Subcortical Vascular Dementia Research Articles

B-type natriuretic peptide plasma levels are elevated in subcortical vascular dementia

High levels of B-type natriuretic peptide (BNP), a serum marker of congestive heart failure, are associated with an increased risk for cognitive decline. However, no study has yet assessed this marker in different subtypes of dementia. We tested the hypothesis that BNP has a more significant association with vascular dementia than Alzheimer disease. Plasma BNP was measured in 15 patients with subcortical vascular dementia, in 19 Alzheimer patients without evidence of vascular comorbidity, and in age-matched controls. Compared with controls (28+/-7 ng/l), BNP was elevated in subcortical vascular dementia (63+/-17 ng/l; P=0.03), but not in Alzheimer disease (36+/-5 ng/l). In conclusion, subcortical vascular dementia is indeed associated with moderately elevated BNP levels, whereas this could not be shown for Alzheimer disease. This probably reflects the larger cardiovascular burden in patients with subcortical vascular dementia.

Diffusion tensor changes in patients with amnesic mild cognitive impairment and various dementias

White matter damage and its contribution to clinical manifestations in patients with dementia have been increasingly recognized. To explore white matter changes in different types of dementia, we examined brain water diffusivity with diffusion tensor imaging (DTI). We measured fractional anisotropy and mean diffusivity of multiple white matter regions in patients with amnesic mild cognitive impairment (MCI, n = 10), Alzheimer's disease (AD, n = 30), subcortical ischemic vascular dementia (SIVD, n = 18), frontotemporal dementia (FTD, n = 7), and control subjects ( n = 20). We performed pairwise comparisons in each region of interest between patients and controls. MCI patients showed diffusion tensor change (DTC) in the left anterior periventricular (PV) area, possibly in the right posterior PV area, and the genu of the corpus callosum. AD patients showed DTC in the corpus callosum, and in frontal and parieto-occipital subcortical and anterior PV areas. In SIVD patients, DTC occurred in the genu of the corpus callosum, and in bilateral frontal subcortical and PV areas. FTD patients differed from controls in showing DTC in the temporal and frontal subcortical areas, the genu of the corpus callosum and PV areas. The degree of DTC correlated with the clinical severity of dementia as assessed by the clinical dementia rating (CDR). Mean diffusivity was diffusely and positively associated with the CDR scores. Fractional anisotropy of the PV areas was negatively associated with the CDR scores, suggesting a critical role of the lateral cholinergic pathways.

Increased binding to 5-HT1A and 5-HT2A receptors is associated with large vessel infarction and relative preservation of cognition

Vascular dementia accounts for approximately 15-20% of all dementias. In addition, a significant subset of people with Alzheimer's disease have concurrent cerebrovascular disease. Vascular dementia is caused by different cerebrovascular morphological abnormalities including large artery territory infarction (multi-infarct vascular dementia) and sub-cortical ischaemic vascular dementia. Despite this distinction, there is a lack of studies examining the neurochemistry of individual vascular dementia subtypes. Serotonin is believed to play an important role in cognition, and serotonin receptors may provide a novel target for future anti-dementia therapeutics. This study aimed to determine levels of two serotonin receptors in subtypes of vascular dementia and relate any changes to cognition. We have determined, using saturation radioligand binding, the binding parameters (affinity and maximal binding) of ((3)H)-WAY 100635 binding to 5-HT(1A) receptors and ((3)H)-ketanserin binding to 5-HT(2A) receptors in post-mortem tissue from the frontal and temporal cortices of patients with either multi-infarct vascular dementia, sub-cortical ischaemic vascular dementia, mixed Alzheimer's disease/vascular dementia or stroke no dementia (SND). 5-HT(1A) and 5-HT(2A) receptor binding was significantly increased in the temporal cortex of patients with either multi-infarct vascular dementia or SND, compared to age-matched controls. 5-HT(1A) receptor maximal binding in the temporal cortex was also positively correlated with cognition as determined by Mini-Mental State Examination (MMSE) and Cambridge Assessment of Mental Health for the Elderly scores (CAMCOG). These results reveal an important distinction between the neurochemistry of multi-infarct vascular dementia/SND and sub-cortical ischaemic vascular dementia, suggesting that pharmacological manipulation of serotonin offers the possibility to develop novel therapies for stroke and multi-infarct vascular dementia patients. The results also highlight the importance of the cortical 5-HT(1A) receptor in mediating cognition.

