The German version of the Mini Suffering State Examination (MSSE) for people with advanced dementia living in nursing homes.

BACKGROUND: The Mini Suffering State Examination (MSSE) has been explicitly recommended to assess suffering in dementia patients. This study aimed to develop a German version of the MSSE and assess its psychometric properties involving people with advanced dementia (PAD) in a nursing home setting. METHODS: The MSSE was translated into German, and 95 primary nurses administered it cross-sectionally to 124 PAD in Zurich, Switzerland. The psychometric properties of the German MSSE version were calculated for this population. RESULTS: The mean age of the PAD was 83.3 years (SD = 9.1, range = 55-102 years), and 98 of them (79.0%) were women. The Kuder-Richardson Formula 20 coefficient for the entire scale (0.58), the eight items relating to objective health conditions (0.39), and the professional and family estimation of the patient's suffering (0.64) indicated low internal consistency. A confirmatory factor analysis indicated an unsatisfactory fit to a one-factor structure, with a comparative fit index and root mean square error of approximation of 0.71 and 0.08, respectively, and a Tucker-Lewis index of 0.64. The MSSE total score was significantly but moderately correlated with the total scores of the Symptom Management-End-of-Life with Dementia (SM-EOLD) scale (Pearson's correlation coefficient (r) = -0.44; p < 0.05), the physical suffering scores (r = 0.41; p < 0.05), and the psychological suffering scores (r = 0.55; p < 0.05). CONCLUSIONS: The German version of the MSSE questionnaire did not perform well in the nursing home setting involving PAD. The instrument had low internal consistency, doubtful validity, and could not discriminate between suffering and other distressing symptoms. We do not recommend its use in this population.

Use of mild cognitive impairment and prodromal AD/MCI due to AD in clinical care: a European survey.

INTRODUCTION: The diagnosis of mild cognitive impairment (MCI) refers to cognitive impairment not meeting dementia criteria. A survey among members of the American Association of Neurology (AAN) showed that MCI was considered a useful diagnosis. Recently, research criteria have been proposed for the diagnosis of Alzheimer's disease (AD) in MCI based on AD biomarkers (prodromal AD/MCI due to AD). The aim of this study was to investigate the attitudes of clinicians in Europe on the clinical utility of MCI and prodromal AD/MCI due to AD criteria. We also investigated whether the prodromal AD/MCI due to AD criteria impacted management of MCI patients. METHODS: An online survey was performed in 2015 among 102 members of the European Academy of Neurology (EAN) and the European Alzheimer's Disease Consortium (EADC). Questions were asked on how often criteria were used, how they were operationalized, how they changed patient management, and what were considered advantages and limitations of MCI and prodromal AD/MCI due to AD. The questionnaire consisted of 47 questions scored on a Likert scale. RESULTS: Almost all respondents (92%) used the MCI diagnosis in clinical practice. Over 80% of the EAN/EADC respondents found a MCI diagnosis useful because it helped to label the cognitive problem, involve patients in planning for the future, and start risk reduction activities. These findings were similar to those reported in the AAN survey. Research criteria for prodromal AD/MCI due to AD were used by 68% of the EAN/EADC respondents. The most common reasons to use the criteria were increased certainty of diagnosis (86%), increased possibilities to provide counseling (51%), facilitation of follow-up planning (48%), start of medical intervention (49%), and response to patients' wish for a diagnosis (41%). Over 70% of the physicians considered that a diagnosis of prodromal AD/MCI due to AD had an added value over the MCI diagnosis. CONCLUSIONS: The diagnostic criteria of MCI and prodromal AD/MCI due to AD are commonly used among EAN/EADC members. The prodromal AD/MCI due to AD were considered clinically useful and impacted patient management and communication.

Cognitive Change at the End of Life in Nursing Home Residents: Differential Trajectories of Terminal Decline.

