Aß (Amyloid Beta) and Tau Tangle Pathology Modifies the Association Between Small Vessel Disease and Cortical Microinfarcts.

BACKGROUND AND PURPOSE: There is increasing recognition of the importance of cortical microinfarcts to overall brain health, cognition, and Alzheimer dementia. Cerebral small vessel pathologies are associated with microinfarcts and frequently coexist with Alzheimer disease; however, the extent to which Aß (amyloid beta) and tau pathology modulates microvascular pathogenesis is not fully understood. Study objective was to examine the relationship of small vessel pathologies, arteriolosclerosis, and cerebral amyloid angiopathy, with cortical microinfarcts in people with differing levels of Aß or tau tangle burden. METHODS: Participants were 1489 autopsied older people (mean age at death, 89 years; 67% women) from 1 of 3 ongoing clinical-pathological cohort studies of aging. Neuropathological evaluation identified cortical Aß and tau tangle burden using immunohistochemistry in 8 brain regions, provided semiquantitative grading of cerebral vessel pathologies, and identified the presence of cortical microinfarcts. Logistic regression models adjusted for demographics and atherosclerosis and examined whether Aß or tau tangle burden modified relations between small vessel pathologies and cortical microinfarcts. RESULTS: Cortical microinfarcts were present in 17% of older people, moderate-to-severe cerebral amyloid angiopathy pathology in 36%, and arteriolosclerosis in 34%. In logistic regression models, we found interactions with Aß and tau tangles, reflecting that the association between arteriolosclerosis and cortical microinfarcts was stronger in the context of greater Aß (estimate, 0.15; SE=0.07; P=0.02) and tau tangle burden (estimate, 0.13; SE=0.06; P=0.02). Interactions also emerged for cerebral amyloid angiopathy, suggesting that the association between cerebral amyloid angiopathy and cortical microinfarcts is more robust in the presence of higher Aß (estimate, 0.27; SE=0.07; P<0.001) and tangle burden (estimate, 0.16; SE=0.06; P=0.005). CONCLUSIONS: These findings suggest that in the presence of elevated Aß or tangle pathology, small vessel pathologies are associated with greater microvascular tissue injury, highlighting a potential link between neurodegenerative and vascular mechanisms.

Review: Relationship of type 2 diabetes to human brain pathology.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are both highly prevalent diseases worldwide, and each is associated with high-morbidity and high-mortality. Numerous clinical studies have consistently shown that T2D confers a two-fold increased risk for a dementia, including dementia attributable to AD. Yet, the mechanisms underlying this relationship, especially nonvascular mechanisms, remain debated. Cerebral vascular disease (CVD) is likely to be playing a role. But increased AD neuropathologic changes (ADNC), specifically neuritic amyloid plaques (AP) and neurofibrillary tangles (NFT), are also posited mechanisms. The clinicopathological studies to date demonstrate T2D to be consistently associated with infarcts, particularly subcortical lacunar infarcts, but not ADNC, suggesting the association of T2D with dementia may largely be mediated through CVD. Furthermore, growing interest exists in insulin resistance (IR), particularly IR within the brain itself, which may be an associated but distinct phenomenon from T2D, and possibly itself associated with ADNC. Other mechanisms largely related to protein processing and efflux in the central nervous system with altered function in T2D may also be involved. Such mechanisms include islet amyloid polypeptide (or amylin) deposition, co-localized with beta-amyloid and found in more abundance in the AD temporal cortex, blood-brain barrier breakdown and dysfunction, potentially related to pericyte degeneration, and disturbance of brain lymphatics, both in the glial lymphatic system and the newly discovered discrete central nervous system lymph vessels. Medical research is ongoing to further disentangle the relationship of T2D to dementia in the ageing human brain.

Apolipoprotein E and change in episodic memory in blacks and whites.

