Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology.

Frontotemporal dementia and parkinsonism linked to chromosome 17 have been associated with mutations in the microtubule associated protein tau (MAPT or tau) gene. This disorder is characterized by a large spectrum of neuronal and glial tau lesions in different brain regions. Pick bodies were found in a family with hereditary Pick's disease with the G272V mutation and in several families with other tau mutations in exons 9 and 11-13. The biochemical composition of Pick bodies varies between these mutations. Until recently, no detailed biochemical characterization of G272V brain material was done owing to unavailability of fresh frozen brain material. We now report a detailed study using the immunohistochemistry, western blots and electron microscopy of two brains with the G272V mutation that recently became available. Both brains showed severe neuronal loss in the temporal cortex, whereas in the frontal cortex the loss was less; and abundant Pick bodies in the dentate gyrus of the hippocampus, and caudate nucleus. The Pick bodies consisted exclusively of three-repeat (3R) isoforms, as was demonstrated by isoform-specific antibodies and supported by western blot analysis of sarkosyl-insoluble tau. These observations confirm that this family diagnosed with hereditary Pick disease meets all the criteria for this condition, including the presence of Pick bodies that are unphosphorylated at Ser262 and contain twisted filaments with long periodicity consisting only of 3R tau.

Lack of association between depression and loss of neurons in the locus coeruleus in Alzheimer disease.

BACKGROUND: Depression, one of the most frequent psychiatric disturbances in Alzheimer disease (AD), is proposed to have its neurobiological basis in neuron loss in the noradrenergic locus coeruleus, although this is not the case in idiopathic depression. METHODS: We performed image analyzer-assisted morphometry of the locus coeruleus in 6 depressed, 6 transiently depressed, and 6 nondepressed patients with AD and in 8 control subjects, emphasizing longitudinal psychiatric evaluations and matching for the clinical and neuropathological severity of dementia. RESULTS: The mean (+/-SD) number of pigmented neurons in the locus coeruleus in controls (11 607+/-946) was higher than in patients with AD, regardless of being depressed (5165+/-928; P=.001), transiently depressed (5647+/-1163; P=.003), or nondepressed (3717+/-661; P=.001). No significant difference was found in the number of pigmented neurons between patients with AD who were depressed, transiently depressed, and nondepressed. Patients who had depression at the onset of AD had a higher pigmented neuron number than other patients with AD. CONCLUSIONS: We confirmed the loss of pigmented neurons in the locus coeruleus of patients with AD; however, no supplementary loss of pigmented neurons in the locus coeruleus was found in patients with depression and AD. This finding resembles the situation in idiopathic depression, but is in contrast with earlier studies on depression in AD.

DNA damage distribution in the human brain as shown by in situ end labeling; area-specific differences in aging and Alzheimer disease in the absence of apoptotic morphology.

DNA damage has been proposed to underlie neuronal degeneration in aging and Alzheimer disease (AD). To determine the histological distribution of DNA damage, in situ end labeling (ISEL) was applied as a marker for DNA breaks on 4 differentially affected brain areas. Occipital cortex showed considerable variation between cortical layers and between patients. Temporal cortex displayed little ISEL-labeling in controls, and in AD, surprisingly. In the hippocampus, which is strongly affected in AD, many ISEL-positive nuclei and glialike cells were found in AD as compared with controls. The hypothalamic supraoptic and paraventricular nuclei showed little DNA-damage, whereas the nucleus basalis was often, but not always, labeled by ISEL. In contrast to others, no apoptotic morphology was observed, only necrotic morphology. Our results in relation to postmortem delay indicate that, area dependent, increased DNA vulnerability may occur in AD. Furthermore, the distribution of DNA damage in cortex differs from that of plaques and tangles, suggesting that these 3 phenomena are, in principle, independent. Whether the enhanced level of hippocampal DNA breaks in AD underlies, or rather is a consequence of, previous degenerative changes in this brain area remains to be established.

Selective deposition of mutant tau in the FTDP-17 brain affected by the P301L mutation.