BACKGROUND: Research on terminal decline has widely documented that cognitive performance steeply declines with nearing death. To date, it is unclear whether these changes are normative, based on pathologies associated with (preclinical) dementia, or both. OBJECTIVES: We analyzed heterogeneity in trajectories of terminal cognitive change in Swiss nursing home residents with the objective of examining whether terminal change is normative or whether one or multiple subgroup(s) with relative stability exist. METHODS: We performed a longitudinal analysis based on routine assessments with the Resident Assessment Instrument - Minimal Data Set in 341 nursing homes between 1998 and 2014. In sum, we used 143,052 observations from 30,054 residents (69% women, average age at death 87 years) in the last 3 years of life. We analyzed trajectories of the Cognitive Performance Scale (CPS) score with latent class growth curve models and examined sociodemographic factors (age at death, sex, marital status, prior living situation) as well as functional and mental health (Activities of Daily Living Index and Depression Rating Scale) and dementia diagnosis as correlates of group membership. RESULTS: We identified three distinct classes based on longitudinal trajectories of the CPS score. In the first group (transition from no to mild impairment, 27%), cognitive impairment increased with time to death (linear and quadratic), but remained at relatively mild levels at all times. The trajectories of the second group (transition from moderate to severe impairment, 43%) were characterized by linear and quadratic changes across time to death. The trajectories of the third group (severe impairment, 30%) were characterized by the lowest amount of linear increase across all groups and no quadratic increase indicating no accelerated change. Better functional health and absence of a dementia diagnosis predicted less impairment. Fewer depressive symptoms were associated with low as opposed to moderate or severe, but also severe versus moderate impairment. CONCLUSION: Our findings suggest that the majority of residents experience terminal change, with the exception of those at already high levels of impairment. Furthermore, late-life cognitive change is related to functional and mental health.

The last phase of life with dementia in Swiss nursing homes: the study protocol of the longitudinal and prospective ZULIDAD study.

BACKGROUND: The proportion of older people with advanced dementia who will die in nursing homes is constantly growing. However, little is known about the dying phase, the type of symptoms, the management of symptoms and the quality of life and dying in people with advanced dementia. The ZULIDAD (Zurich Life and Death with Advanced Dementia) study aims at extending the current scientific knowledge by providing first data from Switzerland. METHODS: The ZULIDAD study employs a prospective design to study nursing home residents with advanced dementia for three years or until their death in eleven nursing homes in Zurich. Observational data from quarterly questionnaires for relatives and primary nurses is combined with data from the Resident Assessment Instrument - Minimum Data Set (RAI-MDS). Special focus is put on 1) the cross-sectional analysis of baseline and post-mortem data regarding quality of life and quality of dying and how the perceptions of these measures differ between relatives and primary nurses, 2) the longitudinal analyses of established health outcome measures (e.g., EOLD, MSSE, BISAD, QUALID) in order to understand their trajectories and 3) international comparisons of cross-sectional and longitudinal data. DISCUSSION: The ZULIDAD study is one of the few existing prospective studies on end-of-life care in dementia and it is the first prospective study to describe the situation in Switzerland. Its multi-perspective approach allows a comprehensive approximation to central health outcome measures at the end of life such as pain, suffering or quality of life. Providing insights into the current provision of care, it can serve as a basis for improving dementia end-of-life care in Switzerland and internationally.

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity.

BACKGROUND: An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. METHODS: Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. RESULTS: The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). CONCLUSIONS: The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

Delphi definition of the EADC-ADNI Harmonized Protocol for hippocampal segmentation on magnetic resonance.

BACKGROUND: This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation. METHODS: The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence-based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests. RESULTS: Agreement was significant on the inclusion of alveus/fimbria (P = .021), whole hippocampal tail (P = .013), medial border of the body according to visible morphology (P = .0006), and on this combined set of features (P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer's disease-related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter-rater (0.94) estimates. DISCUSSION: Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol.

The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey.

We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aß42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

Hippocampal atrophy in subcortical vascular dementia.

BACKGROUND AND PURPOSE: New research criteria for subcortical vascular dementia (SVaD) have been suggested to define a more homogeneous subgroup of vascular dementia. Hippocampal (Hc) atrophy is a hallmark of Alzheimer's disease (AD), but it also occurs in other dementia disorders including vascular dementias. So far, it is unknown to which extent Hc atrophy is present in SVaD. METHODS: From a larger consecutive referral population in a memory clinic, 11 patients fulfilling the research criteria for SVaD were carefully matched with comparison groups of healthy controls and patients with AD. To estimate the extent of Hc atrophy in SVaD, both Hc volumetry and visual rating of medial temporal lobe atrophy (MTA) were applied. RESULTS: In SVaD, significant Hc atrophy occurred. The extent was intermediate between controls and patients with AD both on Hc volumetry and visual MTA ratings. At the same level of global cognition, Hc volumes were reduced by 11.6% in SVaD and 16.6% in AD, relative to controls. CONCLUSIONS: Patient groups with AD and SVaD as identified by current research criteria appear to overlap considerably with regard to the feature of Hc atrophy. While contamination with AD is a likely cause, other mechanisms of Hc atrophy in SVaD also deserve consideration. The findings have implications for the design of future clinical trials of SVaD.

