Biomedical subjects

Joel H Kramer

Publications and source records attributed to Joel H Kramer.

At least 19 recordsLinked to original sources

PubMed2025

Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease.

The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate 'pro-aging' or 'pro-youthful' effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer's disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1-7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer's disease cohort included 35 adults with sporadic Alzheimer's disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting 'pro-youthful' levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer's disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer's disease and related dementias and warrant further investigation.

Alzheimer’s disease↗

PubMed2006

Multiple cognitive deficits in amnestic mild cognitive impairment.

OBJECTIVE: To determine if more widespread cognitive deficits are present in a narrowly defined group of patients with the amnestic form of mild cognitive impairment (MCI). METHODS: From a larger sample of patients clinically diagnosed as meeting the criteria of Petersen et al. for amnestic MCI, we selected 22 subjects who had Clinical Dementia Rating scores of zero on all domains besides memory and orientation. These MCI subjects with presumably isolated memory impairments were compared to 35 age-matched normal controls and 33 very mild Alzheimer's disease (AD) patients on a battery of neuropsychological tests. RESULT: In addition to the expected deficits in episodic memory, the amnestic MCI group performed less well than the controls but better than the AD group on design fluency, category fluency, a set shifting task and the Stroop interference condition. Over half the amnestic MCI group (vs. none of the normal controls) scored at least 1 standard deviation below control means on 4 or more of the nonmemory cognitive tasks. CONCLUSIONS: Isolated memory impairment may be fairly uncommon in clinically diagnosed amnestic MCI patients, even when the criteria for amnestic MCI are fairly narrow. Additional cognitive impairments are likely to include fluency and executive functioning. These more diffuse deficits argue for comprehensive cognitive assessments, even when the patient and family are reporting only memory decline, and are consistent with the increase in attention paid to the heterogeneity of MCI.

Aged↗

PubMed2006

The California Verbal Learning Test--second edition: test-retest reliability, practice effects, and reliable change indices for the standard and alternate forms.

The California Verbal Learning Test - second edition (CVLT-II) is one of the most widely used neuropsychological tests in North America. The present study evaluated the 1-month test-retest reliability and practice effects associated with the standard and alternate forms of the CVLT-II in a sample of 195 healthy adults. Eighty participants underwent repeat assessment using the standard form of the CVLT-II on both occasions, whereas the remaining 115 individuals received the standard form at baseline and the alternate form at follow-up. Consistent with prior research, results revealed generally large test-retest correlation coefficients for the primary CVLT-II measures in both the standard/standard (range=0.80-0.84) and standard/alternate (range=0.61-0.73) cohorts. Despite exhibiting slightly lower test-retest reliability coefficients, participants in the alternate form group displayed notably smaller practice effects (Cohen's d range=-0.01 to 0.18) on the primary indices relative to individuals who received the standard form on both occasions (Cohen's d range=0.27-0.61). Reliable change indices were also generated and applied to primary CVLT-II variables to determine the base rates of significant improvements (range=2-10%), declines (range=0-7%), and stability (range=85-97%) in performance over time. Overall, findings from this study support the test-retest reliability of the standard and alternate forms of the CVLT-II in healthy adults and may enhance the usefulness of this test in longitudinal neuropsychological evaluations.

Adolescent↗

PubMed2006

Cognitive impact of subcortical vascular and Alzheimer's disease pathology.

OBJECTIVE: To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis [HS], and Alzheimer's disease [AD]), cognitive status, and apolipoprotein E genotype. METHODS: We report clinicopathological correlations from 79 autopsy cases derived from a prospective longitudinal study of subcortical ischemic vascular disease and AD. RESULTS: Thirty percent of the cases had significant cerebrovascular parenchymal pathology scores (CVDPS), 54% had significant AD pathology, and 18% had HS. In an ordinal logistic regression analysis that included interaction terms to assess the effects of each pathological variable when the other variables are interpolated to zero, each of the three pathology variables contributed independently to cognitive status: Braak and Braak stage odds ratio (OR) = 2.84 (95% confidence interval, 1.81-4.45), HS score OR = 2.43 (95% confidence interval, 1.01-5.85), and CVDPS OR = 1.02 (95% confidence interval, 1.00-1.04). Only Braak and Braak stage contributed to a global neuropsychological measure of cognitive impairment. Apolipoprotein E4 genotype was associated with Braak and Braak stage (OR, 1.31 [95% confidence interval, 1.03-1.68]), but not CVDPS or HS scores. INTERPRETATION: In this convenience sample enriched for subcortical ischemic vascular disease, HS was a common unsuspected neuropathological finding. Apolipoprotein E4 genotype was associated with cerebral amyloid angiopathy, but not HS or arteriosclerosis. When Braak and Braak stage was interpolated to zero, both CVDPS and HS contributed to cognitive impairment. However, advancing stages of AD pathology overwhelmed the effects of CVDPS and HS, to become the major determinant of dementia.

