Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel disease with an identified gene, along with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The exact prevalence of CARASIL is currently unknown, and to date approximately 50 patients have been reported, most of them from Japan and two from China. Genetically, no founder haplotype has been identified, and thus the disease is expected to be found more widely. The main clinical manifestations of CARASIL are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. The most characteristic findings on brain magnetic resonance imaging are diffuse white matter changes and multiple lacunar infarctions in the basal ganglia and thalamus. Histopathologically, CARASIL is characterized by intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials or amyloid deposition. CARASIL is a prototype single-gene disorder of cerebral small vessels secondary to and distinct from CADASIL. CARASIL-associated mutant HTRA1 exhibited decreased protease activity and failed to repress transforming growth factor-ß family signaling, indicating that the increased signaling causes arteriopathy in CARASIL. Therefore, HTRA1 represents another new gene to be considered in future studies of cerebral small-vessel diseases, as well as alopecia and degenerative vertebral/disk diseases.

Predictive accuracy of MCI subtypes for Alzheimer's disease and vascular dementia in subjects with mild cognitive impairment: a 2-year follow-up study.

AIM: The aim of this study was to investigate the prognostic accuracy of different subtypes of mild cognitive impairment (MCI): amnestic MCI, multiple domain MCI, and single non-memory domain MCI, for the development of Alzheimer's dementia (AD) and vascular dementia (VaD). PATIENTS: Nondemented patients from a memory clinic cohort (n = 118), and a stroke cohort (n = 80, older than 55 years and with a cognitive impairment). RESULTS: 'Multiple domain MCI' had the highest sensitivity for both AD (80.8%) and VaD (100%), and 'amnestic MCI' had the highest specificity (85.9% for AD, 100% for VaD). The positive predictive value was low for all subtypes (0.0-32.7%), whereas the negative predictive value was high (72.8-100%). DISCUSSION: The subtype 'multiple domain MCI' has high sensitivity in identifying people at risk for developing AD or VaD. The predictive accuracy of the MCI subtypes was similar for both AD and VaD.

Pathological validation of a CT-based scale for subcortical vascular disease. The OPTIMA Study.

The validity of a computed tomography (CT)-based rating scale that separately rates leukoaraiosis, patchy lesions, and lacunes was tested using neuropathological findings collected on 87 subjects enrolled in the Oxford Project to Investigate Memory and Ageing. The CT-based score (range 0-64) was associated with both small vessel disease (p = 0.015) and microinfarcts (p = 0.002) on pathology. A sum score of subcortical cerebrovascular disease (CVD) on pathology was computed, 0 indicating absent/mild small vessel CVD and no microinfarcts, 1 moderate small vessel CVD or microinfarcts, and 2 and higher both conditions or severe small vessel CVD. Subjects with a sum score of 0 were decreasing with increasing severity of CT-based score (64, 46, and 25% in those with CT-based scores of 0, 1-38, and 39 and higher), while those with a sum score of 2 and higher were increasing (0, 14, and 44%; p = 0.002). A standardized assessment of subcortical CVD on CT films can be compounded into a unique score that is in good agreement with neuropathology. This supports the validity of the CT-based visual rating scale as a valid tool to detect subcortical vascular changes in elderly persons.

[Vascular dementia and vascular cognitive impairment].

Vascular dementia (VaD) subtypes include multi-infarct dementia, subcortical ischemic vascular dementia, strategic-infarct dementia, etc. Poststroke dementia may be related to preexisting cognitive level, and the frequency increased with aging, lower educational level and accompanied vascular risk factors. Vascular cognitive impairment (VCI) forms a spectrum that includes VaD, mixed Alzheimer's disease (AD) with a vascular component, and VCI without dementia. The concept of VCI will improve the early diagnoses and secondary prevention and treatment of VaD, and promote the further research on vascular component in neurodegenrative disorders.

CADASIL or CADVaSIL?

In the present study, morphological examination of patients from two unrelated Polish families with CADASIL was performed. Using light microscopy, there were evident changes characteristic to the disease. On electron microscopy, deposits of granular osmiophillic material (GOM) were found not only in cerebral arteries and veins but also in cerebral capillaries and vessels of the internal organs. These findings indicate that pathological process in CADASIL is generalized and involves also small vessels devoid of smooth muscle cells. Therefore, we propose to consider a replacement for the name CADASIL that better reflects the morphological picture of the disease like, for example, cerebral autosomal dominant vasculopathy with subcortical infarcts and leukoencephalopathy (CADVaSIL) or, to preserve the commonly known acronym, cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy.

Defining dementia: clinical criteria for the diagnosis of vascular dementia.