Individualized quantification of brain ß-amyloid burden: results of a proof of mechanism phase 0 florbetaben PET trial in patients with Alzheimer's disease and healthy controls.

PURPOSE: Complementing clinical findings with those generated by biomarkers--such as ß-amyloid-targeted positron emission tomography (PET) imaging--has been proposed as a means of increasing overall accuracy in the diagnosis of Alzheimer's disease (AD). Florbetaben ([(18)F]BAY 94-9172) is a novel ß-amyloid PET tracer currently in global clinical development. We present the results of a proof of mechanism study in which the diagnostic efficacy, pharmacokinetics, safety and tolerability of florbetaben were assessed. The value of various quantitative parameters derived from the PET scans as potential surrogate markers of cognitive decline was also investigated. METHODS: Ten patients with mild-moderate probable AD (DSM-IV and NINCDS-ADRDA criteria) and ten age-matched (≥ 55 years) healthy controls (HCs) were administered a single dose of 300 MBq florbetaben, which contained a tracer mass dose of < 5 µg. The 70-90 min post-injection brain PET data were visually analysed by three blinded experts. Quantitative assessment was also performed via MRI-based, anatomical sampling of predefined volumes of interest (VOI) and subsequent calculation of standardized uptake value (SUV) ratios (SUVRs, cerebellar cortex as reference region). Furthermore, single-case, voxelwise analysis was used to calculate individual "whole brain ß-amyloid load". RESULTS: Visual analysis of the PET data revealed nine of the ten AD, but only one of the ten HC brains to be ß-amyloid positive (p = 0.001), with high inter-reader agreement (weighted kappa ≥ 0.88). When compared to HCs, the neocortical SUVRs were significantly higher in the ADs (with descending order of effect size) in frontal cortex, lateral temporal cortex, occipital cortex, anterior and posterior cingulate cortices, and parietal cortex (p = 0.003-0.010). Voxel-based group comparison confirmed these differences. Amongst the PET-derived parameters, the Statistical Parametric Mapping-based whole brain ß-amyloid load yielded the closest correlation with the Mini-Mental State Examination scores (r = -0.736, p < 0.001), following a nonlinear regression curve. No serious adverse events or other safety concerns were seen. CONCLUSION: These results indicate florbetaben to be a safe and efficacious ß-amyloid-targeted tracer with favourable brain kinetics. Subjects with AD could be easily differentiated from HCs by both visual and quantitative assessment of the PET data. The operator-independent, voxel-based analysis yielded whole brain ß-amyloid load which appeared valuable as a surrogate marker of disease severity.

Decreased cerebral α4ß2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer's disease assessed with positron emission tomography.

PURPOSE: Postmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer's disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the α4ß2* nicotinic acetylcholine receptor (α4ß2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD. METHODS: Nine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(18)F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BP(ND)) of 2-[(18)F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis. RESULTS: Both patients with AD and MCI showed a significant reduction in 2-[(18)F]FA-85380 BP(ND) in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[(18)F]FA-85380 BP(ND) correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n = 5) had a reduction in 2-[(18)F]FA-85380 BP(ND). CONCLUSION: 2-[(18)F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in α4ß2* nAChRs which seems to be an early event in AD. In addition, 2-[(18)F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.

Acetylcholine receptors in dementia and mild cognitive impairment.