BACKGROUND: Apolipoprotein E (APOE) ε4 is related to faster decline in episodic memory in Whites, but the relation is unknown in Blacks. The purpose of this study was to determine whether ε4 has a selective effect on decline in episodic memory in Blacks. METHODS: Data are from two cohort studies with similar design. The sample consisted of 1,211 participants [28.4% Blacks, mean age = 78.6 years (SD = 7.4), education = 14.7 years (SD = 3.1)] without dementia at baseline, who underwent annual clinical evaluations for up to 6 years. Summary measures of 5 cognitive abilities were derived from 18 neuropsychological tests. RESULTS: In mixed models that controlled for age, sex, education, and race, possession of ε4 (present in 32.9% of Blacks and 21.0% of Whites, p < 0.001) was related to faster decline in episodic memory and 4 other cognitive abilities (all p values <0.01). In separate models that examined the interaction of race and ε4 on decline, there was no significant difference between Blacks and Whites in the effect of ε4 on decline in episodic memory, perceptual speed, or visuospatial ability. By contrast, the effect of ε4 differed for semantic memory and working memory. Results were similar after adjusting for vascular conditions. CONCLUSIONS: The results suggest that APOE ε4 is related to a faster rate of decline in episodic memory in Blacks similar to Whites. In addition, there were racial differences in the effect of ε4 in other cognitive abilities such that the ε4 allele was related to faster decline in semantic memory and working memory for Whites but not for Blacks.

Pathology and temporal onset of visual hallucinations, misperceptions and family misidentification distinguishes dementia with Lewy bodies from Alzheimer's disease.

OBJECTIVE: To determine whether the temporal onset of visual phenomena distinguishes Lewy body disease (LBD) from Alzheimer's disease (AD), and to characterize the extent Lewy bodies and neurofibrillary tangles are associated with these clinical features. METHODS: Consecutive cases of autopsy-confirmed LBD (n = 41), AD (n = 70), and AD with amygdala-predominant Lewy bodies (AD-ALB) (n = 14) with a documented clinical history of dementia were included. We mailed questionnaires to next-of-kin asking about symptoms during life. Lewy pathology and neurofibrillary tangle pathology were assessed. RESULTS: The occurrence of visual hallucinations, misperceptions and family misidentification did not distinguish LBD from AD or AD-ALB, but the onset was earlier in LBD compared to AD and AD-ALB. When visual hallucinations developed within the first 5 years of dementia, the odds were 4-5 times greater for autopsy-confirmed LBD (or intermediate/high likelihood dementia with Lewy bodies) and not AD or AD-ALB. In LBD, limbic but not cortical Lewy body pathology was related to an earlier onset of visual hallucinations, while limbic and cortical Lewy body pathology were associated with visual misperceptions and misidentification. Cortical neurofibrillary tangle burden was associated with an earlier onset of misidentification and misperceptions in LBD and AD, but only with earlier visual hallucinations in AD/AD-ALB. CONCLUSION: When visual hallucinations occur within the first 5 years of the dementia, a diagnosis of LBD was more likely than AD. Visual hallucinations in LBD were associated with limbic Lewy body pathology. Visual misperceptions and misidentification delusions were related to cortical Lewy body and neurofibrillary tangle burden in LBD and AD/AD-ALB.

Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies.

