[Show abstract][Hide abstract] ABSTRACT: Some studies have reported associations between intracranial atherosclerosis and Alzheimer disease pathology. We aimed to correlate severity of cerebral atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy with neurofibrillary tangles, neuritic plaques, and cerebral infarcts.
This autopsy study (n=163) was drawn from a longitudinal study of subcortical ischemic vascular disease, Alzheimer disease, and normal aging. Multivariable logistic regression models were used to test associations among the 3 forms of cerebrovascular disease and the presence of ischemic and neurodegenerative brain lesions. Apolipoprotein E genotype was included as a covariate in these multivariable models.
Cerebral atherosclerosis was positively associated with microinfarcts (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.2-4.4) and cystic infarcts (OR, 2.0; 95% CI, 1.0-4.2) but not Alzheimer disease pathology. Arteriolosclerosis showed a positive correlation with lacunar infarcts (OR, 2.0; 95% CI, 1.0-4.2) but not Alzheimer disease pathology. Cerebral amyloid angiopathy was inversely associated with lacunar infarcts (OR, 0.6; 95% CI, 0.41-1.1), but positively associated with Braak and Braak stage (OR, 1.5; 95% CI, 1.1-2.1) and Consortium to Establish a Registry for Alzheimer Disease plaque score (OR, 1.5; 95% CI, 1.1-2.2).
Microinfarcts, which have been correlated with severity of cognitive impairment, were most strongly associated with atherosclerosis. Possible pathogenetic mechanisms include artery-to-artery emboli, especially microemboli that may include atheroemboli or platelet-fibrin emboli. Arteriolosclerosis was positively, whereas cerebral amyloid angiopathy was negatively correlated with lacunar infarcts, which might prove helpful in clinical differentiation of arteriolosclerotic from cerebral amyloid angiopathy-related vascular brain injury.
[Show abstract][Hide abstract] ABSTRACT: Hippocampal sclerosis (HS) is a common and often asymmetric neuropathological finding among elderly persons who experience progressive memory loss, but its cause is unknown and it is rarely diagnosed during life. In order to improve both understanding and diagnosis of late-life HS, bilateral hippocampi and cerebral hemispheres were reviewed in 130 consecutive autopsy cases drawn from a longitudinal study of subjects with subcortical ischemic vascular dementia (IVD), Alzheimer disease (AD) and normal aging. HS was found in 31 of 130 cases (24.5%). Of these, 45% were bilateral, 32% left-sided, and 23% right-sided. The majority of HS cases involved the entire rostral-caudal extent of the hippocampus. However, in 7 cases HS was focal in nature and was only found at or anterior to the lateral geniculate nucleus. In 77% of cases, HS was accompanied by other types of pathology (‘mixed’ HS), but in 23% of cases it was the sole neuropathologic finding (‘pure’ HS). TDP-43-positive cytoplasmic inclusions were found in dentate granule cells in 93% of all HS cases, 55% of AD cases with no HS, but 0% of IVD cases with no HS. MRI hippocampal volumes were significantly lower in bilateral HS compared to AD (p < 0.001) and in unilateral HS cases compared to cases with intact hippocampi (p < 0.001).
Since HS may occur unilaterally in approximately a quarter of cases, its prevalence may be underestimated if only one cerebral hemisphere is examined. The presence of TDP-43 inclusions in HS cases, regardless of accompanying pathologies (e.g., AD, IVD, FTLD), is consistent with an underlying neurodegenerative pathogenetic mechanism. Further studies are warranted to determine whether greater severity of hippocampal atrophy on MRI may assist the clinical differentiation of HS from AD.