PURPOSE: To clarify whether changes in the cholinergic transmission occur early in the course of Alzheimer's disease (AD), we carried out positron emission tomography (PET) with the radioligand 2-[(18)F]F-A-85380, which is supposed to be specific for alpha4beta2 nicotinic acetylcholine receptors (nAChRs). METHOD: We included patients with moderate to severe AD and patients with amnestic mild cognitive impairment (MCI), presumed to present preclinical AD. RESULTS: Both patients with AD and MCI showed significant reductions in alpha4beta2 nAChRs in brain regions typically affected by AD pathology. These findings indicate that a reduction in alpha4beta2 nAChRs occurs during early symptomatic stages of AD. The alpha4beta2 nAChR availability in these regions correlated with the severity of cognitive impairment, indicating a stage sensitivity of the alpha4beta2 nAChR status. CONCLUSION: Together, our results provide evidence for the potential of 2-[(18)]F-A-85380 nAChR PET in the diagnosis of patients at risk for AD. Because of the extraordinary long acquisition time with 2-[(18)F]F-A-85380, we developed the new alpha4beta2 nAChR-specific radioligands (+)- and (-)-[(18)F]norchloro-fluoro-homoepibatidine (NCFHEB) and evaluated them preclinically. (-)-[(18)F]NCFHEB shows twofold higher brain uptake and significantly shorter acquisition times. Therefore, (-)-[(18)F]NCFHEB should be a suitable radioligand for larger clinical investigations.

Does the hippocampal atrophy correlate with the cortical theta power in elderly subjects with a range of cognitive impairment?

A previous study with a small sample (N = 39) showed a significant correlation between the cortical theta activity and the hippocampal volume in different stages of cognitive impairment in aged subjects. The recent study was aimed to replicate these results in a much bigger sample. The authors examined a sample of 121 right-handed subjects. The sample consisted of 37 healthy controls, 40 patients with questionable dementia, and 44 patients with mild dementia assessed by Clinical Dementia Rating. All subjects underwent EEG and brain MRI. Mean spectral power was calculated, and volume of hippocampal segments was measured. EEG theta power of the left and right hemisphere correlated significantly with the hippocampal volume on the left and right side in different stages of cognitive impairment. An increase of theta power was associated with decreased hippocampal volume. No other significant correlations were found for alpha or beta band power. No correlation was found between cortical theta and global brain volume. There seems to be a direct relationship between neuronal loss of the hippocampus and changed cortical theta activity for different stages of cognitive impairment in aged subjects.

Morphometry of the amygdala in patients with questionable dementia and mild dementia.

The volume of the amygdala is reduced in advanced Alzheimer's disease (AD). However, there is controversy whether amygdala atrophy is present in mild AD and in the transitional phase between health and the onset of dementia. The aim of this prospective longitudinal study was to investigate whether amygdala atrophy is present in subjects with questionable dementia and mild dementia and whether amygdala volume is associated with the future rate of cognitive change, that is the annual change in the Mini Mental State Examination (MMSE). At baseline, volumes of the amygdala were measured in 97 participants aged 70-87 years (40 controls, 33 patients with questionable dementia, 24 patients with mild AD) using magnetic resonance imaging. Eighty-six participants were clinically re-examined after 2.3 years on average. At baseline, significant differences in mean amygdala volume were found between controls and participants with mild AD. There was no significant correlation between the longitudinal annual change in MMSE and the baseline amygdala volume in any of the three groups.

Evidence-based evaluation of magnetic resonance imaging as a diagnostic tool in dementia workup.

BACKGROUND: The diagnostic utility of magnetic resonance imaging in dementia workups has increased recently. The basic use is to exclude space-occupying processes in the brain. However, magnetic resonance imaging offers major opportunities for studying atrophy of specific brain areas. A great interest has been put in whether atrophy in the medial temporal lobe can serve as an early diagnostic marker for Alzheimer disease. METHODS AND RESULTS: In this evaluation, we used evidence-based techniques and reviewed more than 400 articles that address this issue. Our main finding is that a variety of methods in studying brain areas were used, and this made it difficult to extract conclusive information in a systematic way. CONCLUSION: However, we were able to conclude that atrophy of the hippocampus can distinguish patients with Alzheimer disease from healthy subjects, but there was a lack of evidence because of insufficient studies concerning the usefulness of medial temporal lobe atrophy as a diagnostic marker in a more general setting.

Serum lipids and hippocampal volume: the link to Alzheimer's disease?

The association between hippocampal volume (as a presumed index of Alzheimer's disease pathology) with serum total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol was studied in 86 elderly subjects with a range of cognitive functions. High-density lipoprotein cholesterol, but not low-density lipoprotein cholesterol or total cholesterol, was associated with hippocampal volume and dementia. This is compatible with protective effects of high-density lipoprotein cholesterol on hippocampal atrophy and Alzheimer's disease.