Neuropathological Correlates of Temporal Pole White Matter Hyperintensities in CADASIL

White matter (WM) hyperintensities on MRI or leukoaraiosis is characteristic of stroke syndromes. Increased MRI signals in the anterior temporal pole are suggested to be diagnostic for cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with 90% sensitivity and 100% specificity. The structural correlates of these specific WM hyperintensities seen on T2-weighted and FLAIR sequences in the temporal pole of CADASIL are unclear. We assessed pathological changes in postmortem tissue from the temporal pole to reveal the cause of CADASIL-specific WM hyperintensities. A combination of tinctorial and immunostaining approaches and in vitro imaging methods were used to quantify the extent of perivascular space (PVS), arteriosclerosis determined as the sclerotic index, WM myelination as the myelin index, and damage within the WM as accumulated degraded myelin basic protein in samples of the anterior temporal pole from 9 CADASIL and 8 sporadic subcortical ischemic vascular dementia cases, and 5 similarly aged (young) and 5 older controls. Luxol fast blue-stained serial sections from a CADASIL case were also used to reconstruct the temporal pole, which was then compared to the MR images. Luxol fast blue sections used to reconstruct the temporal pole revealed an abundance of enlarged PVS in the WM that topographically appeared as indistinct opaque regions. The mean and total areas of the PVS per WM area (%PVS) were significantly greater in CADASIL compared to the controls. The myelin index was severely reduced in CADASIL in relation to the subcortical ischemic vascular dementia and control sample that was consistent with increased immunoreactivity of degraded myelin basic protein, indicating myelin degeneration. Cerebral microvessels associated with the PVS exhibited a 4.5-fold greater number of basophilic (hyalinized) vessels and a 57% increase in the sclerotic index values in CADASIL subjects compared to young controls. A significant correlation between the quantity of hyalinized vessels and sclerotic index values was also apparent (P<0.05). Our findings suggest that MRI hyperintensities in the temporal pole of CADASIL patients are explained by enlarged PVS and degeneration of myelin accompanied by lack of drainage of the interstitial fluid rather than lacunar infarcts. Consistent with the lack of MR hypersignals in the temporal pole of older subcortical ischemic vascular dementia subjects, our observations imply greater progression of pathological changes in CADASIL patients.

Differences Exist in the Cognitive Profile of Mild Alzheimer’s Disease and Subcortical Ischemic Vascular Dementia

Background/Aims: Our objective was to characterize the cognitive profile of patients with mild Alzheimer’s disease (AD) and subcortical ischemic vascular dementia (SIVD) matched using a functional scale. Methods: AD and SIVD were diagnosed using the NINCDS-ADRDA and the criteria proposed by Erkinjuntti et al., respectively. The Clinical Dementia Rating (CDR) scale was used to guide the identification of patients with mild dementia from a prospective clinical database. Regression analysis was applied to compare the 2 groups on global and individual cognitive domains. Results: The greatest cognitive differences between the 2 groups were observed in the domains of visuospatial function (p = 0.001), working memory (p = 0.013) and visuomotor speed (p = 0.028). No significant variation was demonstrated in the executive function domain (p = 0.646). Statistically significant differences between AD and SIVD patients were found in episodic memory delayed recall tasks but not in the immediate recall tasks. A trend towards severer depressive symptoms (p = 0.052) was observed among the SIVD patients. Conclusions: SIVD patients with mild dementia have greater deficits in visuospatial function, working memory and visuomotor speed and may also be more depressed compared to AD patients. Executive function tests in general do not distinguish the 2 groups, although timed executive tasks can separate them.

