**2. Brain biomarkers and cognitive function in normal aging**

lived people are the French, at 80.6 years, the Swedes, at 80.6 years, the Italians, at 79.9 years, the Greeks, at 79.3 years, the Dutch, at 79.1 years, and the Germans, at 78.9 years. It is predicted that in Europe from 2005 to 2050, the number of people following into their 80th year of life

In psychological studies on the elderly, three subperiods were stratified among people over 60 years old; these included *young olds* (65–75 years of age), *old olds* (75–85 years old), and *eldest olds* (over 85 years of age). Deterioration of cognitive functions was visible in the *eldest olds* age group, while asymptomatic structural changes in the brain, such as cortical atrophy, poli- and leukoaraiosis (deterioration of white matter, present in 8–90% of the elderly with no signs of dementia), or decreased glucose metabolism and deteriorated subcortical and cortical flow,

Progressive aging of the population is one of the factors determining the increasingly frequent occurrence of cognitive impairment and dementia syndromes. Dementia, due to its prevalence in the population (it occurs in approximately 10% of those 65 years of age and in approximately 30–40% of those 90 years of age), requires great concern and clinical care. It is estimated that by 2040, the number of elderly people with dementia in the world will exceed 80 million [3].

According to the classification of mental disorders in the American Psychiatric Association's DSM – IV (Diagnostic and Statistical Manual of Mental Disorders) [4], there is no isolated, separate diagnostic category for "dementia," but the criteria for this diagnosis are contained in the various types of dementia, for example, Alzheimer's disease (AD), vascular dementia (VD), or in other diseases. According to these criteria, a diagnosis of dementia is necessary to determine the presence of multiple cognitive deficits that cause significant disturbances in the

*Dementia* is a progressive impairment of the functional status and significantly reduces the quality of life of older people in all its dimensions, since physical disability and the loss of sphincter control coexist along with dementia. The most common cause of dementia in the oldest patients is the degenerative process that is underway in the brain in the course of AD. In old age, an important process associated with the degeneration of neurons in AD is cerebral arteriosclerosis. Dementia, with dying neurons, is caused by both pathologies. A high per‐ centage of the causes of dementia in the elderly may develop depression. In these patients, the following is observed especially often: loss of interest, sleep disturbances, psychomotor disturbances, and problems with concentration. In turn, the use of multiple drugs in dementia

*Depression* is defined as an emotional distress syndrome (states of depressed mood, depres‐ sion), which is often co-morbid with somatic diseases and/or with intensifying their symptoms. Depression is a common and serious problem among the elderly and increases mortality. Approximately 15% of people over the age of 65 have symptoms of depression, which impede

It is believed that the functional and cognition changes observed in older persons are associated with disturbances at the molecular level in the aging body. Molecular changes in the aging

functioning of social exclusion and mental illness (depression) and delirium.

complicates the diagnosis of depression [4].

daily functioning [2, 4].

could be detected by neuroimaging even among the *young olds* [2].

will increase by 43 million [1].

252 Update on Dementia

Central changes leading to impaired brain and cognition functions have been reported in normal brain aging, but data are inconclusive [5, 6]. A study [5] using functional magnetic resonance imaging (MRI) with gadolinium contrast confirmed changes in the hippocampus associated with impairment of cognitive function in elderly people. Also, a study conducted on 564 cognitively normal individuals (average age was 78 years) using MRI and fluorodeox‐ yglucose positron emission tomography (FDG-PET) and Pittsburgh Compound B (PiB) PET indicated impairment of cognition and imaging biomarkers. The causes of these central changes in the brain of the aged subjects seem to have been increased β-amyloid (Aβ) levels [6]. In the senescent brain, accumulation of Aβ deposits is eminent, in the form of senile plaques as well as fibrillary tangles in the neurons. The lesions may develop in the human brain as late as in one's 80s (frequently with no signs of dementia). The slower the accumulation of lesions is, the longer the time period required to develop dementia [7, 8]. Cerebral amyloidosis has been associated not only with Aβ deposition but also with higher pulse pressure in the presence of neurodegeneration, which may lead to more rapid progression of dementia [9]. However, more recent data indicate that Aβ deposition may in time exceed brain structural changes, such as grey matter volume, as measured by MRI, and neuronal hypometabolism assessed using PET with 18F-fluorodeoxyglucose (FDG) [10]. Moreover, the cognitive decline in elderly patients is associated with brain infarcts [11]. Also dietary factors, such as ω-3 polyunsaturated fatty acids (PUFAs), were shown to be associated with normal brain function; the PUFA concentration remains in reverse correlation with brain atrophy in cognitively normal elders [10].