Brain and Behavior 07/2012; 2(4):435-42. DOI:10.1002/brb3.66 · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To investigate loss of neurons in the nucleus basalis (NB) of Meynert in patients with subcortical ischemic vascular disease (SIVD) compared with healthy controls, patients with Alzheimer disease (AD), and patients with mixed AD and SIVD. DESIGN: Autopsied cases drawn from a longitudinal observational study of patients with SIVD, patients with AD, and healthy controls. SETTING: Multi center, university-affiliated, program project neuropathology core. Patients Patients with pathologically defined SIVD (n = 16), AD (n = 20), and mixed AD and SIVD (n = 10) and healthy controls matched by age and educational level (n = 17) were studied. MAIN OUTCOME MEASURES: The NB neuronal cell counts in each group and their correlation with the extent of magnetic resonance imaging white matter lesions and Clinical Dementia Rating (CDR) scores closest to death. RESULTS: No significant loss of neurons was found in SIVD patients compared with age-matched controls in contrast to the AD and mixed groups, who had significant neuronal loss. A significant inverse correlation between NB neurons and CDR scores was found in the AD group but not in the SIVD and mixed groups. The NB cell counts were not correlated with either the extent of white matter lesions or cortical gray matter volume in the SIVD or AD groups. CONCLUSIONS: These findings inveigh against primary loss of cholinergic neurons in SIVD patients but do not rule out the possibility of secondary cholinergic deficits due to disruptions of cholinergic projections to cerebral cortex.
Archives of neurology 03/2012; 69(7). DOI:10.1001/archneurol.2011.2874 · 7.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
[Show abstract][Hide abstract] ABSTRACT: Studies suggest that frontotemporal lobar degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity and the validity of the subtypes, we studied neuropathological variation within the frontal and temporal lobes of 94 cases of FTLD-TDP using quantitative estimates of density and principal components analysis (PCA). A PCA based on the density of TDP-43 immunoreactive neuronal cytoplasmic inclusions, oligodendroglial inclusions, neuronal intranuclear inclusions, and dystrophic neurites, surviving neurons, enlarged neurons, and vacuolation suggested that cases were not segregated into distinct subtypes. Variation in the density of the vacuoles was the greatest source of variation between cases. A PCA based on TDP-43 pathology alone suggested that cases of FTLD-TDP with progranulin (GRN) mutation segregated to some degree. The pathological phenotype of all four subtypes overlapped but subtypes 1 and 4 were the most distinctive. Cases with coexisting motor neuron disease (MND) or hippocampal sclerosis (HS) also appeared to segregate to some extent. We suggest: (1) pathological variation in FTLD-TDP is best described as a 'continuum' without clearly distinct subtypes, (2) vacuolation was the single greatest source of variation and reflects the 'stage' of the disease, and (3) within the FTLD-TDP 'continuum' cases with GRN mutation and with coexisting MND or HS may have a more distinctive pathology.
[Show abstract][Hide abstract] ABSTRACT: Neurofibrillary tangles and beta-amyloid plaques have been observed in the amygdala in Alzheimer disease. A disproportionate abundance of this abnormality in the amygdala may cause behavioral symptoms similar to Klüver-Bucy syndrome.
To describe an atypical behavioral presentation of Alzheimer disease and to review the literature on the subject.
Outpatient specialty clinic.
A 70-year-old man with progressive behavioral symptoms of hyperorality, hypersexuality, hypermetamorphosis, visual agnosia, hyperphagia, and apathy who died at age 77 of asphyxiation on a foreign object.
Clinical symptomatology, brain imaging, and neuropathology.
The pathologic diagnosis was Alzheimer disease with abundant tangles and plaques in the lateral amygdala.
This case represents a variant of Alzheimer disease with prominent amygdala abnormalities and a Klüver-Bucy phenotype that was misdiagnosed as frontotemporal dementia. Clinical and imaging findings that may aid in accurate diagnosis are reviewed.
Archives of neurology 02/2009; 66(1):125-9. DOI:10.1001/archneurol.2008.517 · 7.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Magnetic resonance (MR) imaging is used widely for assessment of patients with cognitive impairment, but the pathological correlates are unclear, especially when multiple pathologies are present.
This report includes 93 subjects from a longitudinally followed cohort recruited for the study of Alzheimer's disease (AD) and subcortical cerebrovascular disease (CVD). MR images were analyzed to quantify cortical gray matter volume, hippocampal volume, white matter hyperintensities, and lacunes. Neuropathological examination quantified CVD parenchymal pathology, AD pathology (defined as Consortium to Establish a Registry for Alzheimer's Disease scores and Braak and Braak stage), and hippocampal sclerosis. Subjects were pathologically classified as 12 healthy control subjects, 46 AD, 14 CVD, 9 mixed AD/CVD, and 12 cognitively impaired patients without significant AD/CVD pathology. Multivariate models tested associations between magnetic resonance and pathological findings across the entire sample.