Lewy bodies are common in the ageing brain and often co-occur with Alzheimer's disease pathology. There is little known regarding the independent role of Lewy body pathology in cognition impairment, decline and fluctuations in community-dwelling older persons. We examined the contribution of Lewy body pathology to dementia, global cognition, cognitive domains, cognitive decline and fluctuations in 872 autopsied subjects (mean age = 87.9 years) from the Rush Religious Order Study (n = 491) and Memory and Aging Project (n = 381) longitudinal community-based clinical-pathological studies. Dementia was based on a clinical evaluation; annual cognitive performance tests were used to create a measure of global cognition and five cognitive domains. Lewy body type was determined by using α-synuclein immunostained sections of substantia nigra, limbic and neocortical regions. Statistical models included multiple regression models for dementia and cognition and mixed effects models for decline. Cognitive fluctuations were estimated by comparing standard deviations of individual residuals from mean trajectories of decline in those with and without Lewy bodies. All models controlled for age, sex, education, Alzheimer's disease pathology and infarcts. One hundred and fifty-seven subjects (18%) exhibited Lewy body pathology (76 neocortical-type, 54 limbic-type and 27 nigra-predominant). One hundred and three (66%) subjects with Lewy body pathology had a pathologic diagnosis of Alzheimer's disease. Neocortical-type, but not nigral-predominant or limbic-type Lewy body pathology was related to an increased odds of dementia (odds ratio = 3.21; 95% confidence interval = 1.78-5.81) and lower cognition (P < 0.001) including episodic memory function (P < 0.001) proximate to death. Neocortical-type Lewy body pathology was also related to a faster decline in global cognition (P < 0.001), decline in all five specific cognitive domains (all P-values < 0.001), and to fluctuations in decline of working and semantic memory (P-values < 0.001). Limbic-type Lewy body pathology was related to lower and faster decline in visuospatial skills (P = 0.042). The relationship of Lewy body pathology to cognition and dementia was not modified by Alzheimer's disease pathology. Neocortical-type Lewy body pathology is associated with increased odds of dementia; lower and more rapid decline in all cognitive domains including episodic memory and fluctuations in decline in semantic and working memory. Limbic-type Lewy body pathology is specifically associated with lower and more rapid decline in visuospatial skills. The effect of Lewy body pathology on cognition appears to be independent of Alzheimer's disease pathology.

Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology.

OBJECTIVE: To examine the relation of nonsteroidal anti-inflammatory drugs (NSAIDs) to incident Alzheimer disease (AD), change in cognition, and AD pathology. METHODS: Participants were 1,019 older Catholic clergy followed up annually for up to 12 years (mean baseline age = 75.0 years, education = 18.1 years, Mini-Mental State Examination score = 28.5), enrolled in the Religious Orders Study, a longitudinal clinical-pathologic study of aging and AD. Clinical evaluations allowed for AD classification and assessment of global cognition and five cognitive domains. NSAIDs were identified by direct medication inspection at baseline and follow-up evaluations. Neuropathologic data were available on 328 deceased participants. AD pathology was summarized as a global measure and as measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles. We used Cox proportional hazards models and mixed models for incident AD and cognitive decline, respectively, and logistic and linear regression for pathologic outcomes, adjusted for age, sex, and education. RESULTS: Overall, we found no apparent relation of NSAIDs to incident AD (n = 209 cases), change in cognition, or AD pathology. The hazard ratio of incident AD was 1.19 (95% CI 0.87-1.62) comparing those using NSAIDs with those not using NSAIDs at baseline, and 0.84 (95% CI 0.63-1.11) for specific use of aspirin. Findings were similar in analyses in which we considered NSAID use during follow-up. NSAIDs were not related to change in cognition (all p values > 0.14). There was no relation of NSAIDs to global AD pathology or plaques or tangles. CONCLUSION: These data do not support a strong relation between nonsteroidal anti-inflammatory drugs and Alzheimer disease or cognition. Consistent findings across clinical and pathologic outcomes provide additional confidence in these results.

Statins, incident Alzheimer disease, change in cognitive function, and neuropathology.