The recognition of cerebrovascular disease (CVD) as a contributing factor and a cause of dementia has led to the development of clinical criteria for vascular dementia (VaD). Due to high specificity, the consensus criteria developed by the National Institute for Neurological and Communicative Disorders and Stroke (NINDS)-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) have been used in controlled clinical trials to select patients with pure VaD. VaD is predominantly a subcortical frontal form of dementia with prominent executive dysfunction. In contrast, the criteria of the NINCDS-Alzheimer's Disease and Related Disorders Association (ADRDA) emphasize memory loss as the main feature to distinguish Alzheimer's disease (AD) from VaD and from other forms of dementia. Moreover, CVD may precipitate the clinical expression of AD. Although no criteria have been created specifically for patients having AD with CVD, the ischemic score, the Informant Questionnaire on Cognitive Decline in the Elderly and a history of prestroke mild cognitive impairment (MCI) may be useful for identifying patients with this mixed form of dementia.

The role of neuroimaging in the diagnosis of vascular dementia.

Vascular dementia (VaD) and Alzheimer's disease share many pathological and clinical characteristics. Whereas clinical criteria can help differentiate VaD from other types of dementia, neuroimaging is required for confirmation of vascular lesions. Neuroimaging also provides information about location and size of vascular lesions that can lead to a better understanding of symptoms and may help guide therapy.

Inherited dementias.

Dementia, defined as progressive cognitive decline, is a feature of a wide variety of genetic disorders. For example, a search of "dementia" in the Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/Omim) reveals 162 entries. Therefore this article cannot be encyclopedic and will be necessarily restricted to more prevalent or illustrative etiologies of familial dementia in adults. These disorders also have in common an initial and primarily dementing clinical presentation. Thus, this article is limited to: familial Alzheimer's disease (AD) and related amyloid angiopathies, frontotemporal dementias (FTD) and related tauopathies, familial prion diseases, British and Danish familial dementias, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cognitive deficits of mild dementia: A comparison between dementia of the Alzheimer's type and vascular dementia.

This study was designed to examine the profiles of cognitive deficits in 11 mildly demented patients with dementia of Alzheimer's type (DAT), five with vascular dementia with multiple subcortical lacunar infarcts (VDS), and seven with vascular dementia with extensive white matter lesions (VDW) in comparison with 23 aged individuals without dementia. Memory, attention, abstract thinking, and visuospatial function were assessed using the Japanese translation of the Wechsler Memory Scale-Revised (WMS-R) and the Japanese version of the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Compared with normal aged individuals, three dementia groups were significantly impaired in the memory and abstract thinking. However, the performances on several tests on attention (i.e. Mental Control and Visual Memory Span Backward from WMS-R) and visuospatial function (i.e. Object Assembly from WAIS-R) differed significantly between the DAT and VDS groups, with VDS being the worst in terms of performance than was DAT. This study suggests that, in the mildly demented stage, the patients with DAT have few problems in the attention and visuospatial function, but those with VDS have impairments in these cognitive abilities.

[Vascular dementia--a concise concept?]. / Vaskuläre Demenz--ein schlüssiges Konzept?

Although cerebrovascular disease are the most common causes of dementia after Alzheimer's disease, vascular dementia (VD) has remained so far an ill-defined term. The main problems in the definition of VD arise from finding criteria for both terms "vascular" and "dementia". The detailed criteria for the diagnosis of VD proposed by several groups or institutions (ADDTC, DSM-IV, ICD-10, NINDS-ARIEN) are critically reviewed. The diagnostic value of some clinical findings, especially the very frequent white matter luciencies in CT (leuko-araiosis), are discussed. The available studies suggest a differentiation of VD into some subtypes (listed according to the frequency): subcortical VD, VD with acute onset, multi-infarct-dementia, mixed types, and specific forms. Nevertheless, these subtypes give only little information about the etiology of the underlying vascular process and, therefore, no clear indication for specific therapeutic strategies.

[Early and differential diagnosis of 1,000 patients examined in a memory clinic]. / Früh- und Differentialdiagnose von 1000 in einer Memory-Clinic untersuchten Patienten.

The results from 1000 patients included in a consecutive sample of older persons showing signs of "age-related memory deficits" clearly demonstrate the necessity for a wide spectrum of differential diagnostic competence. The patients included in the study were diagnosed in succession by an interdisciplinary team of psychiatrists, neurologists, geriatric medical specialists, psychologists and gerontologists. The diagnostic process for clarification of DSM-III-R and ICD-10 criteria are discussed in detail. In all, 49.6% of the patients were diagnosed as suffering from dementia of the Alzheimer type, 31% from vascular dementia and 10% from a mixed form. In all, 12.5% of the patients were somatically ill and 31.4% displayed other psychiatric conditions, 50% of which were evaluated as being treatable with psychotherapy. The results are primarily discussed for their relevance to the reality of current treatment.

