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Brain aging and senile dementias: focusing on Alzheimer disease Torna agli editoriali

Anna Giulia Cattaneo
DBSM, University of Insubria. Varese, Italy.

Decreased or altered memory and cognitive functions are a quite common feature in older individuals, often limited to a range that permits a good adaptation to private and social life. In this case the impaired function is commonly considered as an expression of a “physiological aging process of the brain”. The problem starts when the initial mild impairment progresses to a true dementia. The possibility to prevent this destructive event, and the timing for intervention, are unknown and represent an important matter of studies in aging.

In older individuals the more frequent cause of dementia is by far Alzheimer disease (AD, 50% of total cases), followed by vascular dementia (10-20%). Causes of dementia can occur pure, but they are often mixed each other. When the pathological conditions are at least in part reversible, a satisfactory clinical recovery and acceptable welfare can be reached by cure; in other cases the addition of two or more causes of dementia leads to even fatal consequences. This is the case, as an example, of the Alzheimer disease (AD) associated with cerebral amyloid angiopathy (CAA) . Individuals became prone to small, multifocal intracerebral haemorrhages or white matter ischemia, which can dramatically deteriorate their global cognitive and perceptional attitudes, and even be fatal in a short period.

The second most frequent cerebral degenerative disease in aged subjects is the dementia with Lewis bodies, but the vascular (not always pure) dementia is the second most prevalent lesion after Alzheimer, increasing by age after the 6th decade, and reaching 10% of all dementia after the 8th decade. No clear sex-linked differences are shown in multicentric studies.

Cognitive changes associated with aging involve a number of functions (memory, speed of mental processes, attention, language and visual or spatial functions) along a continuum from a state of minor memory changes through mild cognitive impairment (MCI) to dementia. Despite the fact that MCI cannot be considered diagnostic of an earlier stage of Alzheimer disease (in fact a significant number of cases do not progress to true dementia nor develop AD), MCI can lasts for years as the only sign of future AD. At the present, no prediction can be done about progression of MCI to AD: prediction and prevention possibilities are a field of intensive studies. The first step is a reliable way for diagnosing and staging the process.

Alzheimer: history of a disease

In 1906-7 the German physician Alois Alzheimer described a new type of progressive dementia in a 51 years aged woman. The clinical and necroscopic neurohistological features (neurofibrillary tangles and senile neuritic plaques) of the disease seemed to be not described before, and the disease became known with the eponym derived from its founder and proposed by Emil Kraepelin in 1910. The Alzheimer disease (AD), or the senile dementia of Alzheimer type (SDAT) will be subsequently recognized as the largest form of senile and pre-senile dementia.

Further knowledge about AD lasted until recently. In 1963 the ultramicroscopic structure of tangles has been demonstrated, and a basic disorder of central cholinergic innervations postulated by Davies and Maloney in 1976 and by Coyle, Price and DeLong in 1983. The National Institute of Aging further dictated criteria for research (1984) and diagnosis (1985). Amyloidal deposits, genetic findings (amyloid’s precursor gene mutation, association with familial apolipoprotein E4 late onset, presenilin 1 and 2 genes, identification of beta-secretase) and development of transgenic mouse model of AD were discovered only in the two last decades.

Diagnostic criteria

Diagnostic criteria for senile dementia have changed from early statements (Roth M J Ment Sc 1955; Slater E & Roth M 1969), when the s.c. arteriosclerotic psychosis and its manifestations have been described, up to the more recent criteria (proposed in 1984 by the NINCDS-ADRDA, the National Institute of Neurological and Communicative Disorders - Alzheimer’s Disease and Related Disorders Association). These clinical research criteria appear to be highly accurate, approaching 90% true prediction, and can be integrated by more sophisticated techniques, like neuroimaging, genomics, proteomics, histopathological findings. An accurate staging of the disease and individuation of underlying causes can improve perspectives for a better treatment and prevention.

1. Standardized techniques for neuropsychological assessment

1.1 Hachinski Score (Hachinski et al., Lancet, 1974): AD vs. multi-infarctual
1.2 McKeit criteria: dementia with Lewy’s bodies (dementia with Parkinsonism)

2. Staging system:

2.1 Braak system, based on the involvement of different brain regions. Stages I and II (transentorhinal) are presymptomatic and can last for years.
2.2 Mini-Mental State Exam
2.3 Global Clinical State

3. Descriptive findings:

3.1 Microscopic: insoluble deposits of tau-protein in neurons (tangles) and in neurites surroundings the senile plaques, focal deposits of amyloid (hydrophobic fragment of a transmembrane glycoprotein) forming the core of the plaque. In more severe cases, amyloid angiopathy is present.
3.1 Macroscopic (necropsy): diffuse, non-evenly distributed atrophy in the brain. The primary sensorimotor areas are relatively spared in comparison with other regions. Tangles and plaques are relatively few in these regions, despite the lack of knowledge between the causative relationships between histological changes and cognitive impairment.
3.3 Imaging: Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI) fairly discriminate between AD and vascular dementia; they could lead to erroneous or unclear diagnosis in AD. On the contrary, functional imaging like PET (Positron Emission Tomography) scan seems to be more useful.
3.4 While no pathognomonic EEG features can be found in AD, this simple and relatively non expensive means for diagnosis can be helpful in excluding other causes of dementia and cognitive impairment, like those due to metabolic or pharmacological agents, or to epileptic focuses.
3.5 Molecular markers are described further.