OBJECTIVE: To examine the relation of statins to incident Alzheimer disease (AD) and change in cognition and neuropathology. METHODS: Participants were 929 older Catholic clergy (68.7% women, mean baseline age 74.9 years, education 18.2 years, Mini-Mental State Examination 28.5) free of dementia, enrolled in the Religious Orders Study, a longitudinal clinical-pathologic study of AD. All agreed to brain autopsy at time of death and underwent annual structured clinical evaluations, allowing for classification of AD and assessment of cognition (based on 19 neuropsychological tests). Statins were identified by direct medication inspection. Neuropathologic data were available on 262 participants. All macroscopic chronic cerebral infarctions were recorded. A measure of global AD pathology was derived from silver stain, and separate measures of amyloid and tangles were based on immunohistochemistry. We examined the relation of statins to incident AD using Cox proportional hazards, change in cognition using mixed effects models, and pathologic indices using logistic and linear regression. RESULTS: Statin use at baseline (12.8%) was not associated with incident AD (191 persons, up to 12 follow-up years), change in global cognition, or five separate cognitive domains (all p values > 0.20). Statin use any time prior to death (17.9%) was not related to global AD pathology. Persons taking statins were less likely to have amyloid (p = 0.02). However, among those with amyloid, there was no relation of statins to amyloid load. Statins were not related to tangles or infarction. CONCLUSIONS: Overall, statins were not related to incident Alzheimer disease (AD) or change in cognition, or continuous measures of AD pathology or infarction.

Lower extremity motor function and disability in mild cognitive impairment.

Recent findings suggest that lower extremity motor dysfunction may be a feature of mild cognitive impairment (MCI), but little is known about the nature and significance of lower extremity motor dysfunction in MCI. The aim of this study was to examine the extent to which MCI is associated with impaired gait, balance, and strength and to examine the relation of lower extremity function to disability among persons with MCI in the Rush Memory and Aging Project, a clinical-pathologic study of common chronic conditions of old age. In a series of analyses adjusted for age, sex, and education, individuals with MCI exhibited more impaired gait and balance than individuals without cognitive impairment. Because vascular factors can contribute to lower extremity motor dysfunction, the authors repeated the initial analyses including terms for vascular risk factors and vascular disease, and the associations between MCI and lower extremity motor dysfunction persisted. Moreover, among those with MCI, impairments in gait and balance were associated with an increased likelihood of disability. These findings suggest that lower extremity motor dysfunction is common and contributes to disability in MCI, but lower extremity motor dysfunction in MCI does not appear to be explained by the vascular factors examined in this study.

Diabetes is related to cerebral infarction but not to AD pathology in older persons.

OBJECTIVE: To examine the potential relation of diabetes to common neuropathologic causes of dementia, cerebral infarction and Alzheimer disease (AD) neuropathology. METHODS: Subjects were 233 older Catholic clergy in the Religious Orders Study, who underwent detailed annual evaluations, including neuropsychological testing, and brain autopsy at time of death (mean age 86 years, 45% men). Diabetes was identified by annual direct medication inspection and history. Cognitive function proximate to death was summarized into five cognitive domains, based on 19 neuropsychological tests. Macroscopic cerebral infarctions were recorded from 1 cm coronal slabs. Neuritic plaques, diffuse plaques, and neurofibrillary tangles were counted in Bielschowsky silver-stained sections and summarized to yield composite measures of neuritic plaques, diffuse plaques, tangles, and overall AD pathology. We also used immunohistochemistry with antibodies to amyloid-beta and PHF-tau to obtain quantitative measures of amyloid burden and neurofibrillary tangle density. Multiple logistic and linear regression analyses were used to examine the relation of diabetes to cerebral infarctions and AD pathology, controlling for age, sex, and education. RESULTS: AD pathology was related to all five cognitive domains (p < 0.01) and infarctions were related to perceptual speed (p < 0.001). Diabetes (present in 15% subjects) was associated with an increased odds of infarction (OR = 2.47, 95% CI: 1.16, 5.24). Diabetes was not related to global AD pathology score, or to specific measures of neuritic plaques, diffuse plaques or tangles, or to amyloid burden or tangle density. CONCLUSION: We found a relation between diabetes and cerebral infarction but not between diabetes and Alzheimer disease pathology in older persons.

Diabetes mellitus, dementia, and cognitive function in older persons.