Pathological correlates of cortical gray matter volume were AD, subcortical vascular pathology, and arteriosclerosis. Hippocampal volume was related to AD pathology and hippocampal sclerosis, and the effects of hippocampal sclerosis were greater for subjects with low levels of AD pathology. White matter hyperintensities were related to age and to white matter pathology. Number of MRI lacunes was related to subcortical vascular pathology.
In this clinical setting, the presence of lacunes and white matter changes provide a good signal for vascular disease. The neuropathological basis of MR defined cerebral cortical and hippocampal atrophy in aging and dementia is complex, with several pathological processes converging on similar brain structures that mediate cognitive decline.
Annals of Neurology 01/2008; 63(1):72-80. DOI:10.1002/ana.21296 · 9.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Few studies have compared the accuracy of [(18)F]fluorodeoxyglucose (FDG) PET to the accuracy of clinical and pathologic diagnosis in dementia patients.
Forty-four individuals with dementia, cognitive impairment, or normal cognitive function underwent clinical initial evaluation (IE) and PET scanning and were followed up for approximately 4 years until a final evaluation (FE) and 5 years until death and autopsy. Clinical, pathologic, and imaging diagnoses were categorized as Alzheimer disease (AD) or not AD.
Sensitivity of the IE for the pathologic diagnosis of AD was 0.76, and specificity was 0.58; PET had values of 0.84 and 0.74, and FE had values of 0.88 and 0.63. Positive predictive values for IE, PET, and FE were 0.70, 0.81, and 0.76. Negative predictive values were 0.65, 0.78, and 0.80. The diagnosis of AD was associated with a 70% probability of detecting AD pathology; with a positive PET scan this increased to 84%, and with a negative PET scan this decreased to 31%. A diagnosis of not AD at IE was associated with a 35% probability of AD pathology, increasing to 70% with a positive PET scan.
As a diagnostic tool, PET is superior to a baseline clinical evaluation and similar to an evaluation performed 4 years later. Although the addition of [(18)F]fluorodeoxyglucose PET to a clinical diagnosis provides useful information that can affect the likelihood of detecting Alzheimer disease pathology, the value of this technique in the current clinical environment with limited therapeutic options is likely to be modest.
[Show abstract][Hide abstract] ABSTRACT: Differentiating the cognitive effects of cerebrovascular disease, particularly small vessel disease, from those of Alzheimer's disease is a difficult clinical challenge. An influential model of how subcortical cerebrovascular disease causes cognitive dysfunction posits that damage to frontostriatal loops impairs frontal lobe function, leading to predominant impairment of executive function and secondary impairments of associated cognitive functions such as memory. Consistent with this, neuropsychological studies of clinically diagnosed patients have reported that individuals with vascular dementia do better on memory tests and worse on executive function tests compared with patients with Alzheimer's disease. This observation has led to the suggestion that predominant cognitive executive dysfunction might serve as a useful diagnostic marker for vascular dementia. We sought to test this idea in a series of cases with autopsy-defined pathologies. Subjects were 62 autopsied cases from a prospective study of vascular contributions to dementia. Using neuropathological features alone, 23 were diagnosed with Alzheimer's disease (AD), 11 with cerebrovascular disease (CVD), 9 with both (mixed pathology) and 19 with normal elderly brain (NEB). Three psychometrically matched composite scales of different cognitive abilities were used: Verbal Memory, Nonverbal Memory and Executive Function. Analysis of group data showed that for Alzheimer's disease memory scores were lower than Executive Function by nearly a standard deviation on average. In contrast, and contrary to the model, CVD was rather equally impaired on Executive Function, Verbal Memory and Nonverbal Memory. Individual patterns of cognitive impairment were examined by defining three profiles based on reliable differences between neuropsychological scores to characterize cases with predominant memory impairment, predominant executive dysfunction, and 'other' patterns. Analysis of individual impairment profiles showed that predominant memory impairment was present in 71% of Alzheimer's disease while predominant executive dysfunction described only 45% of CVD. A stronger pattern emerged when cognitively normal cases were excluded; among the six cognitively impaired CVD patients four had predominant executive dysfunction and none had predominant memory impairment. This report, comprised of a substantial sample of autopsy confirmed cases, delineates the patterns of neuropsychological impairment associated with small vessel cerebrovascular disease and Alzheimer's disease While the findings show that memory loss usually exceeds executive dysfunction in patients with Alzheimer's disease, the reverse is not the case in CVD. Taken as a whole, the results indicate that the cognitive effects of the small vessel cerebrovascular disease are variable and not especially distinct, thus raising question about the utility of executive impairment as a diagnostic marker for vascular dementia.