Aged↗

PubMed2006

Response bias and aging on a recognition memory task.

UNLABELLED: Response bias reflects the decision rule an individual uses when faced with uncertainty on recognition memory tasks. Recent studies indicate frontal regions may mediate response bias performance. One theory of aging also implicates frontal lobe contributions in age-related cognitive changes. This suggests that frontal lobe changes may mediate response bias in older adults. Consistent with this frontal aging hypothesis, we predicted that response bias would become more liberal with age. METHODS: Participants were 181 younger (30-49) and 112 older normal adults (75+) that were part of the California Verbal Learning Test-second edition (CVLT-2) normative sample (total n = 1078). We used parametric measures of discriminability and response bias provided by the CVLT-2 scoring program. Groups were similar in IQ and education. Multi-level regression models were created to examine the effects of moderating variables. The interaction between age and age group significantly predicted response bias. Post hoc analysis indicated that increasing age was associated with more liberal bias in the older but not in the younger group. In the light of reported relationships between frontal regions and both aging and response bias, we hypothesize that frontal changes may be the underlying mechanism explaining the increase in liberal response bias with age.

Adult↗

PubMed2006

Fresh blood and aged stored blood are equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans.

BACKGROUND: Erythrocytes are transfused to treat or prevent imminent inadequate tissue oxygenation. 2,3-diphosphoglycerate concentration decreases and oxygen affinity of hemoglobin increases (P50 decreases) with blood storage, leading some to propose that erythrocytes stored for 14 or more days do not release sufficient oxygen to make their transfusion efficacious. The authors tested the hypothesis that erythrocytes stored for 3 weeks are as effective in supplying oxygen to human tissues as are erythrocytes stored for less than 5 h. METHODS: Nine healthy volunteers donated 2 units of blood more than 3 weeks before they were tested with a standard, computerized neuropsychological test (digit-symbol substitution test [DSST]) on 2 days, 1 week apart, before and after acute isovolemic reduction of their hemoglobin concentration to 7.4 and 5.5 g/dl. Volunteers randomly received autologous erythrocytes stored for either less than 5 h ("fresh") or 3 weeks ("stored") to return their hemoglobin concentration to 7.5 g/dl (double blinded). Erythrocytes of the alternate storage duration were transfused on the second experimental day. The DSST was repeated after transfusion. RESULTS: Acute anemia slowed DSST performance equivalently in both groups. Transfusion of stored erythrocytes with decreased P50 reversed the altered DSST (P < 0.001) to a time that did not differ from that at 7.4 g/dl hemoglobin during production of acute anemia (P = 0.88). The erythrocyte transfusion-induced DSST improvement did not differ between groups (P = 0.96). CONCLUSION: Erythrocytes stored for 3 weeks are as efficacious as are erythrocytes stored for 3.5 h in reversing the neurocognitive deficit of acute anemia. Requiring fresh rather than stored erythrocytes for augmentation of oxygen delivery does not seem warranted.

2,3-Diphosphoglycerate↗

PubMed2005

Clinical and neuropsychological features of corticobasal degeneration.

In this paper, we review the history, clinical, cognitive, imaging and neuropathological features of corticobasal degeneration (CBD). Additionally, we report new findings on the neuropsychological profile of 14 patients with CBD compared to 14 with Alzheimer's disease. Increasing awareness of this disorder has led to the realization that specific cognitive and imaging changes are common with CBD degeneration and that these changes help with clinical diagnosis.

Alzheimer Disease↗

PubMed2005

Neuroanatomical correlates of impaired recognition of emotion in dementia.