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a familial neurological disorder exhibiting autosomal dominant inheritance. Linkage analyses have led to the identification of many exonic and intronic mutations in the tau gene in affected families. Because FTDP- 17 causes extensive neuronal loss and intracellular tau deposits in affected regions, investigation of this disease should provide an important insight into the significance of tau deposits leading to neurodegeneration. Using site-specific antibodies that distinguish between wild-type and mutant tau, we have analyzed the proportions of wild-type and mutant tau in the soluble and insoluble fractions of the P301L brain. Western blotting showed that mutant tau was selectively deposited in the Sarkosyl-insoluble fraction. Consistent with this, immunocytochemistry showed that intraneuronal tau deposits consisted exclusively of mutant tau. In one case in which abundant senile plaques occurred, in addition to mutant tau, small amounts of wild-type tau were also deposited. On the other hand, the protein levels of mutant tau in the soluble fraction were selectively decreased despite no detectable decrease in the levels of mutant tau mRNA.

Hypothalamic lesions in multiple sclerosis.

Demyelinating lesions of fiber bundles in and adjacent to the hypothalamus (i.e. the fornix. anterior commissure, internal capsule, and optic system) may be the basis for autonomic and endocrine alterations in multiple sclerosis (MS) patients. Therefore we investigated the presence and immunological activity of lesions in hypothalamic fiber bundles of 17 MS patients and 14 controls. In the MS group, 16 of 17 patients showed demyelinated lesions. The incidence of active lesions was high (60%) and outnumbered chronic inactive lesions in the internal capsule (p = 0.005). In 4 of 17 MS patients, axonal damage was observed and in 3 of 17 MS patients grey matter lesions were apparent. Duration of MS was inversely related to the active hypothalamic MS lesion score (r = -0.72, p = 0.001). Since comparison of hypothalamic lesions with MS lesions in other areas of the brain in the same patients (n = 7) showed a great similarity both as stage and appearance was concerned, this negative relation in all likelihood reflects the clinical consequences of high disease activity throughout the whole brain. In controls no demyelinating lesions were seen but in 11 control cases HLA expression was observed that was lower than that present in MS patients (p = 0.02). In the median eminence region that lacks a blood-brain barrier, all controls showed a strong HLA expression around the blood vessels. We conclude that systematic pathological investigation of the hypothalamus in MS patients reveals an unexpected high incidence of active lesions that may impact on hypothalamic functioning.

Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression.

Circadian rhythm disturbances are frequently present in Alzheimer disease (AD). In the present study, we investigated the expression of vasopressin (AVP) mRNA in the human suprachiasmatic nucleus (SCN). The in situ hybridization procedure on formalin-fixed paraffin-embedded material was improved to such a degree that we could, for the first time, visualize AVP mRNA expressing neurons in the human SCN and carry out quantitative measurements. The total amount of AVP mRNA expressed as masked silver grains in the SCN was 3 times lower in AD patients (n = 14; 2,135 +/- 597 microm2) than in age- and time-of-death-matched controls (n = 11; 6,667 +/- 1466 microm2) (p = 0.003). No significant difference was found in the amount of AVP mRNA between AD patients with depression (n = 7) and without depression (n = 7) (2,985 +/-1103 microm2 and 1,285 +/- 298 microm2, respectively; p = 0.38). In addition, the human SCN AVP mRNA expressing neurons showed a marked day-night difference in controls under 80 years of age. The amount of AVP mRNA was more than 3 times higher during the daytime (9,028 +/- 1709 microm2, n = 7) than at night (2,536 +/- 740 microm2, n = 4; p = 0.02), whereas no clear diurnal rhythm of AVP mRNA in the SCN was observed in AD patients. There was no relationship between the amount of AVP mRNA in the SCN and age at onset of dementia, duration of AD and the neuropathological changes in the cerebral cortex. These findings suggest that the neurobiological basis of the circadian rhythm disturbances that are responsible for behavioral rhythm disorders is located in the SCN. It also explains the beneficial effects of light therapy on nightly restlessness in AD patients.

Lack of evidence for dysfunction of the blood-brain barrier in Alzheimer's disease: an immunohistochemical study.