Utility of ischemic scores in the differential diagnosis of Alzheimer's disease and ischemic vascular dementia.

Despite new developments in the concept of vascular dementia, the Hachinski Ischemic Score (HIS) and its modified versions continue to be widely used in the clinical differentiation of Alzheimer's disease (AD) and ischemic vascular dementia (IVD). The sensitivity of the HIS and two modified versions in the diagnosis of AD, IVD, and single infarcts in a large, geriatric population with mild cognitive impairment (N = 100) was evaluated. Sensitivity for identification of AD was greater than 90% but was less than 70% for IVD. Over one third of patients with one or more infarcts on computed tomographic brain scans and 63% of mixed cases were classified as having probable AD. It is concluded that ischemic scores may be useful at predicting prevalence rates if individual case accuracy is ignored. Despite being sensitive to identifying AD, ischemic scores are insensitive to both cerebral infarction and IVD and cannot reliably exclude IVD. Finally, patients with mixed dementia should not be expected to have intermediate scores.

1995 IPA/Bayer Research Awards in Psychogeriatrics. Reclassification of the vascular dementias: comparisons of infarct and noninfarct vascular dementias.

This article focuses on some of the long-standing problems that exist in the classification of the vascular dementias. To clarify the definition of vascular dementia, mental status and other cognitive processes were investigated in 12 patients with a single cerebral infarct (mean age, 74.8 years), 17 patients with multiple cerebral infarcts (mean age, 71.4 years), 21 vascular patients with no cerebral infarcts (mean age, 76.9 years), and 16 demographically equivalent normal elderly persons (mean age, 70.4 years). The following null hypotheses /hypotheses were tested: (a) The cognitive impairment of single-infarct, multiple-infarct, and noninfarct vascular patients is not/is significantly greater than and outside the range of that in normal aging, and (b) there are/are not significant differences between single-infarct, multiple-infarct, and noninfarct vascular patients on mental status and other cognitive measures. Measures used included the Mini-Mental State Examination, Dementia Rating Scale, Western Aphasia Battery, and Boston Naming Test. Results indicate that vascular disorders involve a decrement in mental status and other cognitive functions that is significantly greater than the age-associated cognitive impairment of normal aging. Also, results from the study indicate that there were no robust, reliable significant differences between single-infarct, multiple-infarct, and noninfarct patients. The validity of the distinction of focal versus generalized or diffuse cerebral lesions is questioned. The nosologic entity of noninfarct vascular dementia is introduced. The future nosology of vascular dementia should provide for noninfarct vascular dementia, defined as vascular dementia caused by underlying vascular mechanisms other than cerebral infarction.

The Mini-Mental State Examination in Alzheimer's disease and multi-infarct dementia.

The aim of this study was to compare the performances on each item of the Mini-Mental State Examination (MMSE) of patients with Alzheimer's disease (AD) and multi-infarct dementia (MID). In order to identify the items that could better distinguish the two groups of patients, 70 AD and 31 MID patients matched for disease severity, age, and education were evaluated. The scores of the 101 patients on each of the MMSE items were entered into a principal component factor analysis using varimax rotation, and two main components were derived. Component 1 was probably representative of recently acquired information, whereas component 2 represented educational level. A score summing the items that loaded on component 1 and the recall item was calculated to generate a measure of episodic memory. Performing analysis of variance and covarying for age and education revealed that this score was statistically different in the two groups, with AD patients having lower values. The data suggest that the MMSE may demonstrate a pattern of impairment of memory that differs between AD and MID. Possible explanations of this finding should take into account the different neuroanatomical impairments and the different degrees of motivation, due to depression or attentional deficits, toward external stimuli.

Variability in scoring the Hachinski Ischaemic Score.

Multi-infarct dementia (MID) may be the second most common form of dementia in later life. A commonly used aid in the clinical diagnosis of MID is the Hachinski Ischaemic Score (HIS). The usefulness of this score is controversial, and we hypothesized that this is because many items of the HIS are open to a wide range of interpretations. We therefore canvassed 45 research and academic centres in the United Kingdom and Ireland with an interest in dementia to assess the variability of interpretation of the HIS. Five template cases were constructed, in which were embedded items which were felt to be potentially contentious. Fifty-five out of 94 (59%) respondents replied. There was a very wide variation in the scores assigned to each vignette. In only five of 65 items was there complete agreement among replies: in general there was a very large range for each item. Thirty of the items showed less than 90% agreement. The apparent simplicity of the HIS conceals possibilities for ambiguous interpretation of individual items. This is a property common to many 'simple' rating scales. It should not lead to outright rejection of these scales, but rather to a refinement and clarification of the scoring and assessment techniques.