Neurodegenerative diseases frequently affect brain regions important for emotional processing, offering a valuable opportunity to study the effects of brain injury on emotion. The current study examined the neuroanatomical correlates of impaired recognition of emotions in patients with neurodegenerative disease. Performance on recognition of facial expressions, as measured by the Florida Affect Battery, was correlated with regional changes in gray matter tissue content in 50 patients with neurodegenerative disease using voxel-based morphometry. Recognition accuracy in the group was poor for negative emotions (fear, anger and sadness) and good for happiness, consistent with previous studies. For negative emotions, a region in the right lateral inferior temporal gyrus (Brodman's area (BA) 20) extending into the right middle temporal gyrus (BA 21) was correlated with accuracy. This effect appeared to be strongest for sadness, which was also independently correlated with atrophy in the superior temporal gyrus. These data suggest that regions in the right lateral and inferolateral temporal lobe are important for visual processing of negative emotions from faces and that functioning of this right temporal network is most critical for recognition of sad faces.

Aged↗

PubMed2005

Age effects on atrophy rates of entorhinal cortex and hippocampus.

The effects of age, subcortical vascular disease, apolipoprotein E (APOE) epsilon4 allele and hypertension on entorhinal cortex (ERC) and hippocampal atrophy rates were explored in a longitudinal MRI study with 42 cognitively normal (CN) elderly subjects from 58 to 87 years old. The volumes of the ERC, hippocampus, and white matter hyperintensities (WMH) and the presence of lacunes were assessed on MR images. Age was significantly associated with increased atrophy rates of 0.04+/-0.02% per year for ERC and 0.05+/-0.02% per year for hippocampus. Atrophy rates of hippocampus, but not that of ERC increased with presence of lacunes, in addition to age. WMH, APOE epsilon4 and hypertension had no significant effect on atrophy rates. In conclusion, age and presence of lacunes should be taken into consideration in imaging studies of CN subjects and AD patients to predict AD progression and assess the response to treatment trials.

Aged↗

PubMed2005

Patterns of autobiographical memory loss in dementia.

BACKGROUND: Several studies have found impaired recall of remote autobiographical memories relative to recent memories in semantic dementia (SD), a pattern opposite to that in Alzheimer's disease (AD). OBJECTIVE: To document dissociation of memory for autobiographical incidents and personal semantic information in individuals with AD, frontotemporal dementia (FTD), and SD. METHODS: The authors administered the Autobiographical Memory Interview to eight individuals with AD, 11 with FTD, eight with SD, and eight normal controls . Autobiographical incidents and personal semantic memory was assessed from three time periods: childhood, early adulthood, and recent life. RESULTS: Individuals with SD recalled more details of autobiographical incidents from the most recent 5 years than from childhood and early adulthood (childhood vs recent life: t(7) = -3.59, p = 0.009; early adulthood vs recent life: t(7) = -4.33, p = 0.003). No difference was found between childhood and early adulthood (t(7) = 1.11, p = 0.305). Recall of personal semantic information was related to the age of the memory with less remembered from earlier time periods (childhood vs recent life: t(7) = -6.52, p < 0.001; childhood vs early adulthood: t(7) = -2.61, p = 0.035; early adulthood vs recent life: t(7) = -9.15, p < 0.001). CONCLUSIONS: SD is a compelling model in which to study the anatomy of episodic memory.

Aged↗

PubMed2005

White matter lesions are associated with cortical atrophy more than entorhinal and hippocampal atrophy.

The goal of this study was to examine the relationship between subcortical vascular disease and brain atrophy in patients with Alzheimer's disease (AD) and mixed dementia (i.e., AD and subcortical vascular disease together). MRI was performed on 77 cognitively normal (CN) subjects, 50 AD and 13 mixed dementia patients. Subcortical vascular disease was determined by white matter hyperintensities (WMH) volume and presence of subcortical lacunes. Brain atrophy was measured using total brain cortical gray matter (CGM), entorhinal cortex (ERC) and hippocampal volumes. CGM volume, but not ERC or hippocampal volume was inversely related to WMH volume in patients and controls. In contrast, no relationship was detected between CGM, ERC, or hippocampal volumes and subcortical lacunes. Furthermore, no interaction was found between WMH and diagnosis on cortical atrophy, implying that WMH affect cortical atrophy indifferently of group. These results suggest that subcortical vascular disease, manifested as WMH, may affect cortical atrophy more than ERC and hippocampal atrophy. Further, AD pathology and subcortical vascular disease may independently affect cortical atrophy.