With immunohistoperoxidase techniques the presence of plasma (serum) proteins was investigated in senile plaques, congophilic angiopathy, neurons and glial cells in brains of patients with Alzheimer's dementia. Other investigators have found plasma proteins in brain parenchyma and suggested that blood-brain barrier dysfunction might be a primary factor in the pathogenesis of Alzheimer's dementia. These studies were performed on formol-fixed brains of patients with Alzheimer's dementia. In the present study we investigated both frozen and formol-fixed brain tissues. The influence of post-mortem delay, prolonged formol fixation and differences in clinical course on detection of plasma proteins by immunocytochemical techniques was also studied. Findings in cases with Alzheimer's dementia were compared with findings in nondemented controls with or without neurological disorders. Plasma proteins could not be demonstrated in the neuropil of a number of patients with Alzheimer's dementia. Moreover, plasma proteins were also found in neuronal cells and astrocytes in brains of nondemented controls. We discussed whether or not cytochemical detection of plasma proteins in the neuropil of post-mortem obtained brains is a reliable technique to investigate blood-brain barrier dysfunction. In our opinion there are, at the moment, no convincing arguments for blood-brain barrier dysfunction in Alzheimer's dementia.

Accuracy and interobserver variation in the interpretation of computed tomography in solitary brain lesions.

The clinical data and computed tomographic findings of 64 patients with solitary supratentorial brain lesions were presented to two panels of six experienced clinicians. The diagnoses predicted by these clinicians were compared with each other (interobserver variation) and with the definite diagnosis, which in almost all cases was based on histologic examination of the involved tissue (validity of predicted diagnosis). The interobserver agreement was only moderate. The predicted diagnoses agreed with the definite diagnoses in only 57% of cases. A high number of errors were made in distinguishing between high-grade and low-grade glioma and between high-grade glioma and cerebral metastasis, and in the detection of primary cerebral lymphoma. Possible implications of these findings for clinical practice are discussed.

Pregnancy-related primary brain and spinal tumors.

We reviewed the literature concerning primary brain and spinal tumors with first manifestation or acceleration of symptoms during pregnancy or within the first postpartum week and encountered four new cases in our center. The incidence of brain tumors that become symptomatic during pregnancy appears to be decreased compared with that in age-matched women. The relative frequency of the different primary brain tumor types is not changed by pregnancy. The number of meningiomas gradually tends to increase during pregnancy, with gliomas and spinal vascular tumors accumulating in the first and third trimesters, respectively. Postpartum amelioration of symptoms has especially been described for meningiomas and spinal vascular tumors. We conclude that different types of tumors are influenced at different stages of pregnancy. Although progesterone receptors predominate compared with estrogen receptors, no definite causal relationship with progesterone has been established.

Pathologic findings in a case of primary progressive aphasia.

We report the histopathologic and immunohistochemical findings of a patient who suffered from primary progressive aphasia for 13 years. During the course of his illness, he was diagnosed as having Pick's disease, based on gradually progressive mild personality changes and MRI findings of severe bilateral temporal lobe atrophy. There was severe neuronal loss in the temporal gyri, intense gliosis throughout the cortex, and mild gliosis of the temporal white matter, without any changes typical for Alzheimer's disease or Pick's disease. Using the antibody Alz-50, we found many Alz-50-positive neurons that exhibited a granular or diffuse cytoplasmic stain without fibrous structures in the temporal and parietal cortex, but no ubiquitin or beta (A4) protein-reactive cells, nor spongiform changes. Staining for Alz-50 and ubiquitin did not reveal the presence of Pick bodies or Lewy bodies. We consider this case to be an example of nonspecific cortical degeneration. Our findings stress the need for histopathologic verification of the primary progressive aphasia syndrome.

Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids.

OBJECTIVE: To provide clinical, MRI, and histopathologic findings in a rare white matter disorder with autosomal dominant inheritance, so-called hereditary diffuse leukoencephalopathy with spheroids (HDLS). BACKGROUND: Progressive leukoencephalopathies often constitute a diagnostic dilemma in both children and adults. In some cases, histopathologic examination of brain tissue is required for a classifying diagnosis. METHODS: Clinical history, MRI, and autopsy findings were reviewed in three patients with HDLS: a father, his daughter, and an unrelated patient. RESULTS: Clinical history consisted of an adult-onset neurologic deterioration with signs of frontal lobe dysfunction, epilepsy, spasticity, ataxia, and mild extrapyramidal disturbances. MRI findings included cerebral atrophy and patchy white matter changes, most pronounced in the frontal and frontoparietal area with extension through the posterior limb of the internal capsule into the pyramidal tracts of the brainstem. Autopsy in two patients revealed a leukoencephalopathy with frontoparietal and frontal preponderance and numerous neuroaxonal spheroids in the abnormal white matter. The pyramidal tracts were affected throughout the brainstem. CONCLUSION: Similar clinical and histopathologic findings have been reported in members of a Swedish pedigree. The homogeneity of the findings strongly suggests that HDLS is a distinct disease entity. In the absence of a biochemical or genetic marker, a definitive diagnosis requires histopathologic confirmation in one of the affected family members. Neuroaxonal spheroids.