[Show abstract][Hide abstract] ABSTRACT: 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.
We report clinicopathological correlations from 79 autopsy cases derived from a prospective longitudinal study of subcortical ischemic vascular disease and AD.
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.
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.
Annals of Neurology 12/2006; 60(6):677-87. DOI:10.1002/ana.21009 · 9.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Studies reporting that ischemic vascular dementia (IVD), compared to Alzheimer's disease (AD), is associated with relatively greater impairment of executive function and relatively preserved episodic memory raise the question of whether there is a distinctive neuropsychological profile of impairment associated with IVD and whether this might be useful in clinical diagnosis. However, prior reports are almost all based on clinically diagnosed cases, raising obvious issues of possible circularity and leaving unanswered questions of validity. Here we report on clinical and neuropsychological findings in 18 prospectively studied cases that had substantial pathology-defined cerebrovascular disease (CVD) at autopsy. Nine cases had minimal AD pathology, while the remainder had moderate or severe degrees of AD pathology. Cognitive status at last evaluation ranged from mild cognitive impairment to moderate dementia. Clinical features were quite variable; only 40% of cases with high CVD levels had elevated Hachinski Ischemia Scale scores and neither abrupt onset nor stepwise progression was found in most high CVD cases, even when AD changes were essentially absent. The presence of dementia was predictably related to the level of neurofibrillary pathology, but was not related to the severity of CVD. Neuropsychologists expert in the evaluation of dementia used a priori criteria to diagnose neuropsychological protocols (blind to all other data) from cases with pathology-informed diagnoses of AD, IVD, and mixed dementia. Sensitivity and specificity were both high for AD, sensitivity for detecting pure IVD was poor, and values were intermediate for detecting IVD irrespective of AD levels. A illustrative case example is included. We conclude that the profile of cognitive impairment in IVD is highly variable, but that in clinical settings neuropsychological readings may contribute to the differential diagnosis of dementia.
The Clinical Neuropsychologist 03/2004; 18(1):63-74. DOI:10.1080/13854040490507163 · 1.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our previous studies found that experimental infection of BALB/c mice with the Gram-positive bacterium Nocardia asteroides induced a parkinsonian-type syndrome with levodopa-responsive movement abnormalities, loss of nigrostriatal dopaminergic neurons, depletion of striatal dopamine, and intraneuronal inclusions in the substantia nigra (SN) with an appearance similar to Lewy bodies. In the present study, an in situ hybridization technique was developed to detect nocardial 16S ribosomal RNA (rRNA), using a Nocardia-specific probe (B77). Cerebral cortical specimens from cynomolgus monkeys were examined for the presence of nocardial RNA 48 h, 3.5 months, and 1 year after experimental infection with N. asteroides. Hybridization reactions were detected within Nocardia-like structures 48 h after infection and within intracellular inclusion bodies (immunoreactive for alpha-synuclein and ubiquitin) in one of two 3.5-month-infected monkeys. The in situ hybridization procedure was then applied in a blinded fashion to 24 human SN specimens with Lewy bodies and 11 human SN specimens without Lewy bodies (including five normal controls). Hybridization reactions were detected in nine Lewy body-containing specimens and none of the others. Reactivity was limited to inclusions with the appearance of Lewy bodies, with the exception of one specimen in which intracellular reactivity was also observed in Nocardia-like structures. These results suggest a possible association between Nocardia and neurodegenerative disorders in which Lewy bodies are present.
[Show abstract][Hide abstract] ABSTRACT: To assess the ability of the current diagnostic criteria for frontotemporal lobar degeneration (FTLD) to differentiate FTLD from AD.
Thirty cases with autopsy-proven FTLD and 30 cases of AD, matched for Mini-Mental State Examination score, were identified from the clinical databases of three dementia subspecialty centers, and their charts were reviewed for the presence of clinical features described in the current criteria for FTLD. The proportion of patients with each clinical feature at the first clinical presentation was compared across groups.