Dementia and cognitive decline are among the most common and most feared conditions of old age making the identification of modifiable risk factors for dementia an urgent public health priority. Recently, an increasing body of data suggests that type 2 diabetes mellitus, a common condition in older persons, is associated with the development of dementia and cognitive decline. A systematic review of the medical literature of the past 15 years identified 40 original-report articles in the English language pertaining to the relation of diabetes to dementia and cognitive function in older persons. Most, but not all, of these studies suggest a detrimental effect of diabetes on cognitive function. Current research efforts are aimed at understanding the underlying neurobiologic mechanisms whereby diabetes causes dementia and cognitive impairment in order to develop rational interventions to prevent this recently documented adverse consequence.

Neuropathology of older persons without cognitive impairment from two community-based studies.

OBJECTIVE: To examine the relation of National Institute on Aging-Reagan (NIA-Reagan) neuropathologic criteria of Alzheimer disease (AD) to level of cognitive function in persons without dementia or mild cognitive impairment (MCI). METHODS: More than 2,000 persons without dementia participating in the Religious Orders Study or the Memory and Aging Project agreed to annual detailed clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed five cognitive domains, including episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. A total of 134 persons without cognitive impairment died and underwent brain autopsy and postmortem assessment for AD pathology using NIA-Reagan neuropathologic criteria for AD, cerebral infarctions, and Lewy bodies. Linear regression was used to examine the relation of AD pathology to level of cognitive function proximate to death. RESULTS: Two (1.5%) persons met NIA-Reagan criteria for high likelihood AD, and 48 (35.8%) met criteria for intermediate likelihood; 29 (21.6%) had cerebral infarctions, and 18 (13.4%) had Lewy bodies. The mean Mini-Mental State Examination score proximate to death was 28.2 for those meeting high or intermediate likelihood AD by NIA-Reagan criteria and 28.4 for those not meeting criteria. In linear regression models adjusted for age, sex, and education, persons meeting criteria for intermediate or high likelihood AD scored about a quarter standard unit lower on tests of episodic memory (p = 0.01). There were no significant differences in any other cognitive domain. CONCLUSIONS: Alzheimer disease pathology can be found in the brains of older persons without dementia or mild cognitive impairment and is related to subtle changes in episodic memory.

Family history of dementia is a risk factor for Lewy body disease.

Genetic factors are important in Alzheimer disease (AD) and Parkinson disease but have not been well characterized in Lewy body dementia (LBD). The authors obtained family history in patients from an autopsy series of AD and LBD and in living healthy controls. A family history of dementia was more common in both LBD and AD compared with controls, suggesting that genetic factors are as important in LBD as they are in AD.

Parkinsonian signs in subjects with mild cognitive impairment.

BACKGROUND: Parkinsonian signs such as gait disturbance, rigidity, bradykinesia, and tremor are common among individuals with dementia and are associated with negative outcomes, but little is known about parkinsonian signs among individuals with mild cognitive impairment (MCI). OBJECTIVE: To examine the extent to which MCI is associated with parkinsonian signs and the relation between cognitive abilities and parkinsonism among individuals with MCI. METHODS: Participants included 835 individuals from the Rush Memory and Aging Project, a clinical-pathologic study of common chronic conditions of old age. All participants underwent detailed clinical evaluations which included assessments of parkinsonian signs and cognitive function, and linear regression models were used to examine the associations of MCI and parkinsonism. RESULTS: In a series of analyses controlled for age, sex, and education, individuals with MCI exhibited significantly more parkinsonism than individuals without cognitive impairment, particularly gait disturbance, bradykinesia, and rigidity. Among individuals with MCI, lower levels of cognitive function, particularly in perceptual speed, were associated with higher levels of parkinsonism; when classified according to MCI subtype, individuals with amnestic vs non-amnestic MCI differed from each other on only one parkinsonian sign, with non-amnestic MCI showing more gait disturbance. Because vascular factors can contribute to cognitive impairment and parkinsonian signs, the authors repeated the core analyses including terms for vascular risk factors and vascular disease and the associations between MCI and parkinsonism persisted. CONCLUSIONS: Mild cognitive impairment (MCI) is accompanied by parkinsonian signs, which are related to the severity and type of cognitive impairment. The association between MCI and parkinsonism is not explained by vascular risk factors or vascular disease.