Histopathologic correlates of white matter changes on MRI in Alzheimer's disease and normal aging.

We investigated the histopathologic correlates of white matter changes in Alzheimer's disease (AD) patients (n = 6) and controls (n = 9) using postmortem MRI. White matter changes were rated on a 0 to 3 scale in 51 regions. Histopathologically, we subjectively rated the loss of myelinated axons in the deep and periventricular white matter, denudation of the ventricular ependyma, gliosis, width of the perivascular spaces, and leptomeningeal congophilic angiopathy; we measured structural changes in the walls of the blood vessels in the white matter in micrometers. The AD brains displayed significantly more white matter hyperintensities on MRI than controls. Histopathologically, the denudation of the ventricular ependyma and the gliosis were significantly more severe in AD than in controls, and there was a trend toward more loss of myelinated axons in the deep white matter in the AD brains (p = 0.07). The MRI abnormalities correlated with the loss of myelinated axons in the deep white matter (r' = 0.37; p < 0.01) and with the denudation of the ventricular lining (r' = 0.54; p < 0.01). We could not find any evidence for arteriolosclerosis, but the mean thickness of the adventitia of the arteries of the deep white matter in AD almost doubled the value in control brains (p = 0.0009). We conclude that white matter abnormalities in AD patients and controls consist of loss of myelinated axons, probably caused by arterial changes and breakdown of the ventricular lining. Since imaging/histopathologic correlation was similar in AD patients and controls, these changes probably represent some form of accelerated aging.

Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis.

Postmortem unfixed whole brains from five multiple sclerosis (MS) patients were examined by MRI using a T2- and T1-weighted spin-echo (SE) sequence and histology to investigate the histopathologic characteristics of hypointense lesions on T1-weighted SE MR images. The degree of hypointensity was scored semiquantitatively by two blinded observers in reference to normal-appearing white matter. Signal intensities of the lesions and the normal-appearing white matter were measured to obtain contrast ratios. Hematoxylin-eosin stain was used to assess degree of matrix destruction (decrease of density of the neuropil) and cellularity of a lesion, Klüver-Barrera stain for degree of demyelination, Bodian stain for axonal density, and immunostaining of glial fibrillary acid protein for reactive astrocytes and fibrillary gliosis. Nineteen lesions were selected for analysis. Nearly all lesions were compatible with the chronic MS plaque: hypocellularity, absence of myelinated axons, in the presence of reactive astrocytes. Contrast ratios of the lesions were highly correlated (R = -0.90; p < 0.01), with degree of hypointensity scored semiquantitatively. Degree of hypointensity on T1-weighted SE images did not correlate with degree of demyelination or number of reactive astrocytes, but was associated with axonal density (R = -0.71; p = 0.001). A trend was found with degree of matrix destruction (R = 0.45; p = 0.052). We conclude that, in our limited sample, hypointense lesions seen on T1-weighted SE MR images are associated histopathologically with severe tissue destruction, including axonal loss. Our results need to be substantiated in a larger study on more varied patient material to evaluate the use of hypointense lesions as a surrogate marker of persistent deficit in MS patients.

Phenotypic variation in leukoencephalopathy with vanishing white matter.