### **3. Molecular changes in normal aging and dementia**

In the aging process, the epigenetic changes lead to expression alteration of genes associated with vital functions of cells, such as mitochondrial function, as well as protective and repair mechanisms, as shown in **Table 1**.

One of genetic hallmarks of aging is genomic instability which includes accumulation of genetic damage both in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). mtDNA is more susceptible to DNA damaging factors than nDNA due to its oxidative environment. Also DNA repair mechanisms are less efficient in mitochondria than in nucleus [23], although mitochondria have most of the DNA repair pathways existing in the nucleus [24]. The mitochondrial reactive oxygen species (ROS) theory of aging (mitochondrial free radical theory of aging [MFRTA]) proposed by Harman assumes that free radicals generated in normal metabolism cause mtDNA mutations and ageing is a result of oxidative damage accumulation. According to MFRTA, maximum life span can be decreased by mtDNA damage caused by oxidative stress [25]. Mitochondrial reactive oxygen species (mtROS) may play signaling role in mitochondrial stress during ageing [26]. It is also suggested that mtDNA mutation accu‐ mulation and mitochondrial dysfunction during aging are a result of decreased activity of autophagy and mitophagy [27]. Moreover, a study performed on 18 three-generation families of women shows decline in mtDNA copy number, mitochondrial protein expression, and oxidative function with age [28]. Oxidative DNA damage and mitochondrial dysfunction lead to neuronal loss and may play a role in the development of dementia. The decreased level of antioxidants was observed among dementia individuals [29, 30]. It was suggested that high levels of ROS and decline in neuronal DNA damage response may be associated with neuronal dysfunction and cognitive impairment characterized by lower Mini-Mental State Examination (MMSE) score [31]. Additionally, it is known that oxidative damage leads to frontal-executive dysfunction [32].


**Table 1.** The role of genes and their encoded products in aging.

Another mechanism involved in aging is epigenetic alterations. Epigenetics is defined as molecular traits that are "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence." The epigenetic pathways include DNA methyla‐ tion, histone modifications, and noncoding RNA [33].

more susceptible to DNA damaging factors than nDNA due to its oxidative environment. Also DNA repair mechanisms are less efficient in mitochondria than in nucleus [23], although mitochondria have most of the DNA repair pathways existing in the nucleus [24]. The mitochondrial reactive oxygen species (ROS) theory of aging (mitochondrial free radical theory of aging [MFRTA]) proposed by Harman assumes that free radicals generated in normal metabolism cause mtDNA mutations and ageing is a result of oxidative damage accumulation. According to MFRTA, maximum life span can be decreased by mtDNA damage caused by oxidative stress [25]. Mitochondrial reactive oxygen species (mtROS) may play signaling role in mitochondrial stress during ageing [26]. It is also suggested that mtDNA mutation accu‐ mulation and mitochondrial dysfunction during aging are a result of decreased activity of autophagy and mitophagy [27]. Moreover, a study performed on 18 three-generation families of women shows decline in mtDNA copy number, mitochondrial protein expression, and oxidative function with age [28]. Oxidative DNA damage and mitochondrial dysfunction lead to neuronal loss and may play a role in the development of dementia. The decreased level of antioxidants was observed among dementia individuals [29, 30]. It was suggested that high levels of ROS and decline in neuronal DNA damage response may be associated with neuronal dysfunction and cognitive impairment characterized by lower Mini-Mental State Examination (MMSE) score [31]. Additionally, it is known that oxidative damage leads to frontal-executive

**Gene/encoded product Locus Role in aging References**

regulation of glucose metabolism, apoptosis,

with impaired oxidative stress response and changes in glucose metabolism. Indirectly may be involved in age-related diseases, for example, retinal degeneration, hypertension, and cardiovascular

cell proliferation and cell migration, and PI3K/AKT/mTOR pathway.

results in healthier aging, slower memory decline, less frequency of

Protection from oxidative stress and reduction of age-related diseases.

and is a risk factor for cardiovascular diseases due to LDL oxidation.