Diabetes mellitus and progression of rigidity and gait disturbance in older persons.

BACKGROUND: Parkinsonian-like signs, including rigidity, gait disturbance, and bradykinesia, are common and progressive in old age and are associated with morbidity and mortality. Few risk factors for these signs have been identified. Diabetes mellitus, also a common chronic condition in old age and known to be associated with physical and neurologic disability, may be associated with parkinsonian-like signs. OBJECTIVE: To examine the relation of diabetes to four parkinsonian-like signs. METHODS: Participants were 822 older Catholic clergymen and women who were without clinically diagnosed Parkinson disease or dementia at baseline. For up to 9 years, they had uniform annual evaluations, which included a modified version of the motor portion of the Unified Parkinson's Disease Rating Scale, from which previously established measures of four specific parkinsonian-like signs were derived. Participants were evaluated for the presence of diabetes, based on direct medication inspection and history. RESULTS: Diabetes was present in 128 (15.6%) participants. In random effects models controlling for age, sex, and education, diabetes was associated with worsening rigidity (p < 0.01) and gait (p < 0.05), over an average of 5.6 years of follow-up, but not with change in bradykinesia or tremor. The presence of stroke did not substantially affect the association of diabetes with rigidity but reduced the association of diabetes with gait to a trend (p = 0.08). CONCLUSION: Diabetes may be a previously unrecognized risk factor for progression of parkinsonian-like signs in older persons.

Early and pre-symptomatic neuropsychological dysfunction in the PPND family with the N279K tau mutation.

The N279K mutation on the tau gene of chromosome 17 leads to an inherited condition that involves pallido-ponto-nigral degeneration (PPND). Patients with PPND develop dementia, but the pattern and onset of cognitive dysfunction has not yet been delineated. Four affected patients underwent neurocognitive evaluation within the first 2 years of PPND motor onset; one of whom underwent five serial neurocognitive evaluations, and another who was not diagnosed with PPND until the third annual evaluation. Impaired letter fluency was found in the early stages of PPND and was also shown to precede the onset of motor symptoms by 2 years. Trail Making A (visual scanning and motor speed) and Trail Making B (divided attention) were impaired within the first 2 years of the disease in all but one patient, but this individual showed clinically significant decline on these tasks by the third year of the disease. Learning, memory, and timed visuospatial sequencing skills were variably affected. Results reveal disproportionate frontal-executive dysfunction early in PPND disease course, a pattern similar to what has been reported in other FTDP-17 kindreds and in sporadic PSP. In addition, results suggest that letter fluency may be a sensitive predictor of incipient PPND.

Recent advances in the understanding of tau protein and movement disorders.

Tau plays an important role in movement disorders. The accumulation of pathological tau is a major substrate of frontotemporal dementia and parkinsonism linked to chromosome 17, progressive supranuclear palsy, and corticobasal degeneration. Over the past year, several new mutations on the tau gene have been found. These mutations have been classified into three groups: (i) mutations in constitutively spliced exons; (ii) mutations in the alternatively spliced exon 10; and (iii) mutations of the exon 10 5' splice site. Some patients presenting with frontotemporal dementia and parkinsonism linked to chromosome 17 transiently respond to levodopa therapy. The significance of Pick bodies was recognized by a recent study on kindred with the Glu342Val tau mutation. In sporadic cases of progressive supranuclear palsy, the presence of the H1 haplotype was found to be a risk factor. Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. This opens the question of whether corticobasal degeneration represents a separate disorder or a spectrum of disease with progressive supranuclear palsy. However, distinguishing features are observed, and include oculomotor abnormalities, which may help to differentiate these two disorders on clinical grounds. Despite recent advances in the understanding of the tauopathies, there are still no curative therapies available. It is hoped that studies in transgenic tau animal models will lead to the development of successful treatments.