Aged↗

PubMed2005

Recall discriminability: utility of a new CVLT-II measure in the differential diagnosis of dementia.

Memory tests that are in a recall format have almost universally measured accuracy in terms of the number of target items reported by the examinee. However, this traditional scoring method can, in certain cases, result in artificially inflated memory accuracy scores. That is, just as a "yes" response bias and high false-positive rate on recognition testing can artificially inflate a patient's hit rate, so, too, a liberal response bias and high intrusion rate on recall testing can artificially inflate a patient's level of target recall. Recognition tests correct for this problem by using a discriminability measure that provides a single score of hit rate relative to false-positive rate; however, recall tests rarely provide a single score of recall accuracy that corrects for intrusion rate. In the present study, we examined the utility of a new recall discriminability measure that analyzes target recall relative to intrusion rate. Patients with Alzheimer's disease (AD) or Huntington's disease (HD) were administered the CVLT-II, which provides both the traditional measure of target recall and a new measure of recall discriminability. The results indicate that the new recall discriminability measure was superior to the traditional level of target recall measure in distinguishing the recall performance of AD and HD patients. Implications of these results for clinical practice and theories of memory disorder in dementia are discussed.

Adult↗

PubMed2005

Mental flexibility: age effects on switching.

Mental flexibility is required to track and systematically alternate between 2 response sets. In this study, 719 individuals, 20 to 89 years old, engaged in 3 different tasks that required verbal and nonverbal cognitive switching. Of importance, each task allowed for independent measurement of component skills that are embedded in the higher level tasks. When gender, education, Full Scale IQ, and component skills were partialed out by multiple regression analyses, significant age effects were revealed for each task. This study provides evidence that executive functions--and verbal and nonverbal cognitive switching in particular--are affected by age independently from age-related changes in component skills. The results are discussed in terms of theories of executive control and neurologic correlates across the adult life span.

Adult↗

PubMed2005

Dissociations in hippocampal and frontal contributions to episodic memory performance.

The hippocampus and frontal lobes both contribute to episodic memory performance. In the present study, the authors evaluated the relative contributions of hippocampus, frontal lobes, anterior temporal cortex, and posterior cortex to memory performance in neurodegenerative patients and normal older controls. Subjects (n=42) were studied with structural MRI and a memory paradigm that measured delayed recall, semantic clustering during recall, recognition discriminability, and recognition response bias. Data were analyzed with multiple regression. Consistent with the authors' hypotheses, hippocampal volumes were the best predictor of delayed recall and recognition discriminability, whereas frontal volumes were the best predictor of semantic clustering and response bias. Smaller frontal volumes were associated with less semantic clustering during recall and a more liberal response bias. Results indicate that hippocampal and frontal contributions to episodic memory can be dissociated, with the hippocampus more important for memory accuracy, and frontal structures more important for strategic processing and decision making.

Aged↗

PubMed2005

Patterns of cognitive and emotional empathy in frontotemporal lobar degeneration.

OBJECTIVE: To examine the relationship between empathy and cognition in frontotemporal lobar degeneration (FTLD). BACKGROUND: Theoretical models suggest empathy has multiple cognitive and affective subcomponents, and recent studies suggest that performance on specific cognitive tests may predict empathy. Qualitative behavioral studies of patients with FTLD suggest empathy loss may occur directly as a result of damage to frontal and temporal structures. METHOD: First-degree relatives used the Interpersonal Reactivity Index (IRI), a measure of cognitive and emotional empathy, to rate 18 patients with frontotemporal dementia (FTD), 19 patients with semantic dementia (SD), 16 patients with Alzheimer disease (AD), and 10 age-matched healthy control subjects (NC). Subjects also underwent cognitive testing. RESULTS: Both FTD and SD groups showed significantly lower levels of empathy than either ADs or NCs. SDs showed disruption of both emotional and cognitive empathy, whereas FTDs showed only disruption of cognitive empathy. Regressions controlling for general cognitive impairment showed 32% of the variance in Perspective Taking score was predicted by Category Fluency (P < 0.001), and 25% of the variance in Fantasy score was accounted for by Phonemic Fluency (P < 0.001). CONCLUSIONS: Although cognitive empathy is at least partly reliant on frontal structures, the emotional components of empathy are likely mediated by structures in the temporal lobes.