Molecular markers for AD (click on the links, please. All names are linked to the OMIM (Online Mendelian Inheritance in Man) of the Johns Hopkins University, describing the genetic loci and their products), and the 3-D structures are linked to their original site.
The molecules listed below can play a significant role in AD development, when modified by a genetic mutation or by a chemical reaction (see the free radicals)

1. Presenilin 1 (chromosome 14, locus 14q24.3)

2. Presenilin 2 (chromosome 1, locus 1q31–q42)
PS1 and PS2 are localized in nuclear structures, both in the interphase and during mitotic events membrane, and in membranes of the endoplasmic reticulum (ER) and Golgi. PS1 is primarily expressed in cortical and hippocampus neurons, the areas in the brain more vulnerable by AD. Both molecules seem to have enzymatic activity (gamma-secretase acting on APP, see below), have similar dimensions (467 and 448 Aa) and several transmembrane domains. A number of mutations of Presenilin 1 and 2 are associated to early-onset (before age 65 years) AD, and mutation at –48 position of presenilin1 gene seems to be involved both in familial and sporadic AD.

3. ApoE (epsilon 4 allele) (chromosome 19, locus 19q13.2). Apolipoprotein E is found in humans four isoforms, epsilon 4 seeming to be associated to AD. The zygosis for this allele is associated with the time of symptoms appearance (earlier in homozygotic and intermediate in heterozygotic). Its role of “pathologic chaperone” seems to be possible in the development of AD and cerebral degeneration: apoE epsilon 4 facilitates aggregation and deposition of amyloid insoluble fibrils.

4. Amyloid beta A4 Precursor Protein (APP) (chromosome 21, locus 21q21): its isoforms are responsible for the deposition of plaque core in AD and in AD associated with Down syndrome. Mutations at the cleavage site for the enzymes (alpha-, beta-, and gamma- secretase) are responsible for production of toxic molecules and cerebral aggregates, but only mutations near the beta- and gamma- cleavage site are associated with AD. The cleavage in these sites produces A 42 and A 40 proteins respectively. The first represents only 10% of catabolic product of APP, is relatively insoluble, it hardly passes through the brain barrier, and is the major component of senile plaques. The second is the major product of APP splicing, is incorporated in mature plaques and represents the most abundant component in amyloid deposits. It is soluble and able to pass through the brain barrier. Alpha cleavage prevents their excess.

5. Protein tau (chromosome 17, locus 17q21.1). The role of this microtubule-associated protein is very important not only in AD, but in a quite large number of cerebral degenerative diseases known as tauopathies. Two different single-nucleotide polymorphisms have been described in association with AD, one of which located in the same gene responsible for frontotemporal dementia with Parkinsonism. Modified tau proteins share inadequacy of their transmembrane domains, and the resulting molecules aggregates as fibrillary proteins in tangles

6. Free radicals (molecules damaged from exposure to)
Most prominent markers of this damage are lipoproteins, because of free radicals are chemically unstable and difficult to measuring. Oxidation of immunoglobulin G, and increasing levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG, a marker of oxidative damage to DNA) are recently proposed markers. In addition, the oxidative state of the tissue under examination must be taken into account.

The known 3-D structures, derived from crystallographic deposited (at the PDB) features, are reported below. The contents of PDB are in the public domain. Online and printed resources are welcome to include PDB data and images from the Structure Explorer pages, as long as they are not for sale as commercial items themselves, and their corresponding citations are included.
No figures are shown for presenilins.

1. apoE epsilon 4: Wilson, C. Weisgraber, K.H. Wardell, M.R. Mahley, R.W. Agard, D.A. Structural Basis for Altered Function in the Common Mutants of Human Apolipoprotein-E To be Published, Deposition: 1991-08-22 Release: 1992-10-15

2. APP: Hynes, T.R. Randal, M. Kennedy, L.A. Eigenbrot, C. Kossiakoff, A.A. X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid beta-protein precursor. Biochemistry v29 pp.10018-10022 , 1990

3. Protein tau: Wintjens, R. Wieruszeski, J.M. Drobecq, H. Rousselot-Pailley, P. Buee, L. Lippens, G. Landrieu, I. 1H NMR study on the binding of Pin1 Trp-Trp domain with phosphothreonine peptides. J.Biol.Chem. v276 pp.25150-25156 , 2001

Apolipoprotein Eepsilon4   APP

Protein tau (complexed with PIN1 WW domain): protein tau is orange , red and light grey

Predictive data and risk factors.