Apathy

The frequency and impact of apathy in subcortical ischemic vascular dementia (SIVD) remain undetermined. The frequency, clinical, neuropsychological, and imaging correlates of apathy were assessed in a large cohort of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a genetic model of SIVD. Apathy was diagnosed based on Neuropsychiatric Inventory assessment. Degree of disability was assessed by modified Rankin scale, cognitive impairment by Mattis Dementia Rating Scale (MDRS) and Mini-Mental State Examination (MMSE), autonomy by the Instrumental Activities of Daily Living (IADL) scale, and quality of life by SEP-59 self-questionnaire. Validated imaging methods were used to determine the total burden of cerebral lesions. Among 132 patients, 54 (41%) were apathetic. Apathetic patients were older than nonapathetic subjects, had a lower MMSE and MDRS score, had more global disability, and were more limited in IADL. Apathetic patients were more frequently depressed compared to nonapathetic patients and more frequently presented additional neuropsychiatric symptoms. Multiple regression modeling showed a significant and independent association between apathy and a lower score of overall quality of life and between apathy and a higher load of white matter and lacunar lesions. The results suggest that apathy is common in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), appears in association with cognitive impairment, global functional disability, and severe neuropsychiatric symptoms during the course of the disease, and can occur separately from depression. Apathy has an independent impact on the overall quality of life in CADASIL.

The value of quantitative EEG in differential diagnosis of Alzheimer's disease and subcortical vascular dementia

Objective To investigate whether quantitative EEG may be useful in differential diagnosis of AD and SVD and to determine the correlation between dementia and abnormalities in EEG. Materials and methods The group under study was consisted of 62 patients with AD (mean age: 73.6 yrs; M 51%), 31 with SVD (mean age: 75.2 yrs, M 43%) and a control group of 14 healthy subjects (mean age: 69.5 yrs, M 43%). The patients were divided into subgroups of those with mild, moderate and marked dementia. EEG findings were classified using eight-degree scale according to the presence of slow waves, and then quantitative analysis was carried out by calculating the alpha/slow wave power ratios and the mean frequencies in all and some selected derivations. Results A significant difference between visual EEGs and QEEGs in AD and SVD was found. Only QEEG parameters differed in AD and SVD subgroups with the same degree of cognitive impairment: the mean wave frequencies of waves in temporal derivations in subgroups with mild and moderate dementia and alpha/delta waves power ratio in subgroups with moderate dementia. Conclusions Visual EEGs and QEEGs could be used in addition to the differential diagnosis between AD and SVD, but only selected parameters of QEEG could be useful in differentiating between AD and SVD subgroups with the same degree of dementia.

Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by mutations in NOTCH3 gene, which encodes a large transmembrane receptor Notch3. The key pathological finding is the accumulation of granular osmiophilic material (GOM), which contains extracellular domains of Notch3, on degenerating vascular smooth muscle cells (VSMCs). GOM has been considered specifically diagnostic for CADASIL, but the reports on the sensitivity of detecting GOM in patients’ skin biopsy have been contradictory. To solve this contradiction, we performed a retrospective investigation of 131 Finnish, Swedish and French CADASIL patients, who had been adequately examined for both NOTCH3 mutation and presence of GOM. The patients were examined according to the diagnostic practice in each country. NOTCH3 mutations were assessed by restriction enzyme analysis of specific mutations or by sequence analysis. Presence of GOM was examined by electron microscopy (EM) in skin biopsies. Biopsies of 26 mutation-negative relatives from CADASIL families served as the controls. GOM was detected in all 131 mutation positive patients. Altogether our patients had 34 different pathogenic mutations which included three novel point mutations (p.Cys67Ser, p.Cys251Tyr and p.Tyr1069Cys) and a novel duplication (p.Glu434_Leu436dup). The detection of GOM by EM in skin biopsies was a highly reliable diagnostic method: in this cohort the congruence between NOTCH3 mutations and presence of GOM was 100%. However, due to the retrospective nature of this study, exact figure for sensitivity cannot be determined, but it would require a prospective study to exclude possible selection bias. The identification of a pathogenic NOTCH3 mutation is an indisputable evidence for CADASIL, but demonstration of GOM provides a cost-effective guide for estimating how far one should proceed with the extensive search for a new or an uncommon mutations among the presently known over 170 different NOTCH3 gene defects. The diagnostic skin biopsy should include the border zone between deep dermis and upper subcutis, where small arterial vessels of correct size are located. Detection of GOM requires technically adequate biopsies and distinction of true GOM from fallacious deposits. If GOM is not found in the first vessel or biopsy, other vessels or additional biopsies should be examined.