Focal degenerative dementia syndromes.

Focal degenerative dementia syndromes are associated with a characteristic clinical picture, such as frontotemporal dementia, primary progressive aphasia, semantic dementia, corticobasal degeneration, and the Balint syndrome. A lobar approach may be used to classify the degenerative dementias. The underlying pathology of these various syndromes seems to be less heterogeneous than previously thought.

Similar subcortical pattern of cognitive impairment in AIDS patients with and without dementia.

The aim of this study was to develop a series of neuropsychological tests that define the cortical and subcortical features of cognitive impairment and the characteristics of memory in demented and mildly cognitively impaired AIDS patients. We attempted to establish a usable method to assess and determine the type and degree of cognitive impairment in individual AIDS patients. We examined 53 patients without central nervous system opportunistic infections. A short battery included two scales of global efficiency (the Mattis dementia rating scale and the Mini Mental State Examination), a psychomotor speed test, an executive control assessment and explicit memory evaluation. Patients were categorized into four groups based on their score on both the Mattis dementia rating scale and the DSM-IV criteria: (1) asymptomatic; (2) having AIDS without cognitive impairment; (3) having AIDS with mild cognitive impairment; and (4) having AIDS dementia. Patients with mildly impaired cognition demonstrated slowed thinking, abnormal initiation and conceptualization, and memory impairment. AIDS dementia patients had slower motor activity and memory recall was more severely affected. The short neuropsychological battery was able to characterize modified cognitive performances in both severely and mildly cognitively impaired AIDS patients. The subcortical pattern of the memory disorder was obvious, regardless of the degree of cognitive impairment.

[Fronto-temporal dementia: a clinical approach]. / Les démences fronto-temporales: approche clinique.

Although the existence of atrophy of the anterior part of the brain has been known for a long time (Pick, 1892), the interest for fronto-temporal dementias (DFT) is relatively recent. Several excellent reviews have been recently published on the topic (Gustafson, 1993; Neary and Snowden, 1996; Pasquier et al., 1998) and, for that reason, we only recall the main aspects of the disease to insist on some lesser known features, illustrated by original observations.

M. tuberculosis molecular variation in CNS infection: evidence for strain-dependent neurovirulence.

OBJECTIVE: To determine the molecular diversity among Mycobacterium tuberculosis isolates associated with central nervous system tuberculosis (CNS TB) in a defined cohort of HIV uninfected patients. DESIGN/METHODS: A retrospective analysis was performed of clinical and laboratory data for all patients with CNS TB diagnosed in Manitoba, Canada, between 1979 and 1996. Restriction fragment-length polymorphisms (RFLP) of archival isolates of M. tuberculosis from CNS TB patients were determined and interpreted against the frequency of different isolates from all TB patients in the years 1992 to 1996. RESULTS: Among 2,334 patients with active TB, CNS TB was diagnosed in 42 (1.8%); meningitis with or without tuberculoma in 76%; and tuberculoma alone in 24%. CNS TB patients were significantly more likely to be young (<40 years old), female, and of Aboriginal origin. Morbidity (fixed/recurrent CNS deficit) rate was 29% and mortality rate was 26%. An adverse outcome, either morbidity or mortality, was significantly more common in those with meningitis. RFLP analysis of isolates (n=19) from CNS TB patients revealed 13 distinct restriction patterns with a predominance of the type 1 pattern (n=6). The frequency of type 1 restriction pattern was significantly greater in patients with CNS TB compared to all TB patients in Manitoba. CONCLUSIONS: CNS TB continues to have a high morbidity and mortality despite modern methods of detection and treatment. Although several strains of M. tuberculosis cause CNS TB, the current study suggests that the occurrence of CNS TB may be strain-dependent.