We investigated regional brain volumes in children and adults with DS to identify the pathophysiological mechanisms related to their cognitive features. We collected imaging data from the participants with DS and the controls and correlated the MRI data of the DS group with cognitive functions evaluated using neuropsychological battery assessments. We applied different neuropsychological tasks to investigate cognitive domains, such as global cognition, memory, and language, and we correlated the results to various regional brain volumes.
Our results confirmed that DS subjects had reduced total brain, cerebrum, cerebellum, brainstem, hippocampus, frontal lobe, parietal lobe, temporal lobe, occipital lobe, and parahippocampal gyrus volumes compared to controls (see figures 3-8,11).
These findings, except for parahippocampal gyrus volume, are consistent with the results of previous neuropathological and neuroimaging studies [5, 6, 15–21]. In contrast to the findings by Kesslak, Nagata  and Raz, Torres  of larger parahippocampal gyrus volume in DS subjects compared to controls, our study showed smaller parahippocampal gyrus volume in DS than controls.
Furthermore, our results indicated reduced white matter and grey matter of the total brain, hippocampal subregions (Dentate gyrus, Ammon’s horn, and Subiculum), angular gyrus, supramarginal gyrus, fusiform gyrus, and superior temporal gyrus volumes in DS participants compared to controls. Our study did not indicate any age-related changes in brain areas in either the DS or control groups. According to our results, DS males have more significant volumes of different brain regions than females compared to controls.
The neuropsychological profile of DS patients showed deficits in different cognition and language domains in our study group. Our study results confirmed the findings of previous studies that impairments in expressive language are more remarkable than deficits in receptive language [22, 23].
Our study group showed a mean IQ of 65, which is consistent with previous studies that confirmed that most people with DS have an IQ between 30 and 70 . Our DS group showed a higher nonverbal IQ than verbal IQ compared to the Evans and Uljarević  study. This study described that children and adolescents with DS have a higher verbal IQ than nonverbal IQ (assessed with the Stanford-Binet Intelligence Scale fourth edition).
We also confirmed deficits in working memory, which is consistent with the finding by Couzens, Haynes . Although the cognitive profile of DS shows relative strength in visuospatial processing skills , our study group showed impairment in visuospatial processing compared to controls. Additionally, this deficit is remarkable when compared with other verbal and nonverbal abilities. A review by Yang, Conners  also described visuospatial working memory as a weak area in DS. Other domains, such as fluid reasoning, knowledge, and quantitative reasoning, show impairment in our study group.
Raz, Torres  found no relationship between total brain volume and cognitive variables. Nevertheless, our results showed an association between total brain volume reduction and deficits in whole IQ and working memory (see figure 9). This finding confirms previous reports that found a positive association between brain volume and intelligence in the general population [28, 29]. There is evidence for the association between the parietal lobe and visuospatial processing skills . This relationship depends on the finding of preserved parietal lobe volume associated with the relative strength in visuospatial processing by previous reports . However, our results of reduced parietal lobe volume and impaired visuospatial processing with a positive correlation contrast with these reports (see figure 9).
Additionally, we observed a correlation between the reduction in parietal lobe volume and deficits in working memory, which Menghini, Costanzo  confirmed (see figure 9). Our study could not confirm the association between reduction in the parietal lobe volume and deficits in linguistic abilities. No similar research has reported the relationship between reduced parietal lobe volume and deficits in language skills. The relationship between the decrease in parietal lobe volume and low total IQ approached significance. Nevertheless, there is evidence of the correlation between the parietal lobe and intelligence in the general population .
Our study results confirmed the association between temporal lobe volume reduction and deficits in working memory, ensuring the temporal lobe's role in memory function [17, 31–33] (see figure 9).
Our results could not confirm the involvement of the temporal lobe in language deficits. Nevertheless, in contrast to a study by Pinter, Eliez , which reported larger corrected volumes of temporal lobe volume, our results showed the reduced volume of the temporal lobe in DS participants.
This result provides neuroimaging evidence for the hypothesis of disproportionately smaller temporal lobe volumes associated with language deficits in DS. The relationship between the reduced temporal lobe volume and low total IQ approached significance. Nevertheless, there is evidence of the correlation between the temporal lobe and intelligence in the general population .
Our study confirmed the link between hippocampal volume reduction and deficits in language and working memory (see figure 9), and this has been reported widely by previous studies [16, 32, 34]. These findings reflect the role of the hippocampus as an essential biomarker for AD and one of the regions that are severely affected by the neuropathological changes of AD .
We found no significant correlation between age and hippocampal volume. This finding is consistent with previous studies by Raz, Torres  and Aylward, Li , who failed to find a correlation between age and hippocampal volume, but contrasts with the study by Kesslak, Nagata , who found a significant correlation between age and hippocampal volume. The age range of these reported studies is between 22-50 years, and our study group's age range is between 6-25 years. This comparison confirms the suggestion that the significant decrease in hippocampal volume before age 30 remains stable and then decreases later when dementia occurs in DS subjects . This decrease in hippocampal volume with increased age is related to changes in the neural pathway associated with memory and learning problems that start at infancy and continue throughout childhood .
The most exciting finding in our study is the reduced volume of the parahippocampal gyrus, which contrasts with the results of Raz, Torres , who reported enlargement of this structure that is severely affected by AD.
We suppose that the parahippocampal gyrus volume follows DS's known neuroanatomical, neurodevelopmental, and pathological pathways.