OBJECTIVE: The objective of this study is to describe milder and later onset variants of a recently described leukoencephalopathy with vanishing white matter. BACKGROUND: The diagnostic criteria used currently for this disease include an early-childhood onset of neurologic deterioration. METHODS: Clinical, MRI, and spectroscopic findings of five patients were reviewed who fulfilled all inclusion criteria for the disease of vanishing white matter, apart from the age at onset. In one patient histopathologic findings were documented. RESULTS: Onset of the disease was in late childhood or adolescence in four patients, and one patient was still presymptomatic in his early twenties. The course of the disease tended to be milder than in the patients with early-childhood onset. MRI revealed a diffuse cerebral hemispheric leukoencephalopathy with evidence of white matter rarefaction. MRS of the abnormal white matter showed a serious decrease but not complete disappearance of all "normal" signals and, in some patients, the presence of extra signals from lactate and glucose. Changes in relative spectral peak heights were compatible with axonal damage or loss, but not with active demyelination or substantial gliosis. Autopsy in one patient confirmed the extensive rarefaction of the cerebral white matter. There was a commensurate loss of axons and myelin sheaths. Within the brainstem, pontine lesions were present, also involving the central tegmental tracts--a phenomenon previously described in early-onset patients. CONCLUSION: Later onset does occur in the disease of vanishing white matter, and both MRS and histopathology are compatible with a primary axonopathy rather than primary demyelination.

Familial aggregation in frontotemporal dementia.

OBJECTIVE AND BACKGROUND: Frontotemporal dementia (FTD) is a common, non-Alzheimer's dementia. Its familial occurrence has been reported, but the frequency of positive family history is unknown. METHODS: We carried out a nationwide genetic-epidemiologic study of FTD in the Dutch population of 15 million people. The family history of dementia was analyzed in 74 FTD patients and 561 age- and gender-matched control subjects. RESULTS: We found one or more first-degree relatives with dementia before age 80 in 38% (28 of 74) of FTD patients, but only in 15% (84 of 561) of control subjects. Ten percent of FTD patients had two or more first-degree relatives with dementia compared with 0.9% of the control subjects. Seven percent of FTD patients showed the ApoE4E4 genotype versus 2.3% of the control subjects. The first-degree relatives of FTD had a risk of 22% for dementia before age 80 compared with 11% in relatives of control subjects. The age of onset of dementia in affected first-degree relatives of FTD patients (60.9+/-10.6 years) was significantly lower than among affected relatives of control subjects (72.3+/-8.5 years). The first-degree relatives of FTD patients were 3.5 times (95% CI, 2.4 to 5.2) more at risk for developing dementia before age 80 than relatives of control subjects. The hazard ratio in the subgroup with unknown linkage to chromosome 17 was 2.4 (95% CI, 1.5 to 3.7). CONCLUSION: This study documents the importance of genetic factors in a proportion of FTD patients with the age at onset of dementia in first-degree relatives being 11 years earlier than in the general population.

Hypofractionated radiation therapy in patients with glioblastoma multiforme: results of treatment and impact of prognostic factors.

PURPOSE: Median survival of patients with glioblastoma multiforme (GBM) is only about 4 months with surgery and about 9 months for surgery followed by radiotherapy. Prolonged treatment is futile for many patients and the time of treatment and hospitalization should be minimized. METHODS AND MATERIALS: This was a prospective, nonrandomized study of 30 patients treated with a hypofractionated radiation scheme (42 Gy in 14 fractions). RESULTS: Median survival was 36 weeks. Age, Karnofsky performance status (KPS) and extent of surgery were strongly interrelated and all correlated with survival (p < 0.05). Three prognostic groups were identified. Patients with three favorable prognostic factors (age <50, KPS 80-100, and > or = 75% of the tumor removed) had the best prognosis (median survival 50 weeks). Patients with no favorable prognostic factors (age > or = 50, KPS < or = 70, and < 75% of the tumor removed) had the worst prognosis (median survival 25 weeks). Median survival of the intermediate group (with one or two favorable prognostic factors) was 38 weeks. No severe acute or late toxicity was observed. CONCLUSION: The treatment results are comparable to those achieved with conventional radiotherapy schemes. Based on the number of favorable prognostic factors (age < 50, KPS 80-100 and > or = 75% of tumor resected) the radiation schedule should be selected.

Increased cortisol levels in aging and Alzheimer's disease in postmortem cerebrospinal fluid.