[Vascular dementia -- diagnosis, prevention and treatment]. / Vaskuläre Demenzen -- Diagnostik, Prävention und Therapie.

OBJECTIVE: In this article, current trends in diagnosis, prevention and therapy of vascular dementias (VaD) are summarized. METHODS: Based on the conceptual background and pathophysiology of VaD, current diagnostic approaches and results from recent large-scale randomised preventative and therapeutic studies are reviewed. RESULTS: Epidemiological cohort studies and first intervention trials with anti-hypertensive drugs demonstrated the usefulness of antihypertensive drugs in the prevention of dementia. For the treatment of manifest VaD, no pharmaceutical substance has been approved to date, despite positive results in controlled studies with acetylcholinesterase inhibitors. CONCLUSIONS: Long-term control of vascular risk factors before dementia has occurred appears to be the most important strategy to reduce the incidence of VaD.

Intracranial volume in mild cognitive impairment, Alzheimer's disease and vascular dementia: evidence for brain reserve?

OBJECTIVE: The possibility of brain volume reserve effects was examined in a sample of geriatric outpatients with mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD). The total intracranial volume (ICV) served as an estimate of the maximum attained brain volume in life. METHODS: Subjects (n = 181, mean age 60.7) were consecutive referrals to a geriatric outpatients clinic (n = 96) and a group of age-matched healthy control subjects (n = 85). ICV and brain volume were attained from T1-weighted magnetic resonance images using a stereological method. Hippocampal atrophy was assessed with a visual rating scale. RESULTS: ICV was significantly smaller in patients with AD and VaD than in control subjects, but effect size was small. After adjusting for age and gender, having ICV in the smallest quartile significantly increased the risk of cognitive impairment (either MCI or dementia). In patients with dementia, but not in MCI, severity of cognitive impairment and ICV were moderately correlated. The effect of ICV on cognition was not mediated by hippocampal atrophy. CONCLUSIONS: These findings are compatible with volume reserve effects that modify the clinical expression of symptoms in both AD and VaD. They may have implications for the design of neuroimaging studies that use ICV for normalization procedures.

Structural correlates of mild cognitive impairment.

The structural correlates of mild cognitive impairment (MCI) were examined in 105 elderly subjects whose cognitive function ranged from intact to demented, including 38 subjects with MCI. Hippocampal volumes (left and right HcV), brain volume (BV), and grey matter volume (GMV) and white matter volume (WMV) were segmented from high resolution magnetic resonance data sets and normalised to intracranial volume (ICV). Hippocampal volume reductions, but not global brain, white or grey matter atrophy, were associated with MCI. White matter lesion severity did not differ over cognitive states. In multiple logistic regression models, normalised HcV and ICV (indicating premorbid brain volume) were significant predictors of MCI versus normality. Normalised BV and ICV significantly predicted dementia versus MCI. Absolute volumetric measures of HcV and BV yielded comparable classification accuracies. Hippocampal atrophy may be the crucial step for the transition from normality to MCI. Widespread brain atrophy may be the step to determine the transition from MCI to dementia. Brain volume reserve effects appear to be involved in both of these steps.

The relationship between head size and intracranial volume in elderly subjects.

OBJECTIVE: To study the relationship between parenchymal head volume (PHV) and intracranial volume (ICV), and to compare the ability of these two measurements to reflect the association between maximum mature brain volume and late-life cognition. METHODS: An elderly sample of humans with a range of cognitive functions from normality, via mild cognitive impairment (MCI) to dementia (mean age 78.6, S.D. 2.8; mean MMSE 25.4, S.D. 4.2) was examined. Head-to-head measurements of ICV and parenchymal head volume (PHV) were obtained from three-dimensional T1 weighted magnetic resonance images using automated procedures. Analyses of cognitive functions were based on continuous and categorial variables. RESULTS: PHV explained 55% of the variance in ICV. The ratio between PHV and ICV remained constant with increasing age and cognitive impairment. Measurements of PHV and ICV yielded comparable correlations with global cognitive performance. Group differences over gender and cognitive states were equally present in ICV and PHV. The relative risks of cognitive impairment that were associated with either small ICV or PHV were comparable. CONCLUSIONS: Measures of PHV can be considered as useful estimates of ICV and cerebral volume reserve.