Another interesting finding related to parahippocampal gyrus volume is the association between this structural volume reduction and deficits in working memory (see figure 9). There was no association between parahippocampal gyrus volume reduction and deficits in total IQ and total language. This result contrasts with that of Raz, Torres , who found a negative correlation between parahippocampal gyrus volume and IQ in DS subjects.
Our results significantly support the suggestion of narrowness of the superior temporal gyrus , although some related studies could not confirm this [6, 18]. The superior temporal gyrus is part of the language network . It contributes to the perceptual analysis of the speech signal during auditory word processing and production and comprehension of spoken words . Our statistical finding of a negative correlation between superior temporal gyrus volume and expressive language when applying partial correlation while controlling for age and total brain volume, which approached significance, confirms superior temporal gyrus function. There was a correlation between a reduction in superior temporal gyrus volume and deficits in working memory (see figure 9). We did not find an association between reduction in superior temporal gyrus volume and scores of total IQ and total language.
We tried to include other specific brain regions related to deficits in language and memory in DS, such as the temporoparietal junction (e.g., angular and supramarginal gyri) and occipitotemporal structures (e.g., fusiform gyrus), which are parts of the language network [5, 9, 10]. We could not confirm the relationship between angular gyrus volume and language deficits. We found a correlation that approached significance between angular gyrus volume and deficits in working memory (see figure 10). This result confirms the role of the angular gyrus in verbal working memory and other complex cognitive functions . We observed a significant negative correlation when we applied a partial correlation between supramarginal gyrus volume and expressive language while controlling for age and total brain volume.
This finding means that the supramarginal gyrus plays a similar role in language processing skills as the superior temporal gyrus.
The reduced fusiform gyrus volume, also known as the occipitotemporal gyrus, is related to deficits in total IQ and working memory (see figure 10).
An interesting finding is an association between reduced fusiform gyrus volume, a parietal lobe subregion, and impairment in visuospatial processing skills (see figure 10). This finding supports our link between reduced parietal lobe volume and deficits in visuospatial processing skills.
As part of our study of the hippocampal formation, we studied three hippocampal subregions (Dentate gyrus, Ammon’s horn, and Subiculum) to understand their role in the cognitive and language skills of DS.
We observed an association between reduced dentate gyrus volume and deficits in total language skills (see figure 10). Dentate gyrus function in the production of long-term memory is evident by studying impaired neurogenesis in DS fetuses and Ts65Dn DS mouse models .
We found an association between reduced Ammon’s horn volume and deficits in total IQ (see figure 10), which confirms reports indicating this hippocampal subregion's role in cognition .
Interestingly, reduced subiculum volume is associated with deficits in total IQ, working memory, visuospatial processing, and quantitative reasoning skills (see figure 10).
We suppose that the subiculum plays a significant role in cognition and memory processing in DS compared to other hippocampal subregions.
The subiculum plays an essential role in the hippocampal circuit. Nevertheless, little is known about its function, although some reports indicate a critical but ill-defined role in spatial navigation and mnemonic processing 
This study is the first to study and assess the neuroanatomy and neuropsychology of DS in detail using high-resolution neuroimaging techniques, considering the limitations of previous related studies. Our results confirm earlier reports regarding overall patterns of brain volumes in individuals with DS and provide new evidence for abnormal volumes of specific regional and subregional brain volumes associated with language and memory domains. Our sample's small size dampens confidence in the observed pattern of neuroanatomic abnormalities. The difficulty in recruiting children and adults with DS and convincing their families to participate in the study, the cost, and the time-consuming nature of radiological and psychological examinations limit the number of subjects included. Additionally, we could not have children under five years of age, which is not due to the rarity of samples but because the skills of the children are not enough to perform the neuropsychological assessment and respond to its content. Although understanding the neuropathological nature of DS deserves to be pursued, studying the relationship between abnormal neuroanatomy and deficits in memory and language is of greater scientific and practical importance. The findings of this study indicate that the brains of subjects with DS show a well-defined pattern of abnormalities. The correlational analysis presented in the results section of this study provides excellent evidence that represents firm conclusions. Within the studied group of intellectually disabled individuals, the degree of the global reduction in brain volume predicts the general level of intellectual performance and memory function. Additionally, a decrease in the parietal lobe volume may be a significant predictor of cognitive disabilities in DS, especially those associated with visuospatial processing skills. Similarly, reduced volumes of the temporal lobe and hippocampus may significantly predict cognitive functions in DS, especially those associated with memory and language skills. The parahippocampal gyrus volume was smaller in DS subjects than in normal controls and was related to deficits in working memory function. Therefore, the phenomenon of parahippocampal gyrus enlargement, indicated twice by independent researchers [16, 18], and its specificity to DS, when compared with normal aging and AD contrasted by our study and these results, may be due to bias occurred by manual measurement of brain regions. Other neuroanatomic abnormalities could also be important markers because of their association with cognitive deficits. These markers include the superior temporal gyrus, which is related to expressive language. Additionally, regions such as the angular gyrus, supramarginal gyrus, and fusiform gyrus are interesting to understand the language network and their association with memory functions. Hippocampal subregions (Dentate gyrus, Ammon’s horn, and Subiculum) are essential to understanding the role of the hippocampal formation and its association with the memory domain. A more extensive and longitudinal study is needed to study neuroanatomical and behavioral changes with increasing age while applying interventional rehabilitation programs to observe the effects of these methods to improve cognitive skills or prevent a greater decline with time. From a practical standpoint, these data can provide educational psychologists and teachers invaluable information for developing rationally grounded interventions to understand and alleviate these individuals' learning difficulties and social problems.