AD is by far a sporadic disease, only 10% of cases having a familial distribution type. These forms of the disease are associated to known gene mutations or to chromosomal aberrations. Presenilin 1 gene mutation is responsible for 70% of all familial cases, presenilin 2 of 20%, APP of 3%; the remaining 7% is represented by early-onset (before 65 years of age) cases: they are also associated to mutations at one of the previously cited loci, or to chromosomal aberration, like the AD associated to Down’s syndrome (chromosome 21). AD seems to warrant the longer survival after symptoms or diagnosis, in comparison with vascular and mixed dementia: the calculated life quotient (ratio between estimated and expected survival) is 0.78 vs. 0.57, respectively (no differences have been shown between pure vascular and mixed dementia).
Established risk factors have been recognized in sporadic AD, the most important being advancing age, followed by the apoE genotype (and namely the zygosis for the epsilon 4 allele, chromosome 19, locus 19q13.2) and the family history. Gender and head injury are postulated but still uncertain risk factors.
Microtubules associated protein tau, found in neurofibrillary tangles, is present not only in AD, but in a wide number of brain degenerative diseases, so called tauopathy. A gene located on chromosome 17 (locus 17q21.1) is responsible for protein tau encoding: focal mutations are responsible for the production of altered protein unable to bound to microtubules.
Detection and measurement of biomarkers in CSF (a poorly invasive procedure) have been partially evaluated in view of obtaining an early diagnosis of AD. Protein tau > 560 pg/ml associated with A beta 42 < 1125 pg/ml identify AD patients with greater than 85% specificity; protein tau < 560 pg/ml associated with A beta 42 > 1125 pg/ml identify normal control with greater than 85% specificity. (Galasko D, Clark C, Chang L, et al. ,1997, Neurology , 632-635).


True prevention and cure for pure AD, (or mixed vascular) are highly expected finding from research in the field of cerebral aging, and a variety of hypothesis have been done, on the basis of epidemiology studies and supposed pathogenesis.
The first and most prominent way to obtain a remission in demented subjects remains a correct diagnosis and treatment of associated and treatable causes of dementia (like depression, Parkinson, metabolic and pharmacological conditions).
Another approach concern detecting possible markers of early damage before the progression into a clear demented status, in search of future efficacious preventive measures and treatment. A number of similar markers have been proposed, and namely: environmental pollutants (Al and Si in drinking water, heavy metals and redox metals, iron included, between others), free radicals toxicity and low antioxidant status measured in serum, malnutrition and lifestyle. Their removal, or the supplement with antagonists, has been claimed to be useful in therapy.
A number of pharmacological treatments have been proposed, summarized below:
1. Dietary supplementation with antioxidant agents (carotenoids, omega-3 fatty acids, alfa-lipoic acid, coenzyme Q10, non-steroidal antinflammatory drugs, selenium and vitamins: C, A., E). This approach appears to be well tolerated and counter-effects free, while not evenly effective. Association with ACE-inhibitors, hormone replacement (both in men and in women, as appropriate) has been proposed as helping.
2. Modulation with cholinergic agents is a causative treatment.
3. The administration of symptomatic therapy (antipsychotic, antidepressant, sedative drugs) does not seem to be useful in contrasting progression of cognitive impairment when no concomitant pathologies are present
4. Metal chelators gave contrasting results, and it has been claimed that their efficacy is conditioned by ability to act even on Fe
5. Therapy with statins is costly and gives contrasting results
6. Immunotherapy against APP splicing products has been recently stopped in a clinical controlled trial because of the development of immunoencephalitis in 6% of subjects.
7. The helpful role of growth and nerve growth factors administration, and even of somatostatin and glucagons, has been proposed

Unfortunately, we do not have well tolerated, approved and standardized measures that have been proved effective in AD’s treatment and prevention, and an excess of cost often charges clinical trials. However, good clinical practice should not forget the emerging data, especially when great tolerance and minimal side effects are associated with a possible amelioration.

Future perspectives

Structural studies on secretases, especially beta- (BACE 1 and 2) open a promising, new perspective for the future treatment of brain degenerative changes by means of specific inhibitors at their functional site.
Mitochondrion is a district of the eucariote cell maximally exposed to the oxidative risk. It is a major site responsible for apoptosis, and hosts a number of active oxidative processes. On the contrary, its DNA is poorly protected from the damage due to free radicals and hydroperoxide production by histone proteins, and age-related deletions have been recognized in the brain and in muscles.
Another promising approach is represented by the development of animal models, in which alterations present in AD and other conditions of brain degeneration can be studied isolated from the complex and often confounding structure present in humans being. From their simplicity, a new integrated and more clear understanding of the entire phenomenon in humans can be expected.

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