The clinical diagnosis and misdiagnosis of senile dementia of Lewy body type (SDLT).

BACKGROUND: Current clinical classifications do not contain specific diagnostic categories for patients with senile dementia of the Lewy body type (SDLT), recently proposed as the second commonest neuropathological cause of dementia in the elderly. This study determines how existing clinical diagnosis systems label SDLT patients and suggests how such patients may be identified. METHOD: A range of clinical diagnostic criteria for dementia were applied to case notes of autopsy-confirmed SDLT (n = 20), dementia of Alzheimer type (DAT; n = 21) and multi-infarct dementia (MID; n = 9) patients who had received psychogeriatric assessment. The predictive validity of each set of clinical criteria was calculated against the external criterion of neuropathological diagnosis. RESULTS: Many SDLT patients erroneously met criteria for MID (35% with Hachinski scores > or = 7) or for DAT (15% by NINCDS 'probable AD', 35% by DSM-III-R DAT and 50% by NINCDS 'possible AD'). Up to 85% of SDLT cases could be correctly identified using recently published specific criteria. CONCLUSIONS: SDLT usually has a discernible clinical syndrome and existing clinical classifications may need revision to diagnose correctly such patients.

[Progress in vascular dementia--an overview of vascular dementia from past to new concepts]. / Vaskuläre Demenz im Wandel--eine Ubersicht zur vaskulären Demenz von zurückliegenden zu neuen Konzepten.

This article summarizes various concepts (Binswangers encephalopathy, multiinfarct-dementia, lacunar state, mixed dementia, dementia due to amyloid angiopathy or vasculitis) and classifications (DSM, ICD, ADDTC) on vascular dementia. It reviews historical, clinical, and diagnostic aspects (i.e. neuroradiology, SPECT, PET) as well as therapeutic approaches. The confusing nomenclature on vascular dementia is discussed, considering especially the non-convincing concept of multiinfarct-dementia that often has been misused as a synonym for vascular dementia. Multiinfarct-dementia is now restricted to a syndrome of vascular dementia due to several large vessels strokes. A current definition and classification of vascular dementia as suggested by NINDS-AIREN international workshop is described. It defines criteria consistent with the diagnosis of "possible", "probable" and "definite" vascular dementia based on clinical, radiologic and neuropathologic features. The criteria of "probable" vascular dementia include all the following: 1. the presence of dementia and cerebrovascular disease defined by focal signs on neurologic investigation and evidence of relevant cerebrovascular disease by brain imaging (multiple lacunae, extensive white matter lesions, multiple large-vessels infarcts or a strategically placed infarct) 2. A relationship between dementia and cerebrovascular disease (onset of dementia within 3 months following a recognized stroke; abrupt deterioration, stepwise progression). This classification of vascular dementia emphasises pathogenetic aspects and includes dementia resulting from small- and large-vessels disease as well as hypoperfusion, haemorrhagic dementia and dementia due to still unknown factors. Operational criteria for the frequent Binswangers encephalopathy--a prototype of vascular dementia--are presented. Thereby a basis for further research and discussion in this exciting area should have been formed.

Multi-infarct dementia.

Vascular dementia and its most common subtype, multi-infarct dementia, are pathologically proven clinical entities. Their prevalence is not as high as previously thought, but they do represent a significant percentage of the population of demented patients. The diagnosis is more difficult to make than is the diagnosis of Alzheimer's disease; however, there are excellent criteria to guide the physician in making the diagnosis. At present the only treatment available is to control the risk factors responsible for the basic disease process; in the majority of cases this requires controlling hypertension.

Reliability and validity of the Hierarchic Dementia Scale.

The aim of the study was to apply a method for measuring cognitive functioning in severely demented patients. Reliability and validity of the Hierarchic Dementia Scale (HDS) were tested. Fifty patients with dementia of the Alzheimer's type (DAT), multi-infarct dementia (MID), and dementia of mixed type (MIX) were studied. The interrater reliability was satisfactory as estimated by means of a kappa coefficient. The test retest reliability was rs = .96. The concurrent validity of the HDS, as measured by the correlation between the HDS and the MMSE, was rs = .86, and between the HDS and the CDR was rs = -.71. The results indicate that HDS is a useful and valid instrument for determination of the heterogeneous cognitive deficits in severe dementia.