Relationships between 24-Hour Blood Pressures, Subcortical Ischemic Lesions, and Cognitive Impairment

Background and PurposeThe most important treatment for subcortical vascular dementia (SVaD) is controlling the blood pressure (BP). However, the few studies that have investigated the relationships between diurnal BP rhythm and subcortical ischemic vascular cognitive impairment have produced inconclusive results. In the study presented here, the 24-hour BP values of three groups of subjects-patients with subcortical vascular mild cognitive impairment (SvMCI), patients with SVaD, and normal controls-were compared using working criteria and 24-hour ambulatory BP (ABP) monitoring.MethodsThe subjects (42 patients with SVaD, 37 patients with SvMCI, and 30 controls) were selected according to the study's inclusion/exclusion criteria. All subjects underwent brain magnetic resonance (MR) imaging and MR angiography, detailed neuropsychological testing, and 24-hour ABP monitoring.ResultsThe prevalence of nondippers differed markedly between the control group and both the SVaD and SvMCI groups. Loss of nocturnal dipping was significantly associated with SVaD [odds ratio (OR), 4.827; 95% confidence interval (CI), 1.07-12.05].ConclusionsIt was found that SVaD is associated with loss of nocturnal BP dipping combined with increased pulse pressure and systolic BP (SBP) variability. Correction of these factors could therefore be important in the prevention of SVaD, independent of measures used to reduce BP.

A novel approach to vascular regeneration in subcortical vascular dementia

A novel approach to vascular regeneration in subcortical vascular dementia

Cognition in CADASIL

CADASIL is an early onset small vessel disease and genetic variant of pure subcortical ischemic vascular dementia (SIVD). The condition has been invaluable in defining the profile and neuroimaging correlates of cognitive deficits in pure SIVD. The recent completion of a randomized trial in cognitively impaired CADASIL patients has illustrated the feasibility of targeted therapeutic trials in narrowly defined subtypes of vascular cognitive impairment. This article highlights some of the advances on cognition in CADASIL.

CADASIL: The Most Common Hereditary Subcortical Vascular Dementia

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is the most common hereditary subcortical vascular dementia. It is caused by the defective NOTCH3 gene, which encodes a transmembrane receptor; over 170 different mutations are known. The main clinical features are migraine with aura (often atypical or isolated), strokes, cognitive decline/dementia and psychiatric symptoms. Executive and organizing cognitive functions are impaired first, memory is affected late. Typical MRI findings are T2 weighted hyperintensities in temporopolar white matter and the capsula externa. Smooth muscle cells in small arteries throughout the body degenerate and vessel walls become fibrotic. In the brain, this results in circulatory disturbances and lacunar infarcts, mainly in cerebral white matter and deep gray matter. The exact pathogenesis is still open: a dominant-negative toxic effect is suggested, possibly related to Notch3 misfolding. Diagnosis is reached either by identifying a pathogenic NOTCH3 mutation or by electron microscopic demonstration of granular osmiophilic material in a (skin) biopsy. Only symptomatic treatment is available at present.

Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice

We sought to establish a mouse model of subcortical ischemic vascular dementia (SIVD) that develops predominant white matter (WM) injury and cognitive dysfunction induced by chronic cerebral hypoperfusion. Adult C57Bl/6 male (n = 48) mice were subjected to bilateral common carotid artery stenosis with external microcoils (inner diameters: 0.16 mm, left; 0.18 mm, right). Mice were categorized according to left-side cerebral blood flow (CBF) value on day 6 into those with severe cerebral hypoperfusion (SCH; n = 16, < 30% of preoperative CBF baseline value) or moderate cerebral hypoperfusion (MCH; n = 21, 30-50% of preoperative value). Another 15 mice were sham operated. Neurological dysfunction was evaluated by Morris water maze, rotating rod, and open field tests. Histopathological examination was performed on day 35 after surgery. MCH animals showed persistent hyperlocomotion with reduced anxiety and spatial reference memory dysfunction. Rarefaction and small necrotic lesions were predominantly confined to the WM, with reactive astrocytosis, microglial infiltration, axonal loss, and myelin disruption, and these changes were dominant on the left side. SCH animals had persistent hyperlocomotion and motor dysfunction, and their ischemic lesions extended from the WM to the hippocampus and cortex. In MCH animals, myelin basic protein and neurofilament fiber densities in the WM were correlated with the time spent in the correct area in the water maze probe trials. Our MCH mouse model with the development of several types of neurological dysfunction with high reproducibility would be useful for investigating the pathomechanisms of WM injury in human SIVD.