The hypothalamo-pituitary-adrenal (HPA) axis is activated during aging and even more so in dementia. Increased levels of corticosteroids may be neurotoxic. Therefore we have investigated cortisol levels in cerebrospinal fluid (CSF) of Alzheimer patients and controls. Ventricular postmortem CSF was collected from clinically and neuropathologically well-defined Alzheimer patients (n = 26) and control subjects (n = 21). In the group of Alzheimer patients the mean CSF total cortisol level was 83% higher than that in the controls. In presenile Alzheimer patients (< 65 years of age; n = 13) the CSF-cortisol level was 5 times higher than that of presenile controls (n = 7). In contrast, senile Alzheimer patients (n = 13) and controls of over 65 years of age (n = 14) did not show a significant difference in CSF-cortisol levels. The presence or absence of a difference in the cortisol-CSF levels in, respectively, presenile or senile Alzheimer patients as compared to controls was due to the 3.5-fold rise of CSF-cortisol in control subjects over 65 years of age as compared with controls under 65 years of age. The CSF-cortisol levels in presenile and senile Alzheimer patients were similar. No significant correlation was observed in the Alzheimer patients between age of onset of the dementia and CSF cortisol levels or duration of Alzheimer's disease and CSF cortisol levels. The finding that in senile Alzheimer patients cortisol levels were similar to those of unaffected age-matched controls does not seem to support the cortisol neurotoxicity hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroepithelioma (neuroblastoma) arising in an adult. A case report.

Cytogenetic studies on neuroblastomas arising in children have revealed consistent abnormalities of the short arm of chromosome number 1. Partly because of the rare occurrence of neuroblastomas in adults, extensive cytogenetic studies in this group of patients have not been performed. We report a case of a neuroepithelioma (neuroblastoma) arising in a 50-year-old male patient. On chromosome analysis of a metastasis, a stemline with karyotype 47,XY, +der1 (1 qter---1 cen::1q21---1 qter) was identified. The possible consequences of this result and those of results previously reported in the literature are discussed.

Cellular and substrate adhesion molecules (integrins) and their ligands in cerebral amyloid plaques in Alzheimer's disease.

Integrins belonging to different subfamilies can be identified immunohistochemically in cerebral amyloid plaques. Monoclonal antibodies against the VLA family beta 1-integrins show staining of the corona of classical amyloid plaques for beta 1, alpha 3 and alpha 6. Immunostaining reveal also the presence of collagen and laminin in the corona. Activated microglial cells in classical plaques strongly express receptors belonging to the LeuCAM family (beta 2 integrins). The ligands ICAM and activated complement C3 are found in both amorphous and classical plaques. Vitronectin receptor (alpha v) is found in glial cells in classical plaques but its ligand vitronectin is seen in both amorphous and classical plaques. The data presented here demonstrate the presence of different cellular and substrate adhesive molecules (integrins) and their ligands in classical plaques. The findings suggest that amyloid plaques show signs of regeneration and tissue remodelling.

Coexistent tau and amyloid pathology in hereditary frontotemporal dementia with tau mutations.

Hereditary frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is associated with different mutations in the microtubule-associated protein (MAP) tau gene. Pathological changes consist of accumulation of hyperphosphorylated tau protein in frontal and temporal cortex, hippocampus, and some subcortical nuclei. We describe the neuropathological findings in five patients with P301L mutation, and in two affected sibs with R406W mutation. The P301L brains all showed a pretangle-type tauopathy of the frontal and temporal cortices. One of these patients, however, also showed an Alzheimer-type tauopathy with neurofibrillary tangles (NFT), neuritic plaques, and amyloid angiopathy of the temporoparietal cortex. Three tau bands (64, 68, and 72 kDa) were seen in the frontal cortex, while the temporal cortex revealed four bands (60, 64, 68, and 72 kDa), containing all six tau isoforms. The first R406W brain showed many NFT in affected regions with only a few diffuse amyloid plaques. The second R406W brain contained a much higher density of NFT in affected regions, and an extensive amyloid deposition consisting of both diffuse and neuritic plaques with dense cores. An intriguing question is whether the FTD and Alzheimer disease changes are concomitant, or whether there is an interaction between tau and amyloid pathology. An acceleration of NFT formation due to amyloid deposition has been observed in nondemented aging and preclinical AD. The question whether this mechanism occurs in FTD with tau mutations remains to be elucidated.