A significantly larger proportion of patients with FTLD showed behavioral abnormalities, particularly social and personal conduct disorders and emotional blunting, than patients with AD. Few differences in language features were seen between the groups, and many of the language features detailed in the criteria were found in only a small proportion of patients. In both groups, many patients showed neuropsychological abnormalities, except for perceptual difficulties, which were present in many patients with AD but only in a few patients with FTLD. Extrapyramidal motor symptoms were more likely to be present in FTLD. Logistic regression revealed that five features-social conduct disorders, hyperorality, akinesia, absence of amnesia, and the absence of a perceptual disorder-correctly classified 93% of patients with FTLD and 97% of patients with AD.
A combination of behavioral, neuropsychological, and physical findings is most useful in distinguishing FTLD from AD. Future studies should be directed at establishing more objective methods of identifying these clinical features.
[Show abstract][Hide abstract] ABSTRACT: Relatively little is known about how cerebrovascular disease affects progression of dementia. Previous studies have found no differences in progression of Alzheimer disease and vascular dementia, but these studies have not specifically examined age effects.
To test whether the rate of cognitive decline is different in Alzheimer disease compared with dementia with associated cerebrovascular disease in clinical and autopsy patient series.
We studied the longitudinal course of cognitive function as measured by the Mini-Mental State Examination (MMSE) in patients with clinically and neuropathologically diagnosed conditions evaluated through a university Alzheimer disease center. Clinical patients were grouped according to possible Alzheimer disease without stroke (n = 37), probable Alzheimer disease without stroke (n = 181), and dementia with stroke (n = 50). Autopsy cases were categorized into Alzheimer disease (n = 78) and dementia with vascular disease (n = 13). Data were analyzed using random-effects modeling of longitudinal change.
There was a significant interaction between age and diagnosis in determining rate of change on the MMSE scores for both the clinical and autopsy samples. Rate of change decreased slightly with advancing age for Alzheimer disease groups, but increased with age for dementia with cerebrovascular disease groups.
Dementia with cerebrovascular disease declined faster in patients 80 years and older compared with Alzheimer disease without associated cerebrovascular pathological conditions, but showed slower decline in patients younger than 80 years. This effect most likely reflects combined Alzheimer and vascular pathological conditions in older patients with cerebrovascular disease.
[Show abstract][Hide abstract] ABSTRACT: Ischemic vascular dementia (IVD) is a relatively uncommon entity, in the course of which multiple ischemic brain lesions result in progressive cognitive and memory impairment. Ischemic brain lesions may also aggravate the neuropsychologic deficit of Alzheimer disease (AD). In this review we summarize our experience based upon autopsy examination of the central nervous system in 20 patients (age range 68-92 years) enrolled in a longitudinal investigation of structural, neurochemical, functional neuroimaging, and neuropsychologic components of IVD, especially dementia associated with cerebral microvascular disease. While cystic infarcts were present in the CNS of 5 patients, the most commonly observed neuropathologic abnormalities were lacunar infarcts and microinfarcts--both types of lesion were encountered in over half of patients' brains. Evidence of (remote) hippocampal injury was found in 11/20 patients. Severe atherosclerosis and arterio/ arteriolosclerosis were both associated with the occurrence of multiple lacunar infarcts. Pronounced cerebral amyloid angiopathy (CAA) was noted in a single patient, who also showed other microscopic changes of severe AD. While fairly unusual as a nosologic entity, IVD appears to correlate with widespread small ischemic lesions distributed throughout the CNS. We furthermore propose an approach to quantifying the burden of ischemic vascular and parenchymal disease that may be associated with a dementia syndrome. A brief review of neuropathologic features of vascular dementia (both familial and sporadic) is presented.
Journal of Neuropathology and Experimental Neurology 12/2000; 59(11):931-45. · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical-MRI-pathological correlations are presented for the first 17 autopsy cases in a prospective longitudinal study of subcortical ischemic vascular dementia (IVD) and Alzheimer disease (AD). A new method to characterize the severity and distribution of ischemic parenchymal brain injury is described; correlations with the Hachinski Ischemic Score and volume of lacunes on MRI are promising, but require further validation. Hippocampal atrophy was found in pure IVD cases, as well as AD, and may be associated with hippocampal sclerosis.
1st International Congress on Vascular Dementia, Edited by Amos D. Korczyn, 10/1999: chapter Diagnosis of Ischemic Vascular Dementia (IVD): Clinical-Pathological Correlations: pages 27-32; Monduzzi Editore S.p.A.., ISBN: 978-8832310030