Impact of MRI markers in subcortical vascular dementia: A multi-modal analysis in CADASIL

CADASIL is an arteriopathy caused by mutations of the Notch3 gene. White matter hyperintensities (WMH), lacunar lesions (LL), cerebral microhemorrhages (CM), brain atrophy and tissue microstructural changes are detected on MRI. Using an integrated multi-modal approach, we examined the relative impact of lesion burden and location of these MRI markers on cognitive impairment and disability. Multi-modal imaging was performed on 147 patients from a two-center cohort study. Volume of LL, WMH and number of CM was determined. Whole brain mean apparent diffusion coefficient (mean-ADC) and brain parenchymal fraction (BPF) were measured. In multivariate models accounting for lesion burden and location, volume of LL, mean-ADC, and BPF each had an independent influence on global cognitive function and disability. BPF explained the largest portion of the variation in cognitive and disability scores (35-38%). Brain atrophy has the strongest independent influence on clinical impairment in CADASIL when all MRI markers in the disease are considered together. The results suggest that the clinical impact of cerebral tissue loss plays a principal role in this genetic model of subcortical ischemic vascular dementia.

CSF levels of β‐amyloid 1‐42, tau and phosphorylated tau protein in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be considered a useful model of pure subcortical vascular dementia (SVD) because it occurs in young adults, unlikely to have concomitant age- and Alzheimer's disease (AD)-related pathology. In patients with CADASIL we evaluated the cerebrospinal fluid (CSF) levels of beta-amyloid 1-42 (Abeta42), total tau protein (t-tau) and phosphorylated tau protein (p-tau), which are well-accepted biomarkers of AD. The CSF Abeta42, t-tau and p-tau levels were determined with Innotest beta-amyloid 1-42, Innotest hTAU-Ag and Innotest Phospho-tau 181p sandwich enzyme-linked immunoassay, in 10 CADASIL patients and 17 healthy age-matched subjects. A case-control statistical analysis was carried out. CSF Abeta42 levels were significantly lower in CADASIL patients than in controls, whereas CSF t-tau and p-tau levels did not differ between the two groups. The pattern found in CADASIL patients is similar to that reported in those with sporadic SVD, suggesting that decreased CSF Abeta42 might be related to the subcortical vascular lesions in the white matter.

Statistical Parametric Analysis of Cerebral Blood Flow in Vascular Dementia with Small-Vessel Disease Using 99mTc-HMPAO SPECT

Background: Subcortical ischemic vascular dementia (SVD) caused by small-artery disease is a major cause of dementia. It still remains unclear, however, whether SVD may present with localized regional cerebral blood flow (rCBF) changes. We aimed to clarify the local rCBF changes associated with dementia in patients with early-stage SVD. Methods: The subjects consisted of 15 patients with early-stage SVD [Mini Mental State Examination (MMSE) score: 20 ± 3.5] without apparent brain atrophy (SVD group), 11 patients without dementia with white matter lesions (non-dementia-WML group) and 16 age-matched controls. All the subjects were right-handed and underwent brain perfusion single photon emission computed tomography (SPECT), magnetic resonance imaging and cognitive function testing. Statistical analysis of the differences in the SPECT rCBF was performed by SPM2. The degree of severity of the WMLs was evaluated based on the Scheltens rating scale. Results: The results of SPM analysis revealed that the rCBF in the SVD group was significantly decreased in the pulvinar nuclei of the thalamus of both sides as compared with that in the controls, and in the left pulvinar nucleus as compared with that in the non-dementia-WML group. On the other hand, SPM analysis revealed no significant reduction in rCBF in the non-dementia-WML group as compared with that in the controls. The WMLs in the left parietal region were severer in the SVD group than in the non-dementia-WML group. Conclusions: In patients with early-stage SVD without apparent brain atrophy, significant rCBF reduction in the bilateral pulvinar nuclei as compared with that in normal controls, and in the left pulvinar nucleus as compared with that in patients without dementia with WMLs was found.