Aged↗

PubMed2004

Effects of white matter lesions and lacunes on cortical function.

BACKGROUND: Subcortical ischemic vascular dementia has been ascribed to prominent frontal lobe dysfunction secondary to ischemic lesions in frontothalamic circuits. Whether small-vessel disease in fact predominantly affects the frontal lobes is not well documented. OBJECTIVE: To investigate the effects of subcortical lesions (lacunes and white matter lesions [WML]) on cortical function, as reflected in glucose metabolism and cognitive function, in elderly individuals. DESIGN: Cross-sectional analyses of case series. SETTING: Multicenter, university-based study of subcortical vascular dementia. PATIENTS: Persons with normal cognition, mild cognitive impairment, or dementia and with and without lacunes on magnetic resonance images. MAIN OUTCOME MEASURES: Regional cerebral glucose metabolism, normalized regional metabolic activity, and neuropsychological test scores. Major hypotheses were that volume of lacunes and WML correlate selectively with hypometabolism of prefrontal cortex and failure of executive cognitive ability. RESULTS: Lacunes correlated with metabolic rates in dorsolateral frontal cortex (DLF); WML substantially reduced metabolic rates throughout cortex, most strongly so in DLF. When regional metabolic activity was normalized to whole brain activity, lacunes remained correlated with DLF activity, whereas the WML effect was no longer found, probably because of its general distribution. Regional cerebral glucose metabolism and normalized activity in DLF also correlated with cortical atrophy. Metabolic activity in DLF correlated with executive function, memory, and global cognitive function, while activity in middle temporal gyrus correlated with memory and global function but not executive function. CONCLUSIONS: The metabolic effects of lacunes and WML are most apparent in DLF, but the effects of WML are generalized and frontal hypometabolism correlates with memory and global impairment, cognitive as well as executive function. The effects of subcortical cerebrovascular disease appear to converge on the frontal lobes but are diffuse, complex, and of modest magnitude.

Aged↗

PubMed2004

17q-linked frontotemporal dementia-amyotrophic lateral sclerosis without tau mutations with tau and alpha-synuclein inclusions.

BACKGROUND: Frontotemporal dementia (FTD) is a clinically heterogeneous condition that can be associated with clinical manifestations of an extrapyramidal disorder or motor neuron disease. A range of histologic patterns has been described in patients with FTD. The most common familial form of this condition is caused by mutations in the microtubule-associated protein tau gene (MAP tau) and is associated with neuronal or glial tau inclusions. OBJECTIVES: To determine the clinical, anatomic, and pathological features of San Francisco family A and to map the mutation responsible for disease in this family. DESIGN: A systematic clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of San Francisco family A was performed. A pathological and biochemical assessment of a family member was made. SETTING: Family study. PATIENTS: San Francisco family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Afflicted family members do not have a MAP tau coding or splice regulatory sequence mutation, and the MAP tau is genetically excluded. MAIN OUTCOME MEASURES: Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS). RESULTS: The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAP tau. All previously identified susceptibility loci for FTD and ALS are excluded. Autopsy findings from an afflicted family member show distinctive tau and alpha-synuclein inclusions. Another unique feature is that the insoluble tau protein consists predominantly of the 4R/0N isoform. CONCLUSION: The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.

Adult↗

PubMed2004

Visual attention in long-term survivors of leukemia receiving cranial radiation therapy.

The effect of cranial radiation therapy (CRT) on visual attention was examined in long-term survivors of childhood acute lymphoblastic leukemia (ALL) compared to peers with no history of ALL (n = 24) using a cued orienting task and a global-local task. ALL participants treated with CRT (n = 13) demonstrated an increased cost in response time with invalid spatial orienting cues and inefficient shifts of attention across hierarchical levels. ALL participants treated only with chemotherapy (n = 8) showed performance similar to the non-ALL comparison group. Participants with exposure to CRT early in life appeared to largely account for the attention deficits, and showed particular difficulties with shifting attention from the local level of stimuli to the global level. The data are consistent with prior reports emphasizing attention deficits following CRT, and suggest that attention shifting may be particularly affected by CRT early in life.

Adolescent↗