6p21.2 Possible promoter of aging due to pro-aging activity of p53.Oxidative stress increases expression of CDKN1A and overexpression of p21 may be involved in age-related diseases such as atherosclerosis,

16q21 Responsible for cholesterol homeostasis in central nervous system.

6q21 Involved in insulin metabolism and insulin/IGF1 signaling pathway.

7q21.3 Decreased level of PON1 with age impairs oxidative stress response

12q23.2 Decreased level of IGF-1 with age leads to cell senescence. [20]

[12]

[13]

[14] [15]

[16] [17]

[18] [19]

[21] [22]

10q21.3 Age-related decreased level of SIRT1 is associated

14q32.32 Decreased level of AKT1 with age alters

amyloidosis, AD, and arthritis.

dementia, and lower AD risk.

Decreased level of CETP

diseases.

**Table 1.** The role of genes and their encoded products in aging.

dysfunction [32].

254 Update on Dementia

*SIRT1* sirtulin 1

*AKT1*

*CDKN1A*

*CETP*

protein

*FOXO3A*

FOXO3A

*IGF-1*

factor 1

*PON1* Paraoxonase 1

protein Kinase B

Cyclin-dependent kinase inhibitor 1 (p21)

Cholesterol ester transfer

Transcriptional factor

Insulin-like growth

The analyses of CpGs methylation changes show that genome-wide global levels of DNA methylation decrease during aging. Despite this, many promoters of genes which are unme‐ thylated in young gain methylation in old individuals [34, 35]. Other authors [36] suggest that DNA methylation changes may result in age-associated immune deficiency. It is possible that hypermethylation is caused by programmed changes, while hypomethylation may be the result of environmental and stochastic processes. Multiple studies have identified genes undergoing hyper- and hypomethylation with age. The first group includes genes involved in process such as cell adhesion, cell-cell signaling, ion transport, neuron differentiation, and other genes associated with development. The hypermethylated genes are regulated by a common group of transcription factors, whereas hypomethylated genes are involved in metabolic process, RNA splicing, regulation of ligase activity and protein ubiquitination, transmission of nerve impulse, and many others. The hypomethylation in neurons may cause age-related memory deficits [36, 37]. The abnormal profile of methylation may contribute to dementia. It is shown that mutation in DNA methyltransferase 1 (*DNMT1*), gene encoding an enzyme crucial for methylation, leads to a condition called hereditary sensory and autonomic neuropathy (HSAN1) with early onset of dementia and hearing loss [38]. Other authors suggest [39] that changes in methylation may be involved in age-related cognitive functions decline.

Histone modification includes acetylation, methylation, phosphorylation, citrullination, ubiquitination, SUMOylation, adenosine diphosphate (ADP) ribosylation, deimination, and proline isomerization, in which the first three are the most-studied topics. Modifications can change the chromatin structure by histone-histone or histone-DNA interactions. The chroma‐ tin packaging affects many processes such as transcription, repair, replication, and chromo‐ some condensation. Acetylation is associated with activation of transcription, while the result of lysine methylation can be either activation or repression [40]. Chromatin packaging changes during aging [41]. It is shown that higher level of histone acetylation facilitates memory and learning processes; therefore, acetylation decrement may lead to cognitive impairments and is associated with aging [42]. Also histone methylation may affect the life span; loss of H3K9 trimethylation which results in reduction of heterochromatin is the hallmark of aging [43]. The acetylation of H4K16 is necessary for maintaining the structure of chromatin and when impaired, the process of double-strand break repair is less efficient [44]. Subsequently, histone tail proteolytic cleavage, especially H3, may be involved in aging, but the exact mechanism remains unclear [45]. Additionally, the decline in histone chaperon levels is observed during aging and may be the answer for defective DNA repair mechanisms [46].

Both age-related changes in DNA methylation and histone modification alter the experiencedependent synaptic plasticity in hippocampus by changing the chromatin structure. Thus, it may be involved in memory loss and learning difficulties. Epigenetic changes may be possible brain biomarkers of cognitive aging [47].