P.5.b.005 Epistasis of butyrylcholinesterase wt/wt and APOE e4 state in subcortical vascular dementia and Alzheimer's disease

Butyrylcholinesterase (BChE) is an enzyme presented in quite high level in blood plasma where it participates in detoxification reactions. Due to fact that the enzyme is constituted in livers, it is a marker of liver parenchyma function. It can be used for diagnosis of poisoning for e.g., nerve agents or carbofuran and intoxication by some drugs such as rivastigmine. The present experiment is devoted for the creation of new spectrophotometric tests for assay of BChE activity in biological samples. Standard Ellman's method was compared with use of 2,6-dichloroindophenol acetate and indoxylacetate as chromogenic substrates. Maximal velocities and Michaelis constants were calculated for the substrates. Considering calibration, 2,6-dichloroindophenol acetate provided the lowest limit of detection: 1.20×10−9 kat and a long linear range. All methods were verified using pooled human plasma samples and tested for potential interferents. 2,6-dichloroindophenol acetate is recommended as suitable substrate for BChE assay in clinical diagnostics.

Computer-aided Detection of Ischemic Lesions Related to Subcortical Vascular Dementia on Magnetic Resonance Images

The purpose of this study was to develop an automated method for detection of the hyperintense ischemic lesions related to subcortical vascular dementia based on conventional magnetic resonance images (T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery images [FLAIR]). Our proposed method was based on subtraction between the T1-weighted image and the FLAIR image. First, a brain region was extracted by an automated thresholding technique based on a linear discriminant analysis for a pixel value histogram. Next, for enhancement of ischemic lesions, the T1-weighted image was subtracted from the fluid-attenuated inversion-recovery image. Ischemic lesion candidates were identified using a multiple gray-level thresholding technique and a feature-based region-growing technique on the subtraction image. Finally, an artificial neural network trained with 15 image features of the ischemic candidates was used to remove false-positives. We applied our method to nine patients with vascular dementia (age range, 64-94 years, mean age, 69.4 years; four males and five females), who were scanned on a 1.5-T magnetic resonance unit. Our method achieved a sensitivity of 90% with 4.0 false-positives per slice in detection of ischemic lesions. The overlap measure between ischemic lesion areas obtained by our method and a neuroradiologist was 60.7% on average. The ratio of ischemic lesion area to the whole brain area obtained by our method correlated with that determined by a neuroradiologist with a correlation coefficient of 0.911. Our preliminary results suggest that the proposed method may have feasibility for evaluation of the ischemic lesion area ratio.

P2-269: Neuropsychiatric symptom difference in Alzheimer's disease, Parkinson's disease dementia, and subcortical vascular dementia in early stage

P2-269: Neuropsychiatric symptom difference in Alzheimer's disease, Parkinson's disease dementia, and subcortical vascular dementia in early stage

Frontal-Subcortical Dementias

Frontal-subcortical dementias are a heterogeneous group of disorders that share primary pathology in subcortical structure and a characteristic pattern of neuropsychologic impairment. Their clinical presentation is characterized by memory disorders, an impaired ability to manipulate acquired knowledge, important changes of personality (apathy, inertia, or depression), and slowed thought processes (or bradyphrenia). It also has marked frontal dysfunction. Classic frontal-subcortical dementias include Huntington chorea, Parkinson disease dementia, progressive supranuclear palsy, thalamic degeneration, subcortical vascular dementia, multiple sclerosis, the acquired immunodeficiency syndrome dementia complex, depressive pseudodementia, and some other rare dementias like spinocerebellar degenerative syndromes, Hallervorden-Spatz disease, choreoacanthocytosis, idiopathic basal ganglia calcification, Guamanian parkinsonism-dementia complex, corticobasal degeneration multiple system atrophy, Wilson disease, metachromatic leukodystrophy, adrenoleukodystrophy, hypoparathyroidism, sarcoidosis, and other CNS inflammatory disorders. Anatomic data suggest that the frontal signs result from a disconnection of the frontal cortex from the basal ganglia. However, most frontal-subcortical dementias show cortical atrophy in later stages, and cortical dementias have subcortical pathology at some point. In fact, the concept might be seen as a continuum, and only the 2 extremes would be represented by pure cortical or subcortical pathology. Anyway, subcortical disorders may still be more similar to one another than they are to AD. Possibly, frontal-subcortical and cortical dementias are the description of the prior main target of the disease process, ending up in both cases in a global dementia. Although the dichotomy cortical versus frontal-subcortical dementia is not strict, the 2 concepts still seem to have advantages.