the cumulative risk of PPD in fathers of AD probands, while similar to that of mothers, was significantly increased over the brothers of AD probands. In addition, the cumulative risk curve of PPD in the offspring of affected fathers was significantly higher than the offspring of no affected parents. While no evidence for maternal transmission in AD was observed, unexpectedly, we did find evidence of increased paternal transmission.

Haroutunian V, Purohit DP, Perl DP, Marin D, Khan K, Lantz M, Davis KL, Mohs RC. · Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA. · Arch Neurol. · Pubmed #10369312 links to  free full text

Abstract: BACKGROUND: The relationship between neuropathological lesions and mild, "preclinical," cognitive impairments of Alzheimer disease is poorly understood. Identification of the lesions that are most closely associated with the earliest symptoms of Alzheimer disease is crucial to the understanding of the disease process and the development of treatment strategies to affect its progression. DESIGN AND MAIN OUTCOME MEASURES: We examined the extent of neurofibrillary tangles (NFTs) in 4 neocortical regions, the hippocampus, the entorhinal cortex, and the amygdala in 65 elderly subjects with no dementia, questionable dementia, mild dementia, or moderate dementia as assessed using the Clinical Dementia Rating Scale (CDR). SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: Neurofibrillary tangles were present in the entorhinal cortex and the hippocampus of all subjects, including those without cognitive deficits. Neocortical NFTs were mostly absent in the nondemented (CDR score, 0.0) subjects. The density of NFTs in the questionably demented (CDR score, 0.5) subjects was not significantly increased (P>.20) relative to the nondemented group in any of the brain regions studied. Significant increases (P<.04) in NFT density become apparent first in the amygdala and the temporal cortex in subjects rated to be mildly impaired (CDR score, 1.0). By the time that cognitive impairments were judged to be moderately severe (CDR score, 2.0), all regions of the brain examined, except for the occipital cortex, were significantly (P<.05) involved. CONCLUSIONS: Some NFTs are present in the entorhinal cortex and hippocampus of most elderly individuals irrespective of their cognitive status, but the density of NFTs increases as a function of dementia severity.

Davis KL, Mohs RC, Marin D, Purohit DP, Perl DP, Lantz M, Austin G, Haroutunian V. · Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029-6574, USA. · JAMA. · Pubmed #10217056 links to  free full text

Abstract: CONTEXT: A central tenet of Alzheimer disease (AD) is the loss of cortical cholinergic function and cholinergic markers in postmortem brain specimens. Whether these profound deficits in cholinergic markers found in end-stage patients are also found in patients with much earlier disease is not known. OBJECTIVE: To determine whether cholinergic deficits in AD precede, follow, or occur in synchrony with the earliest signs of cognitive deterioration. DESIGN, SETTING, AND PATIENTS: Postmortem study of nursing home residents with Clinical Dementia Rating (CDR) Scale scores of 0.0 to 2.0 and 4.0 to 5.0 who underwent autopsy between 1986 and 1997, comparing the activity of the cholinergic marker enzymes in the cortices of 66 elderly subjects with no (CDR score = 0.0; n = 18), questionable (CDR score = 0.5; n = 11), mild (CDR score = 1.0; n = 22), or moderate (CDR score = 2.0; n = 15) dementia vs subjects with severe dementia (CDR score = 4.0-5.0; n = 15). MAIN OUTCOME MEASURES: Activity of the cholinergic marker enzymes choline acetyltransferase and acetylcholinesterase in 9 neocortical brain regions. RESULTS: The activity of choline acetyltransferase and acetylcholinesterase in 9 neocortical brain regions did not differ significantly in subjects with CDR scores of 0.0 to 2.0, but was significantly lower in subjects with severe dementia (CDR score = 4.0-5.0). Choline acetyltransferase levels were significantly correlated with severity of neuropathological lesions of AD, as measured by density of neuritic plaques and neurofibrillary tangles. CONCLUSIONS: Although neocortical cholinergic deficits are characteristic of severely demented AD patients, in this study, cholinergic deficits were not apparent in individuals with mild AD and were not present until relatively late in the course of the disease. These results suggest that patients with more severe disease should be a target for cholinergic treatment.

Silverman JM, Smith CJ, Marin DB, Birstein S, Mare M, Mohs RC, Davis KL. · Department of Psychiatry, Mt. Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. · Am J Hum Genet. · Pubmed #10053018 links to  free full text

Abstract: 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.

Sheu KF, Brown AM, Haroutunian V, Kristal BS, Thaler H, Lesser M, Kalaria RN, Relkin NR, Mohs RC, Lilius L, Lannfelt L, Blass JP. · Burke Medical Research Institute, White Plains, NY 10605, USA. · Ann Neurol. · Pubmed #9894876 No free full text.

Abstract: The mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC) is deficient in Alzheimer's disease (AD). The DLST gene encodes the core, dihydrolipoyl succinyltransferase (DLST) component of KGDHC, and recent reports indicate an association between polymorphisms of DLST and AD in both white and Japanese patients. We therefore examined the relationship between AD and the DLST and apolipoprotein E (APOE) genes in elderly (89 +/- 7 years) AD patients, in whom the epsilon4 allele of APOE (APOE4) is a weak risk factor for AD. Polymorphisms of DLST (A19,117G and T19,183C), shown to be of interest in previous studies, were analyzed by restriction fragment length polymorphism analysis after polymerase chain reaction amplification. In a series of 429 white subjects from two Jewish nursing homes, an association of APOE4 with AD was found only in patients homozygous for the G,C allele of DLST. Similar relationships occurred in the "very elderly" (> or =85 years, n = 302) subgroup of this series, and also in an autopsy series (n = 225) that included white subjects from the Jewish nursing homes as well as other white subjects. These findings suggest a relationship between APOE4 and a DLST locus in the pathogenesis of AD in very elderly subjects.